SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics

This manuscript (permalink) was automatically generated from greenelab/covid19-review@fce6c96 on October 26, 2020.



Since late 2019, Coronavirus disease 2019 (COVID-19) has spread around the world, resulting in the declaration of a pandemic by the World Health Organization (WHO). This infectious disease is caused by the newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Research on the SARS-CoV-2 virus and the disease it causes is emerging rapidly through global scientific efforts. Short-term mitigation of viral impacts will require public health interventions, and long-term mitigation will require new diagnostic and therapeutic technologies. The urgency of the pandemic has led to a rapidly emerging scientific literature on SARS-CoV-2 and COVID-19. This manuscript represents a collaborative effort to organize and consolidate this body of literature. We present information about the virus in the context of what is known about related viruses, describe the pathogenesis of COVID-19, and synthesize studies emerging about the diagnosis and treatment of COVID-19 alongside literature about related illnesses. We summarize this emerging literature with an eye towards discussing elements of the disease that will be fundamental to efforts to develop interventions. Our review is a collaboratively-authored, evolving document into which we seek to incorporate the ever-expanding body of information on the topic. This document provides a snapshot as of October, 2020. We continue to accept new contributions and anticipate future snapshots until technologies to mitigate the pandemic are widely deployed.

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1 Introduction

On January 21, 2020, the World Health Organization (WHO) released its first report concerning what is now known as the Coronavirus Disease 2019 (COVID-19) [1]. This infectious disease came to international attention on December 31, 2019 following an announcement by national officials in China describing 44 cases of a respiratory infection of unknown cause. The first known cases were located in Wuhan City within the Hubei province of China, but the disease spread rapidly throughout China and subsequently around the world. At the time of the WHO’s first situation report [1], 282 confirmed cases had been identified. Most of these cases were in China, but one to two exported cases had also been identified in each of several neighboring countries (Thailand, Japan, and the Republic of Korea). One week later, 4,593 confirmed cases had been identified, spanning not only Asia, but also Australia, North America, and Europe [2]. On March 11, 2020, the WHO formally classified the situation as a pandemic [3]. On April 4, 2020, the WHO reported that the global number of confirmed cases had surpassed one million [4].

Global COVID-19 deaths since January 22, 2020. 1,149,780 COVID-19 deaths had been reported worldwide as of October 24, 2020 (Figure 1).

Figure 1: Cumulative global COVID-19 deaths since January 22, 2020. Data are from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [5].

As international attention remains focused on the ongoing public health crisis, the scientific community has responded by mobilizing resources and turning much of its attention to the virus and disease. This rapid influx of information is disseminated by traditional publishing mechanisms, preprint servers, and press releases, which provide a venue for scientists to release findings without undergoing the formal publication process. While having information available is valuable to efforts to understand and combat COVID-19, many contributions come from researchers across a wide range of fields who have varying degrees of experience working on coronaviruses and related topics. The volume of information available, much of which has not gone through rigorous peer review, presents a significant challenge to individual efforts to keep abreast of the state of COVID-19 research [6]. However, research on these topics is proceeding so rapidly that any static review is likely to quickly become dated. Our goal as a community is to consolidate information about the virus in the context of related viruses and to synthesize rapidly emerging literature centered on the diagnosis and treatment of COVID-19. We used an open publishing framework, Manubot [7], to manage hundreds of contributions from the community to create a living, scholarly document. We designed software to generate figures, such as Figure 1, that automatically update using external data sources. Our primary goal is to sort and distill informative content out of the overwhelming flood of information [6] and help the broader scientific community become more conversant on this critical subject. Thus, our approach has been to develop a real-time, collaborative effort that welcomes submissions from scientists worldwide into this ongoing effort. This document represents the first snapshot, which aims to reflect the state of the field as of October, 2020. We plan to refine and expand this document until technologies to mitigate the pandemic are widely available.

1.1 Interdisciplinary Context

Collaboration across several broad areas of research is critical, as different areas provide different information and context necessary to understanding the virus and disease. This review provides a biological perspective on the SARS-CoV-2 virus and efforts to develop diagnostic, prophylactic, and therapeutic responses to COVID-19. We provide only brief summaries of two other important perspectives on this pandemic: epidemiology and public health. Research in these areas often seeks to anticipate, model, and prevent outbreaks of infectious disease or to understand and manage human behavior relevant to health and disease. Their insights are critical to mounting a global response to the pandemic. Epidemiological analyses have investigated patterns of transmission within and between communities, the symptoms associated with and the duration of infection and/or contagiousness, and how the virus propagates, among other characteristics [8]. Epidemiology also has a close relationship to public policy because it provides model-based insights into how preventative measures and public response can shift outcomes [9]. Public health addresses social and human factors influencing individuals’ exposure and susceptibility to pathogens, such as resource availability, inequality, human behavior, and access to accurate information. Strategies from public health and epidemiology for managing the current epidemic have included the promotion of hand hygiene, social distancing, and personal protective equipment such as masks to mitigate spread, as well as containment approaches such as test, trace, and isolate, which depends on widespread testing, contact tracing, and quarantining. An effective public health management strategy involves response coordination, disease surveillance, intervention monitoring, risk communication, and health education (including the containment of “infodemics” of false information) [10]. Epidemiology and public health intersect with the topics addressed in this manuscript because they both inform and benefit from relevant biotechnological developments. For example, the development of accurate and fast diagnostic testing is relevant to test, trace, and isolate strategies for containment, and public education will be critical to deploying vaccines once they become available.. The present analysis focuses less on human and social factors and more on the basic biology of infection, diagnosis, and recovery, but these areas are inextricable in understanding and responding to the COVID-19 pandemic.

1.2 Initial Characterization of SARS-CoV-2

The first genome sequence of the virus was released on January 3, 2020 and revealed that the cluster of pneumonia cases seen in Wuhan were caused by a novel coronavirus [11]. Multiple research groups have drafted the genome sequence of SARS-CoV-2 based on sequences developed from clinical samples collected from the lower respiratory tract, namely bronchoalveolar lavage fluid (BALF), and the upper respiratory tract, in the form of throat swabs [12,13,14]. Analysis of the SARS-CoV-2 genome revealed significant sequence homology with two coronaviruses known to infect humans, with about 79% identity to SARS-CoV and 50% to MERS-CoV [14]. However, the highest degree of similarity was observed between SARS-CoV-2 and bat-derived SARS-like coronaviruses (bat-SL-CoVZC45 and bat-SL-CoVZXC21) [13,14], with identity between SARS-CoV-2 and RATG13 as high as 96.2% [13,15]. This evidence therefore suggests the SARS-CoV-2 virus is the result of zoonotic transfer of a virus from bats to humans. Nevertheless, some fragments between SARS-CoV-2 and RATG13 differ by up to 17%, suggesting a complex natural selection process during zoonotic transfer. While the S region is highly similar to that of viruses found in pangolins [16], there is no consensus about the origin of S in SARS-CoV-2, as it could potentially be the result either of recombination or coevolution [15,17]. Though the intermediate host serving as the source for the zoonotic introduction of SARS-CoV-2 to human populations has not yet been identified, the SARS-CoV-2 virus has been placed within the coronavirus phylogeny through comparative genomic analyses. Genomic analyses and comparisons to other known coronaviruses suggest that SARS-CoV-2 is unlikely to have originated in a laboratory – either purposely engineered and released, or escaped – and instead evolved naturally in an animal host [18]. While the position of the SARS-CoV-2 virus within the coronavirus phylogeny has been largely resolved, the functional consequences of molecular variation between this virus and other viruses, such as its bat and pangolin sister taxa or SARS-CoV, remain unknown [18]. Fortunately, the basic genome structure of coronaviruses is highly conserved, and insight into the mechanisms the virus uses to enter cells, replicate, and spread is likely to be available from prior research in coronaviruses.

1.3 Coronaviruses and Humans Hosts

Coronaviruses have long been known to infect animals and have been the subject of veterinary medical investigations and vaccine development efforts due to their effect on the health of companion and agricultural animals [19]. Most coronaviruses show little to no transmission in humans. However, today it is thought that approximately one-third of common cold infections are caused by four HCoV (HCoV-229E, HCoV-NL63, HCoV-OC43 and HCoV-HKU1) [20,21]. The first coronavirus species infecting humans (human coronavirus or HCoV) were identified in the 1960s: HCoV-229E in 1965 [22] and HCoV-OC43 in 1967 [23]. Both of these viruses cause cold-like symptoms [24,25]. Two additional HCoV were subsequently identified [26,27]. In 2003, HCoV-NL63 [26] was first identified in a 7-month-old infant and then in clinical specimens collected from seven additional patients, five of whom were infants younger than 1 year old and the remainder of whom were adults. CoV-HKU1 was identified in samples collected from a 71-year-old pneumonia patient in 2004 and then found in samples collected from a second adult patient [27]. These viruses are associated with respiratory diseases of varying severity, ranging from common cold to severe pneumonia, with severe symptoms mostly observed in immunocompromised individuals [28]. In addition to these relatively mild HCoV, however, highly pathogenic human coronaviruses have been identified, including the severe acute respiratory syndrome coronavirus 1 (SARS-CoV or SARS-CoV-1) and the Middle East respiratory syndrome coronavirus (MERS-CoV) [20,29,30].

At the time that SARS-CoV emerged in the early 2000s, no HCoV had been identified in almost 40 years [29]. The first case of SARS was reported in November 2002 in the Guangdong Province of China, and over the following month, the disease spread more widely within China and then into several countries across multiple continents [29,31]. Unlike previously identified HCoV, SARS was much more severe, with an estimated death rate of 9.5% [31]. It was also highly contagious via droplet transmission, with a basic reproduction number (R0) of 4 (i.e., each person infected was estimated to infect four other people) [31]. However, the identity of the virus behind the infection remained unknown until April of 2003, when the SARS-CoV virus was identified through a worldwide scientific effort spearheaded by the WHO [29]. SARS-CoV belonged to a distinct lineage from the two other HCoV known at the time [31]. By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices [29]. A decade later, a second outbreak of severe respiratory illness associated with a coronavirus emerged, this time in the Arabian Peninsula. This disease, known as Middle East respiratory syndrome (MERS), was linked to another novel coronavirus, MERS-CoV. The fatality rate associated with MERS is much higher than that of SARS, at almost 35%, but the disease is much less easily transmitted, with an R0 of 1 [31]. Although MERS is still circulating, its low reproduction number has allowed for its spread to be contained [31]. The COVID-19 pandemic is thus associated with the seventh HCoV to be identified and the fifth since the turn of the millennium, though additional HCoVs may be in circulation but remain undetected.

SARS-CoV and MERS-CoV were ultimately managed largely through infection management practices (e.g., mask wearing) and properties of the virus itself (i.e., low rate of transmission), respectively [29,31]. Vaccines were not used to control either virus, although vaccine development programs were established for SARS-CoV [32]. In general, care for SARS and MERS patients focuses on supportive care and symptom management [31]. Clinical treatments for SARS and MERS developed during the outbreaks generally do not have strong evidence supporting their use. Common treatments included Ribavirin, an antiviral, often in combination with corticosteroids or sometimes interferon (IFN) medications, which would both be expected to have immunomodulatory effects [29]. However, retrospective and in vitro analyses have reported inconclusive results of these treatments on SARS and the SARS-CoV virus, respectively [29]. IFNs and Ribavirin have shown promise in in vitro analyses of MERS, but their clinical effectiveness remains unknown [29]. Therefore, only limited strategy for the pharmaceutical management of COVID-19 can be adopted from previous severe HCoV infections. Research in response to prior outbreaks of HCoV-borne infections, such as SARS and MERS, have, however, provided a strong foundation for hypotheses about the pathogenesis of SARS-CoV-2 as well as potential diagnostic and therapeutic approaches.

1.3.1 Human Immune Response to Viral Threats

Understanding the fundamental organization of the human immune response to viral threats is critical to understanding the varied response to SARS-CoV-2. The human immune system utilizes a variety of innate and adaptive responses to protect against the pathogens it encounters. The innate immune system consists of barriers, such as the skin, mucous secretions, neutrophils, macrophages, and dendritic cells. It also includes cell-surface receptors that can recognize the molecular patterns of pathogens. The adaptive immune system utilizes antigen-specific receptors that are expressed on B and T lymphocytes. These components of the immune system typically act together; the innate response acts first, and the adaptive response begins to act several days after initial infection following the clonal expansion of T and B cells [33]. After a virus enters into a host cell, its antigen is presented by major histocompatibility complex 1 (MHC 1) molecules and is then recognized by cytotoxic T lymphocytes.

In the case of COVID-19, there is also concern about the immune system become over-active. One of the main immune responses contributing to the onset of acute respiratory distress syndrome (ARDS) in COVID-19 patients is the cytokine storm, which causes an extreme inflammatory response due to a release of pro-inflammatory cytokines and chemokines by immune effector cells. In addition to respiratory distress, this mechanism can lead to organ failure and death in severe COVID-19 cases [34]. Details of how the human body responds to SARS-CoV-2, both in healthy and pathological ways, and how these mechanisms can inform the identification of diagnostic, prophylactic, and therapeutic responses are explored in detail throughout this manuscript.

1.3.2 Clinical Presentation of COVID-19

A great diversity of symptom profiles has been observed for COVID-19, although a large study from Wuhan, China suggests fever and cough as the two most common symptoms on admission [35]. One early retrospective study in China described the clinical presentations of patients infected with SARS-CoV-2 as including lower respiratory tract infection with fever, dry cough, and dyspnea [36]. This study [36] noted that upper respiratory tract symptoms were less common, which suggests that the virus targets cells located in the lower respiratory tract. However, data from the New York City region [37,38] showed variable rates of fever as a presenting symptom, suggesting that symptoms may not be consistent across samples. These differences are present when comparing both between institutions in similar locations and between different regions experiencing COVID-19 outbreaks, leading to conflicting reports of the frequency of fever as a presenting symptom for patients upon hospital admission. For example, even within New York City, one study [37] identified low oxygen saturation (<90% without the use of supplemental oxygen or ventilation support) in a significant percentage of patients upon presentation, while another study [38] reported cough, fever, and dyspnea as the most common presenting symptoms. The variability of both which symptoms present and their severity makes it difficult for public health agencies to provide clear recommendations for citizens regarding what symptoms indicate SARS-CoV-2 infection and should prompt isolation.

1.4 Role of the COVID-19 Review

Figure 2: Summary of the relationships among topics covered in this review.

Several review articles on aspects of COVID-19 have already been published. These have included reviews on the disease epidemiology [39], immunological response [40], diagnostics [41], and pharmacological treatments [40,42]. Others [43] and [44] provide narrative reviews of progress on some important ongoing COVID-19 research questions. With the worldwide scientific community uniting during 2020 to investigate SARS-CoV-2 and COVID-19 from a wide range of perspectives, findings from many disciplines are relevant on a rapid timescale to a broad scientific audience. Additionally, many findings are published as preprints, which are available prior to going through the peer review process. As a result, centralizing, summarizing, and critiquing new literature broadly relevant to COVID-19 can help to expedite the interdisciplinary scientific process that is currently happening at an advanced pace. We are particularly interested in providing background to the development of diagnostic, prophylactic, and therapeutic approaches to COVID-19. Two major concerns within diagnosis include the detection of current infections in individuals with and without symptoms, and the detection of past exposure without an active infection. In the latter category, identifying whether individuals can develop or have developed sustained immunity is also a major consideration. The development of high-throughput, affordable methods for detecting active infections and sustained immunity will be critical to understanding and controlling the disease. The identification of interventions that can mitigate the effect of the virus on exposed and infected individuals is a significant research priority. Some possible approaches include the identification of existing pharmaceuticals that reduce the severity of infection, either by reducing the virus’ virulence (e.g., antivirals) or managing the most severe symptoms of infection. Due to the long timeline for the development of novel pharmaceuticals, in most cases, research surrounding possible pharmaceutical interventions focuses on the identification and investigation of existing compounds whose mechanisms may be relevant to COVID-19. Other foci of current research include the identification of antibodies produced by survivors of COVID-19 and the development of vaccines. Understanding the mechanisms describing host-virus interactions between humans and SARS-CoV-2 is thus critical to identifying candidate therapeutics. An overview of the topics covered is visualized in Figure (Figure 2). Thus, in this review, we seek to consolidate information about efforts to develop strategies for diagnosis and therapeutics as new information is released by the scientific community. We include information from both traditional peer-reviewed scientific literature and from preprints, which typically have not undergone peer review but have been critically evaluated by the scientists involved in this effort. The goal of this manuscript is to present preliminary findings within the broader context of COVID-19 research and to identify the broad interpretations of new research, as well as limitations to interpretability.

2 Pathogenesis

The current COVID-19 pandemic, caused by the SARS-CoV-2 virus, represents an acute global health crisis where symptoms can range from mild to severe or fatal [45], can affect a variety of organs and systems, and includes outcomes such as acute respiratory distress and acute lung injury, among other complications. Viral pathogenesis is typically broken down into three major components: entry, replication, and spread [46]. However, in order to draw a more complete picture of pathogenesis, it is also necessary to examine how infection manifests clinically, identify systems-level interactions between the virus and the human body, and consider the possible effects of variation or evolutionary change on pathogenesis and virulence. Though hCoV are not common and the SARS-CoV-2 virus appears to have emerged only recently, the rapid release of the genomic sequence of the virus in January 2020 provided early opportunities for comparative genomic analysis of the virus compared to its close phylogenetic relatives. Because many mechanisms of pathogenicity are conserved among coronaviruses, this phylogenetic analysis provided an important basis for forming hypotheses about how the virus interacts with hosts. Additionally, worldwide sequencing of viral samples has provided some preliminary insights into possible mechanisms of adaptation in the virus, and omics-based analysis of patient samples has elucidated some of the biological changes the virus induces in its human hosts. In this way, both biomedicine and genomics are important pieces of the puzzle of SARS-CoV-2 presentation and pathogenesis.

2.1 Fundamental Viral Pathogenesis

As discussed above, the virus clusters with known coronaviruses (order Nidovirales, family Coronaviridae, subfamily Orthocoronavirinae). Coronaviruses are large viruses that can be identified by their distinctive “crown-like” shape. Their spherical virions are made from lipid envelopes ranging from 100 to 160 nanometers (nm) in which peplomers of two to three spike (S) glycoproteins are anchored, creating the crown [47,48]. These spikes, which are critical to both viral pathogenesis and the host immune response, have been visualized using cryo-electron microscopy [49]. Because they induce the human immune response, they are the target of many proposed therapeutic agents. Phylogenetic analysis of the coronaviruses reveals four major subclades, each corresponding to a genus: the alpha, beta, delta and gamma coronaviruses. Among them, alpha and beta coronaviruses infect mammalian species, gamma coronaviruses infect avian species, and delta coronaviruses infect both mammalian and avian species [50]. Phylogenetic analysis of a PCR amplicon fragment from five patients along with the full genomic sequence revealed SARS-CoV-2 to be a novel betacoronavirus belonging to the B lineage, also known as sarbecovirus, which also includes the coronavirus SARS-CoV that causes SARS in humans [51]. Because viral structure and mechanisms of pathogenicity are highly conserved within the order, this phylogenetic analysis provides a basis for forming hypotheses about how the virus interacts with hosts, including which tissues, organs, and systems would be most susceptible to SARS-CoV-2 infection.

2.1.1 Genomic Structure of Coronaviruses

Genome structure is highly conserved among coronaviruses, meaning that the relationship between the SARS-CoV-2 genome and its pathogenesis can be inferred from prior research in related viral species. The genomes of viruses in the Nidovirales order share several fundamental characteristics. They are non-segmented, which means the viral genome is contained in a single capsid, and are enveloped, which means that the genome and capsid are encased by a lipid bilayer. Coronaviruses have large positive-sense RNA (ssRNA+) genomes ranging from 27 kilobases (Kb) to 32 Kb in length [14,52]. The SARS-CoV-2 genome lies in the middle of this range at 29,903 bp [14]. Genome organization is highly conserved within the order [52]. There are three major regions: one containing the replicase gene and one containing the genes encoding structural proteins [52]. The replicase gene comprises about two-thirds of the genome of coronaviruses and consists of two open reading frames that are translated with ribosomal frameshifting [52]. This polypeptide is then translated into 16 non-structural proteins (nsp1-16, except in Gammacoronaviruses, where nsp1 is absent) that form replication machinery used to synthesize viral RNA [53]. The remaining third of the genome encodes structural proteins, including the spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins. Additional accessory genes are sometimes present between these two regions, depending on the species or strain. Much attention has been focused on the S protein, which is a critical structure involved in cell entry.

2.1.2 Pathogenic Mechanisms of Coronaviruses

While, like most viruses, it is possible that SARS-CoV and SARS-CoV-2 can enter cells through endocytosis, coronaviruses are able to target cells for entry through fusion with the plasma membrane [54,55]. This process is conserved among coronaviruses and is closely associated with the content of their genomes. Cell entry proceeds in three steps: binding, cleavage, and fusion. First, the viral spike protein binds to a host cell via a recognized receptor. Coronaviruses can bind to a range of host receptors [56,57], with binding conserved only at the genus level [50]. Viruses in the betacoronavirus genus, to which SARS-CoV-2 belongs, are known to bind to CEACAM1, Neu 5,9 Ac2, and Angiotensin-Converting Enzyme 2 (ACE2) [56]. SARS-CoV-2 has a high affinity for the human ACE2 receptor, which is expressed in the vascular epithelium, other epithelial cells, and cardiovascular and renal tissues [58,59]. The binding process is guided by the molecular structure of the spike protein, which is structured in three segments: an ectodomain, a transmembrane anchor, and an intracellular tail [60]. The ectodomain forms the crown-like structures on the viral membrane and contains two subdomains known as the S1 and S2 subunits [61]. The S1 (N-terminal) domain forms the head of the crown and contains the receptor binding motif (RBM), and the S2 (C-terminal) domain forms the stalk that supports the head [61]. The S1 subunit guides the binding of the virus to a host cell receptor, and the S2 subunit guides the fusion process [60].

After the binding of the S1 subunit to a receptor, the spike protein is often cleaved at the S1-S2 boundary by a host protease [62,63,64]. Similar to SARS-CoV, SARS-CoV-2 exhibits redundancy in which host proteases can cleave the S protein [65]. Specifically, both transmembrane protease serine protease-2 (TMPRSS2) and cathepsins B/L have been shown to mediate SARS-CoV-2 S protein proteolytic priming, and small molecule inhibition of these enzymes fully inhibited viral entry in vitro [65,66]. Proteolytic priming prepares the S protein for fusion [63,64]. The two subunits remain bound by van der Waals forces, with the S1 subunit stabilizing the S2 subunit during the membrane fusion process [62]. Electron microscopy suggests that in some coronaviruses, including SARS-CoV and MERS-CoV, a six-helix bundle separates the two subunits in the postfusion conformation, and the unusual length of this bundle facilitates membrane fusion through the release of additional energy [50]. Cleavage at a second site within S2 by these same proteases activates S for fusion by inducing conformational changes [62]. The viral membrane can then fuse with the endosomal membrane to release the viral genome into the host cytoplasm. Once the virus enters a host cell, the replicase gene is translated and assembled into the viral replicase complex. This complex then synthesizes the double-stranded RNA (dsRNA) genome from the genomic ssRNA(+). The dsRNA genome is transcribed and replicated to create viral mRNAs and new ssRNA(+) genomes [52,67]. From there, the virus can spread in other cells. In this way, the genome of SARS-CoV-2 provides some insight into the pathogenic behavior of the virus.

2.1.3 Immune Evasion Strategies

Research in other coronaviruses that affect humans provides some indication of how SARS-CoV-2 infection proceeds in spite of the human immune response. By infecting the epithelium, viruses such as SARS-CoV are known to bypass the physical barriers such as skin and mucus that comprise the immune systems’ first line of defense [68]. Once the virus infiltrates host cells, it is adept at evading detection. CD163+ and CD68+ macrophage cells especially are crucial for the establishment of SARS-CoV in the body [68]. These cells most likely serve as viral reservoirs that help shield SARS-CoV from the innate immune response. According to a study on the viral dissemination of SARS-CoV in Chinese macaques, viral RNA could be detected in some monocytes throughout the process of differentiation into dendritic cells [68]. This lack of active viral replication allows SARS-CoV to escape innate immunity because reduced levels of detectable viral RNA allow the virus to avoid both natural killer (NK) cells and Toll-like receptors [68]. Even during replication, SARS-CoV is able to mask its dsRNA from detection by the immune system. Although dsRNA is a pathogen-associated molecular pattern (PAMP) that would typically initiate a response from the innate immune system [69], in vitro analysis of nidoviruses including SARS-CoV suggests that these viruses can induce the development of double-membrane vesicles that protect the dsRNA signature from being detected by the host immune system [70]. This protective envelope can therefore insulate these coronaviruses from the innate immune response’s detection mechanism [34].

HCoV are also known to interfere with the host immune response, rather than just evade it. For example, the virulence of SARS-CoV is increased by nonstructural protein 1 (Nsp1), which can suppress host gene expression. Nsp1 accomplishes this by stalling mRNA translation and inducing endonucleolytic cleavage and mRNA degradation [71]. SARS-CoV also evades the immune response by interfering with type I IFN induction signaling, which is a mechanism that leads to cellular resistance to viral infections. SARS-CoV employs methods such as ubiquitination and degradation of RNA sensor adaptor molecules MAVS and TRAF3/6 [72]. Also, MERS-CoV downregulates antigen presentation via MHC class I and MHC class II, which leads to a reduction in T cell activation [72]. These evasion mechanisms, in turn, can lead to systemic infection. Coronaviruses such as SARS-CoV are also able to evade the humoral immune response through other mechanisms, such as inhibiting certain cytokine pathways or down-regulating antigen presentation by the cells [70].

2.1.4 Host Cell Susceptibility

ACE2 and TMPRSS2 have been identified as a primary receptor and a critical protease, respectively, facilitating the entry of SARS-CoV/CoV-2 into a target cell [49,65,73,74,75]. This finding has led to a hypothesized role for ACE2 and TMPRSS2 expression in determining which cells, tissues, and organs are most likely to be infected by SARS-CoV-2. The ACE2 receptor is expressed in numerous organs, such as the heart, kidney, and intestine, but it is most prominently expressed in alveolar epithelial cells; this pattern of expression is expected to contribute to the virus’ association with lung pathology [58,76]. Clinical investigations of COVID-19 patients have detected SARS-CoV-2 transcripts in BALF (93% of specimens), sputum (72%), nasal swabs (63%), fibrobronchoscopy brush biopsies (46%), pharyngeal swabs (32%), feces (29%) and blood (1%) [77]. Two studies reported that SARS-CoV-2 could not be detected in the urine specimens [77,78]; however, a third study identified four urine samples (out of 58) that were positive for SARS-CoV-2 nucleic acids [79]. Although respiratory failure remains the leading cause of death for COVID-19 patients [80], SARS-CoV-2 infection can damage many other organ systems including the heart [81], kidneys [82,83], liver [84], and gastrointestinal tract [85,86]. As it becomes clear that SARS-CoV-2 infection can damage multiple organs, the scientific community is pursuing multiple avenues of investigation in order to build a consensus about how the virus affects the human body.

2.2 Clinical Presentation of COVID-19

Reports have described diverse symptom profiles associated with COVID-19. A large study from Wuhan, China suggested that fever and cough are the two most common symptoms at hospital admission [35], and another early retrospective study in China described the clinical presentations of patients infected with SARS-CoV-2 as including lower respiratory tract infection with fever, dry cough, and dyspnea [36]. This study [36] noted that upper respiratory tract symptoms were less common, which suggested that the virus was targeting cells located in the lower respiratory tract. A later study reported radiographic findings such as ground-glass opacity and bilateral patchy shadowing in the lungs of many hospitalized patients, and most COVID-19 patients had lymphocytopenia, meaning they had low levels of lymphocytes (a type of white blood cell) [35]. However, data from the New York City region [37,38] showed variable rates of fever as a presenting symptom, suggesting that symptoms may not be consistent across samples. These differences persist when comparing both between institutions in similar locations and between different regions experiencing COVID-19 outbreaks, leading to conflicting reports of the frequency of fever at hospital admission. For example, even within New York City, one study [37] identified low oxygen saturation (<90% without the use of supplemental oxygen or ventilation support) in a significant percentage of patients upon presentation, while another study [38] reported cough, fever, and dyspnea as the most common presenting symptoms. Patients may also experience loss of smell, myalgias (muscle aches), fatigue, or headache. Radiographic findings such as ground-glass opacity and bilateral patchy shadowing in the lungs of many hospitalized patients have also been reported, and most COVID-19 patients had lymphocytopenia, meaning they had low levels of lymphocytes (a type of white blood cell) [35]. The variability of both which symptoms present and their severity makes it difficult for public health agencies to provide clear recommendations for citizens regarding what symptoms indicate SARS-CoV-2 infection and should prompt isolation. For example, evidence suggests that gastrointestinal symptoms presentation does occur [87], and the CDC has updated its list of symptoms suggestive of COVID-19 to include nausea and vomiting, as well congestion and runny nose [45]. A recent preprint using data from an app-based survey of 500,000 individuals in the US found that among those tested for SARS-CoV-2, a loss of taste or smell, fever, and a cough were significant predictors of a positive test result [88]. It is important to note that in this study, the predictive value of symptoms may be underestimated if they are not specific to COVID-19 because the outcome measured was a positive, as opposed to a negative, COVID-19 test result. At the time the surveys were conducted, due to limits in US testing infrastructure, respondents typically needed to have some symptoms known to be specific to COVID-19 in order to qualify for testing in the first place. Widespread testing of asymptomatic individuals may therefore provide additional insight into the range of symptoms associated with COVID-19.

COVID-19 can affect diverse body systems in addition to causing respiratory problems [89]. For example, COVID-19 can lead to acute kidney injury, especially in patients with severe respiratory symptoms or certain preexisting conditions [90]. It can also cause neurological complications [91,92], potentially including stroke, seizures or meningitis [93,94]. COVID-19 has also been associated with an increased incidence of large vessel stroke, particularly in patients under the age of 40 [95], and other thrombotic events including pulmonary embolism and deep vein thrombosis [96]. The mechanism behind these complications has been suggested to be related to coagulopathy, with reports indicating the presence of antiphospholipid antibodies [97] and elevated levels of d-dimer and fibrinogen degradation products (FDP) in deceased patients [98]. Other viral infections have been associated with coagulation defects and changes to the coagulation cascade; notably SARS was also found to lead to disseminated intravascular coagulation (DIC) and was associated with both pulmonary embolism and deep vein thrombosis [99]. The mechanism behind these insults has been suggested to be related to inflammation-induced increases in the von Willebrand factor (VWF) clotting protein, leading to a pro-coagulative state [99]. Abnormal clotting (thromboinflammation or coagulopathy) has been increasingly discussed recently as a possible key mechanism in many cases of severe COVID-19, and may be associated with the high d-dimer levels often observed in severe cases [100,101,102]. This excessive clotting in lung capillaries has been suggested to be related to a dysregulated activation of the complement system, part of the innate immune system [103,104].

2.2.1 Cytokine Release Syndrome

Symptoms of a disease can be caused by a pathogen, but they can also be caused by the immune system’s reaction to the pathogen. A dysregulated immune response can cause significant damage to the host [105,106,107]. The inflammatory response has received particular attention for its role in both a healthy response to infection and a pathogenic one. Inflammation is one of the most visible components of the immune response, as it is responsible for hallmarks of injury such as pain, heat, and swelling [108]. In response to injury or to signaling by pattern recognition receptors (PRRs) indicating the detection of a molecular pattern associated with a pathogen or foreign body, the immune system stimulates leukocytes that travel to the site of the threat, where they then produce cytokines [108]. Cytokines are a diverse group of small proteins that play an important role in intercellular signaling [109]. Cytokines can be both pro- and anti-inflammatory, which means they can either stimulate or inhibit the production of additional cytokines [109,110]. Some notable pro-inflammatory cytokines include the interleukins IL-1β and IL-6 and tumor necrosis factor α (TNF-α) [110]. Anti-inflammatory cytokines play an immunoregulatory role complementary to the cascading effect of pro-inflammatory cytokines [??? 10.1128/MMBR.05015-11,110]. A number of interleukins and interferons play anti-inflammatory roles, and receptors or receptor antagonists for inflammatory cytokines are also important for regulating inflammation [110]. IL-10 is an anti-inflammatory cytokines of particular note because it regulates the expression of TNF-α, IL-1, and IL-6 [110]. When the pro- and anti-inflammatory responses are both commensurate with the threat posed, the immune system drives a shift back to homeostasis [111]. However, when the responses are disproportionate, the cytokine response can become dysregulated. Too low of an inflammatory response will not eliminate the immune threat [111]. In contrast, if the response is dysregulated towards excessive pro-inflammatory cytokine activity, inflammation can cascade [112] and cause cell damage, among other problems [108]. Elevated levels of inflammation over the long-term are associated with many chronic health conditions, including type 2 diabetes, dementia and Alzheimer’s, and arthritis, among others [113]. On a shorter timescale, dysregulated systemic inflammation can cause sepsis, which can lead to multi-organ failure and death [???,109].

Cytokines have been investigated for their role in the immune response to lung infections long before the COVID-19 pandemic. Dysregulation of the inflammatory response, including elevated levels of pro-inflammatory cytokines, is found in patients with ARDS, which is a severe condition that can arise from pneumonia, SARS, and COVID-19 [112]. One study of patients with and at risk for ARDS (specifically, those who were intubated for medical ventilation) found that shortly after the onset of ARDS, anti-inflammatory cytokine concentration in BALF increased relative to the concentration of pro-inflammatory cytokines [114]. However, patients with severe ARDS were excluded from this study. The results suggest that an increase in pro-inflammatory cytokines such as IL-6 may signal the onset of ARDS, but recovery depends on an increased anti-inflammatory response [114]. Acute phase response to an infection can also cause damage to the capillary endothelium, allowing leaks that disrupt the balance between pro-inflammatory cytokines and their regulators [114]. Hyperactivity of the pro-inflammatory response due to lung infection is commonly associated with acute lung injury and more rarely with the more severe manifestation, ARDS [109]. The heightened inflammatory response in the lungs can also serve as a source for systemic inflammation, or sepsis, which can lead to multi-organ failure [109]. The shift from local to systemic inflammation is a phenomenon often referred to broadly as a cytokine storm [109] or, more precisely, as cytokine release syndrome (CRS) [115]. Sepsis is a known possible complication of pneumonia, and in an analysis of over 1400 US pneumonia patients, IL-6, tumor necrosis factor (TNF), and IL-1β were found to be elevated at intake in patients who developed severe sepsis and/or ultimately deceased [116]. IL-6 and TNF are pro-inflammatory cytokines, while IL-1β is anti-inflammatory [116]. However, this study reported that unbalanced pro-/anti-inflammatory cytokine profiles were rare, although they measured only the three cytokines listed above. Prior work therefore made it clear that pulmonary infection and injury were associated with systemic inflammation through sepsis. While IL-6 is a biomarker sometimes used to assess cytokine storm activity in sepsis [109], the relationship between cytokine profiles and the risks associated with sepsis may be more complex. IL-6 is a pleiotropic cytokine that plays an integral role in both the inflammatory and anti-inflammatory responses and is associated with both healthy and pathological responses to viral threat [117].

The inflammatory response was identified early on as a potential driver of COVID-19 outcomes due to existing research in SARS and emerging research in COVID-19. In addition to the known role of cytokines in ARDS and lung infection more broadly, immunohistological analysis at autopsy of patients who deceased from SARS revealed that ACE2-expressing cells that were infected by SARS-CoV showed elevated expression of IL-6, IL-1β, and TNF-α [118]. Similarly, the introduction of the S-protein from SARS-CoV to mouse macrophages was found to increase production of IL-6 and TNF-α [119]. For SARS-CoV-2 infection leading to COVID-19, early reports described a cytokine storm-like response in patients with particularly severe infections [76,120,121]. Among patients hospitalized with COVID-19 in Wuhan, China, 112 out of 191 (59%) developed sepsis, including all 54 of the non-survivors [36]. However, the argument has been made that while the cytokine levels observed in COVID-19 patients fall outside of the normal range, they are not be as high as typically found in patients with ARDS [122]. Regardless, inflammation has received significant interest both in regards to the pathology of COVID-19 as well as potential avenues for treatment, as the similarities between the cytokine storm and the pathophysiology of COVID-19 has led to the suggestion that a number of immunomodulatory pharmaceutical interventions could hold therapeutic value for the treatment of COVID-19 [123].

2.2.2 Pediatric Presentation

The presentation of COVID-19 infection can vary greatly among pediatric patients and in some cases manifests in distinct ways from COVID-19 in adults. A review examined symptoms reported in 17 studies of children infected with COVID-19 during the early months of the COVID-19 epidemic in China and one study from Singapore [124]. Of the more than a thousand cases described, the most commonly reports were for mild symptoms such as fever, dry cough, fatigue, nasal congestion and/or runny nose, while three children were reported to be asymptomatic. Severe lower respiratory infection was described in only one of the pediatric cases reviewed. Gastrointestinal symptoms such as vomiting or diarrhea were occasionally reported. Radiologic findings were not always reported in the case studies reviewed, but when they were mentioned they included bronchial thickening, ground-glass opacities, and/or inflammatory lesions [124]. Neurological symptoms have also been reported [125].

These analyses indicate that most pediatric cases of COVID-19 are not severe. However, serious complications and, in rare cases, deaths have occurred [126]. Of particular interest, children have occasionally experienced a serious inflammatory syndrome, multisystem inflammatory syndrome in children (MIS-C), following COVID-19 infection. This syndrome is similar in some respects to Kawasaki disease or to Kawasaki disease shock syndrome [127,128,129] and is thought to be a distinct clinical manifestation of SARS-CoV-2 due to its distinct cytokine profile and the presence of burr cells in peripheral blood smears [130,131]. MIS-C has been associated with heart failure in some cases [132]. One case study [133] described an adult who appeared to show symptoms similar to MIS-C after exposure to COVID-19, but cautioned against broad conclusions; a second possible adult case has also been reported [134]. The presentation of SARS-CoV-2 infection is therefore likely to be largely distinct between adult and pediatric populations.

2.3 Systems-Level Effects

Systems biology provides a cross-disciplinary analytical paradigm through which the host response to an infection can be analyzed. This field integrates the “omics” (genomics, transcriptomics, proteomics, metabolomics, etc.) with bioinformatics and other computational strategies. These cutting-edge research approaches hold enormous potential for the study of the complexity of biological systems and human diseases [135]. Over the last decade, systems biology approaches have been used widely to study the pathogenesis of diverse types of life-threatening acute and chronic infectious diseases [136]. Omics-based studies have also provided meaningful information regarding host immune responses and surrogate protein markers in several viral, bacterial and protozoan infections [137]. Though the complex pathogenesis and clinical manifestations of SARS-CoV-2 infection are not yet fully understood, “omics” technologies offer the opportunity to discovery-drive analysis of biological changes associated with SARS-CoV-2 infection. For example, previous studies suggest that infection by coronaviruses such as SARS-CoV and MERS-CoV and other viruses is associated with the upregulation of ACE2. In several preliminary assays and an analysis of previous microarray data, ACE2 expression was reported to be significantly upregulated following infection of human embryonic kidney cells and human airway epithelial cells [76]. This study also reported that direct stimulation with inflammatory cytokines such as type I interferons (e.g., IFNβ) resulted in the upregulation of ACE2 in human bronchial epithelial cells, with treated groups showing four-fold higher ACE2 expression than control groups at 18 hours post-treatment [76]. Whether SARS-CoV-2 facilitates the positive regulation of its own transmission between host cells is still unclear, the host immune response itself likely plays a key role in mediating infection-associated pathologies. A systems-biology approach allows for analyses such as these to identify possible phenotypic and endophenotypic responses to SARS-CoV-2 infection and to develop new hypotheses about how pathogenesis proceeds.

2.3.1 Transcriptomics

In addition to the study described above, two other studies have profiled expression following SARS-CoV-2 infection using human cell lines. The first study [138] compared transcriptional responses to SARS-CoV-2 and to other respiratory viruses, including MERS-CoV, SARS-CoV, human parainfluenza virus 3 (HPIV3), respiratory syncytial virus (RSV), and influenza A virus (IAV). They analyzed the responses of three human cell lines: A549 (adenocarcinomic human alveolar basal epithelial cells), Calu-3 (human airway epithelial cells derived from human bronchial submucosal glands), and MRC-5 (human fetal lung fibroblast cells). As the viral receptor ACE2 has low expression in A549 cells, they supplemented the A549 cells with adenovirus (AdV)-based vectors expressing either mCherry (a fluorescent protein used as a control) or ACE2 (A549-ACE2). The authors also measured host transcriptional responses to SARS-CoV-2 in primary normal human bronchial epithelial cells (HBEC or NHBE cells), nasal washes from an animal model (ferret), and lung samples from two COVID-19 patients. Differential expression (DE) analysis was then carried out to compare infected cells with control cells that underwent only a mock treatment. In the hosts where SARS-CoV-2 was able to replicate efficiently, DE analysis revealed that the transcriptional response was significantly different from the response to all of the other viruses tested. A unique proinflammatory cytokine signature associated with SARS-CoV-2 was present under in cells exposed to both high and low doses of the virus, with the cytokines IL-6 and IL1RA uniquely elevated in response to SARS-CoV-2 relative to other viruses. However, the A549-ACE2 cells showed significant IFN-I or IFN-III expression when exposed to high, but not low, doses of SARS-CoV-2. This finding suggests that IFN induction is dependent on the extent of exposure. Similarly, in cells from the NHBE line, ferrets, and COVID-19 patients, chemokine signaling was significantly enriched, but there was no significant induction of IFN-I or IFN-III. Together, these results suggest that SARS-CoV-2 induces a limited antiviral state with low IFN-I or IFN-III expression and a moderate IFN-stimulated gene response, in contrast to other viruses. However, in ACE2-expressing A549 cells, this state could be overcome by using a 10-fold increase in SARS-CoV-2 exposure. This finding suggests that the SARS-CoV-2 antagonist is insufficient for large doses of the virus [138]. This hypothesis was further supported by a recent study [139] that showed that the SARS-CoV-2 ORF3b gene suppresses IFNB1 promoter activity (IFN-I induction) more efficiently than the SARS-CoV_ORF3b_ gene. Taken together, these findings suggest that a unique cytokine profile is associated with the response to the SARS-CoV-2 virus, and that this response differs depending on the extent of exposure.

Another study [140] analyzed cells’ transcriptional response to SARS-CoV-2 and SARS-CoV over time. They characterized the response of three human cell lines, H1299 (human non-small cell lung carcinoma cell line), Calu-3, and Caco-2 (human epithelial colorectal adenocarcinoma cell line), at 4 to 36 hpi. Using poly(A) bulk RNA-seq, the authors found negligible susceptibility of H1299 cells (< 0.08 viral read percentage of total reads) compared to Caco-2 and Calu-3 cells (>10% of viral reads). This finding suggests that the risk of infection varies among cell types, and that cell type could influence which hosts are more or less susceptible. Based on visual inspection (microscopy images) and transcriptional profiling, the authors also showed distinct responses among the host cell lines evaluated. In contrast to Caco-2, Calu-3 cells infected with SARS-CoV-2 showed signs of impaired growth and cell death at 24 hpi, as well as moderate IFN induction with a strong up-regulation of IFN-stimulated genes. Interestingly, the results were similar to those reported in Calu-3 cells exposed to much higher levels of SARS-CoV-2 [138], as described above. This finding suggests that IFN induction in Calu-3 cells is not dependent on the level of exposure, in contrast to A549-ACE2 cells. The discrepancy could be explained by the observations that Calu-3 cells are highly susceptible to SARS-CoV-2 and show rapid viral replication [66], whereas A549 cells are incompatible with SARS-CoV-2 infection [141]. This discrepancy raises the concern that in vitro models may vary in their similarity to the human response, underscoring the importance of follow-up studies in additional models.

2.3.2 Proteomics

No comprehensive proteomic analyses of the pathogen or of patients suffering from its infection have yet been reported. One study investigated proteomics associated with in vitro infection using Caco-2 cells infected with SARS-CoV-2 [142]. This study reported that SARS-CoV-2 induced alterations in multiple vital physiological pathways, including translation, splicing, carbon metabolism and nucleic acid metabolism in the host cells. Another area of interest is whether SARS-CoV-2 is likely to induce similar changes to other hCoV. For example, because of the high level of sequence homology between SARS-CoV-2 and SARS-CoV, it has been hypothesized that sera from convalescent SARS-CoV patients might show some efficacy in cross-neutralizing SARS-CoV-2-S-driven entry [65]. However, despite the high level of sequence homology, certain protein structures might be immunologically distinct, which would be likely to prohibit effective cross-neutralization across different SARS species [143]. Consequently, proteomic analyses of SARS-CoV might also provide some essential information regarding the new pathogen [144,145]. Considering the paucity of omics-level big data sets for SARS-CoV-2 currently available, existing data hubs that contain information for other coronaviruses such as UniProt, NCBI Genome Database, The Immune Epitope Database and Analysis Resource (IEDB), and The Virus Pathogen Resource (ViPR) will serve as useful resources for computational and bioinformatics research on SARS-CoV-2. Using such databases, the systems-level reconstruction of the protein-protein interaction (PPI) will enable the generation of hypotheses about the mechanism of action of SARS-CoV-2 and suggest potential drug targets. In an initial study [146], 26 of the 29 SARS-CoV-2 proteins were cloned and expressed in HEK293T kidney cells, allowing for the identification of 332 high-confidence human proteins interacting with them. Notably, this study suggested that SARS-CoV-2 interacts with innate immunity pathways. Ranking pathogens by the similarity between their interactomes and that of SARS-CoV-2 suggested West Nile Virus, Mycobacterium tuberculosis, and human papillomavirus as the top three hits. Therefore, given the lung symptoms associated with COVID-19, the Mycobacterium tuberculosis host-pathogen interactome in particular might provide new insights to the mechanism of SARS-CoV-2 infection. Additionally, it was suggested that the envelope protein (E) could disrupt host bromodomain-containing proteins, i.e., BRD2 and BRD4, that bind to histones, and the spike protein could likely intervene in viral fusion by modulating the GOLGA7-ZDHHC5 acyl-transferase complex to increase palmitoylation, which is a post-translational modification that affects how proteins interact with membranes [147]. Another study [148] used patient-derived peripheral blood mononuclear cells (PBMCs) to identify 251 host proteins targeted by SARS-CoV-2. This study also reported that more than 200 host proteins were disrupted following infection. In particular, a network analysis showed that non-structural proteins 9 and 10 (nsp9 and nsp10) interacted with NF-Kappa-B-Repressing Factor (NKRF), which encodes a transcriptional repressor that mediates repression of genes responsive to Nuclear Factor kappa-light-chain-enhancer of activated B-cells (NF-kB). These genes are important to pro-, and potentially also anti-, inflammatory signaling [149]. This finding could explain the exacerbation of the immune response that shapes the pathology and the high cytokine levels characteristic of COVID-19, possibly due to the chemotaxis of neutrophils mediated by IL-8 and IL-6. Finally, it was suggested [150] that the E protein of both SARS-CoV and SARS-CoV-2 has a conserved Bcl-2 Homology 3 (BH3)-like motif, which could inhibit anti-apoptosis proteins, e.g., BCL2, and trigger the apoptosis of T cells. Several compounds are known to disrupt the host-pathogen protein interactome, largely through the inhibition of host proteins. Therefore, preliminary research in the proteomics of SARS-CoV-2 infection suggests that drugs modulating the protein-level interactions between virus and host might be worth investigating.

2.4 Viral Evolution and Virulence

Like that of SARS-CoV, the entry of SARS-CoV-2 into host cells is mediated by interactions between the viral spike glycoprotein (S) and human angiotensin-converting enzyme 2 (ACE2) [62,65,151,152,153,154,155,156]. Differences in how the S proteins of the two viruses interact with the human ACE2 (hACE2) receptor could also partially account for the increased transmissibility of SARS-CoV-2. Recent studies have reported conflicting binding constants for the S-hACE2 interaction, though they have agreed that the SARS-CoV-2 S protein binds with equal, if not greater, affinity to the SARS-CoV S protein does [49,62,154]. The C-terminal domain of the SARS-CoV-2 S protein in particular was identified as the key region of the virus that interacts with hACE2, and the crystal structure of the C-terminal domain of the SARS-CoV-2 S protein in complex with hACE2 reveals stronger interaction and a higher affinity for receptor binding than that of SARS-CoV [155]. Among the 14 key binding residues identified in the SARS-CoV S protein, 8 are conserved in SARS-CoV-2, and the remaining 6 are semi-conservatively substituted, potentially explaining variation in binding affinity [62,154]. Recent crystal structures have shown that the receptor-binding domain (RBD) of the SARS-CoV-2 S protein, like that of other coronaviruses, undergoes stochastic hinge-like movement that flips it from a “closed” conformation, in which key binding residues are hidden at the interface between protomers, to an “open” one [49,62]. Because the RBD plays such a critical role in viral entry, blocking its interaction with ACE2 represents a promising therapeutic approach. Nevertheless, despite the high structural homology between SARS-CoV-2 RBD and that of SARS-CoV, monoclonal antibodies targeting SARS-CoV-RBD failed to bind to SARS-CoV-2-RBD [49]. Promisingly, though, sera from convalescent SARS patients inhibited SARS-CoV-2 viral entry in vitro, albeit with lower efficiency than it inhibited SARS-CoV [65].

Comparative genomic analysis reveals that several regions of the coronavirus genome are likely critical to virulence. The S1 domain of the spike protein, which contains the RBM, evolves more rapidly than S’s S2 domain [56,57]. However, even within the S1 domain, some regions are more conserved than others, with the receptors in S1’s N-terminal domain (S1-NTD) evolving more rapidly than those in its C-terminal domain (S1-CTD) [57]. Both S1-NTD and S1-CTD are involved in receptor binding and can function as RBDs to bind proteins and sugars [56], but RBDs in the S1-NTD typically bind to sugars, while those in the S1-CTD recognize protein receptors [50]. Viral receptors show higher affinity with protein receptors than sugar receptors [50], which suggests that positive selection on or relaxed conservation of the S1-NTD might reduce the risk of a deleterious mutation that would prevent binding. The SARS-CoV-2 S protein also contains a an RRAR furin recognition site at the S1/S2 junction [49,62], setting it apart from both bat coronavirus RaTG13, with which it shares 96% genome sequence identity, and SARS-CoV [13]. Such furin cleavage sites are commonly found in highly virulent influenza viruses, and as such may contribute to the heightened pathogenicity of SARS-CoV-2 [157,158]. Effective cell entry is a critical component to pathogenesis and therefore an important process to understand when examining possible therapeutics.

Evolution in SARS-CoV-2 has also been observed over a short timescale. After zoonotic transfer, SARS-CoV-2 continued evolving in the human population [159]. The SARS-CoV-2 mutation rate is moderate compared to other RNA viruses [160], which likely restricts the pace of evolution in SARS-CoV-2. Nevertheless, genomic analyses have yielded statistical evidence of ongoing evolution. There are two known variants of the spike protein that differ by a single amino acid at position 614 (G614 and D614), and there is evidence that G614 had become more prevalent than D614 by June 2020 [161]. While there is a hypothesis that this genomic change increased the SARS-CoV-2 infectivity and virulence, this hypothesis has not yet been tested due to a lack of data [162]. Another study [160] identified 198 recurrent mutations in a dataset of 7666 curated sequences. This pattern of convergent evolution at some sites could indicate that certain mutations confer an adaptive advantage. While it is evident that SARS-CoV-2 exhibits moderate potential for ongoing and future evolution, the relationship between mutations and pathogenicity is not yet known. Additional data is needed in order to understand patterns of evolutionary change and whether they are likely to affect virulence.

3 Transmission and Susceptibility

3.1 Mechanism of Transmission

Person-to-person viral transmission of a virus can occur through several possible mechanisms. The primary mechanisms associated with respiratory viruses are contact, droplet, and aerosol transmission [163]. Contact transmission can occur through either direct contact with a contagious person or indirect contact with active viral particles on a contaminated surface [???]. This latter mode of transmission is also called fomite transmission [164]. Viral particles can enter the body if they then come in contact with the oral, nasal, eye, or other mucus membranes [???]. Droplet transmission occurs when a contagious individual sneezes, coughs, or exhales and produces respiratory droplets that can contain a large number of viral particles [???]. Contact with these droplets can occur either through direct exposure to the droplets, such as breathing in droplets produced by a sneeze, or exposure to particles that have settled on a surface [???]. Aerosol transmission refers to much smaller particles (less than 5 micrometers) that are also produced by sneezing, coughing, or exhaling [???,163]. The small size of these particles allows them to remain suspended over a longer period of time and potentially to be moved by air currents [???]. Additionally, viral particles deposited on surfaces via large respiratory droplets can also later be aerosolized [???]. Droplet and/or contact transmission are both well-accepted modes of transmission for many viruses associated with common human illness, including influenza and rhinovirus [???]. The extent to which aerosol transmission contributes to the spread of respiratory viruses is less clear. In influenza A, for example, viral particles can be detected in aerosols produced by infected individuals, but the extent to which these particles drive the spread of influenza A infection remains under debate [???,163,165,166,167]. Regardless of its role in the spread of influenza A, however, aerosol transmission likely played a role in outbreaks such as the 1918 Spanish Influenza (H1N1) and 2009 “swine flu” (pH1N1) [167]. Contact, droplet, and aerosol transmission are therefore all worth evaluating when considering possible modes of transmission for a respiratory virus like SARS-CoV-2.

3.1.1 Transmission of HCoV

All three of these mechanisms have been identified as contributors to the transmission of HCoV [???], including the highly pathogenic coronaviruses SARS-CoV and MERS-CoV [29,168]. Transmission of SARS-CoV is thought to proceed primarily through droplet transmission, but aerosol transmission is also considered possible [???], and fomite transmission may have also played an important role in some outbreaks [169]. Similarly, the primary mechanism of MERS transmission is thought to be droplets because inter-individual transmission appears to be associated with close interpersonal contact (e.g., household or healthcare settings), but aerosolized particles of the MERS virus have been reported to persist much more robustly than influenza A under a range of environmental conditions [170,171]. While droplet-based and contact transmission were initially considered to be the primary modes by which SARS-CoV-2 spread [172], as additional information has emerged, the possibility of aerosol transmission has also been raised [173,174,175]. For example, the detection of SARS-CoV-2 viral particles in air samples taken from hospitals treating COVID-19 patients led to the concern that the virus could be spreading via aerosols [176]. The stability of the virus both in aerosols and on a variety of surfaces appeared similar to that of SARS-CoV [174], and fomite transmission could also play a role in transmission (e.g., [177]). However, while the possibility of aerosol transmission seems plausible, the evidence suggests that droplet and contact transmission are the dominant mechanisms driving the spread of the virus [178], and the risk of fomite transmission under real-world conditions is likely to be substantially lower than the conditions used for experimental analyses [179]. These mechanisms may differ in their relevance to different types of transmission events, such as transmission within households, nosocomial transmissions, and transmission in indoor versus outdoor spaces.

3.1.2 Symptoms and Viral Spread

Other aspects of pathogenesis are also important to understanding how the virus spreads, especially the relationship between symptoms, viral shedding, and contagiousness. Symptoms associated with reported cases of COVID-19 range from mild to severe [45], but some individuals who contract COVID-19 remain asymptomatic throughout the duration of the illness [180]. The incubation period, or time period between exposure and the onset of symptoms, has been estimated at five to eight days (4.91 and 7.54 in two different cities) [181,182], and estimates suggest that viral shedding may begin long before the onset of symptoms (12.3 days with a 95% CI of 5.9 - 17.0) and peak around the onset of symptoms [183]. As these trends became apparent, concerns arose due to the potential for individuals who did not or did not yet show symptoms to transmit the virus [184]. Recovered individuals may also be able to transmit the virus after their symptoms cease. Estimates of the communicable period based on twenty-four individuals who tested positive for SARS-CoV-2 prior to or without developing symptoms estimated that individuals may be contagious for one to twenty-one days, but they note that this estimate may be low [180]. Initially, viral nucleic acids were reported to remain at observable levels in the respiratory specimens of recovering hospitalized COVID-19 patients for a median of 20 days and with a maximum observed duration through 37 days, when data collection for the study ceased [36]. As more estimates of the duration of viral shedding are released, they are beginning to converge around approximately three weeks from first positive PCR test and/or onset of symptoms (which, if present, are usually identified within three days of the initial PCR test). For example, viral shedding was reported for up to 28 days following symptom onset by a second study [185] and for one to 24 days from first positive PCR test with a median of 12 days [78]. On the other hand, almost 70% of patients were reported to still have symptoms at the time that viral shedding ceased, although all symptoms reduced in prevalence between onset and cessation of viral shedding (CVS) [186]. They also reported that the median time that elapsed between the onset of symptoms and cessation of viral RNA shedding (CVS) was 23 days and between first positive PCR test and CVS was 17 days [186]. The fact that this study reported symptom onset to predate the first positive PCR test by an average of three days, however, suggests that there may be some methodological differences between it and related studies. Furthermore, an analysis of residents of a nursing home with a known SARS-CoV-2 case measured similar viral load in residents who were asymptomatic regardless of whether they later developed symptoms, and the load in the asymptomatic residents was comparable to that of residents who displayed either typical of atypical symptoms [187]. Taken together, these results suggest that the presence or absence of symptoms are not reliable predictors of viral shedding or of SARS-CoV-2 status (e.g, [188]. However, viral shedding is not necessarily indicative of contagiousness. The risk of spreading the infection was low after ten days from the onset of symptoms, as viral load in sputum was found to be unlikely to pose a significant risk based on their efforts to culture samples in vitro [185].

The extent to which asymptomatic (or presymptomatic) individuals are able to transmit SARS-CoV-2 has been a question of both scientific and community interest. Early reports (February and March 2020) described transmission from presymptomatic SARS-CoV-2-positive individuals to close family contacts [189,190]. One of these reports [190] also included a description of an individual who tested positive for SARS-CoV-2 but never developed symptoms. Later analyses also sought to estimate the proportion of infections that could be traced back to a presymptomatic or asymptomatic individual (e.g., [191]). Estimates of the proportion of individuals with asymptomatic infections have varied widely. The proportion of asymptomatic individuals on board the Diamond Princess cruise ship, which was the site of an early COVID-19 outbreak, was estimated at 17.9% [???], In contrast, a model using the prevalence of antibodies among residents of Wuhan, China estimated a much higher of asymptomatic cases, at approximately 7 in 8, or 87.5% [???]. An estimate of the population of care homes in London found that, among the residents (median age 85), the rate of asymptomatic infection was 43.8%, and among the caretakers (median age 47), the rate was 49.1% [192]. The duration of viral shedding may also be longer in individuals with asymptomatic cases of COVID-19 compared to those who do show symptoms [193]. As a result, the potential for individuals who do not know they have COVID-19 to spread the virus raises significant concerns. In Singapore and Tianjin, two cities studied to estimate incubation period, an estimated 40-50% and 60-80% of cases, respectively, were estimated to be caused by contact with an asymptomatic individuals [181]. An analysis of viral spread in the Italian town of Vo’, which was the site of an early COVID-19 outbreak, revealed that 42.5% of cases were asymptomatic and that the rate was similar across age groups [194]. They argued that the town’s lockdown was imperative for controlling the spread of COVID-19 because it isolated the asymptomatic individuals. While more models are likely to emerge to better explore the effect of asymptomatic individuals on SARS-CoV-2 transmission, these results suggest that strategies for identifying and containing asymptomatic but contagious individuals are important for managing community spread.

3.1.3 Estimating the Fatality Rate

Estimating the occurrence of asymptomatic and mild COVID-19 cases is important to identifying the mortality rate associated with COVID-19. The mortality rate of greatest interest would be the total number of fatalities as a fraction of the total number of people infected. One metric reported is often case fatality rate (CFR), which simply compares the number of COVID-19 related deaths to the number of confirmed or suspected cases. However, in locations without universal testing protocols, it is impossible to identify all exposed or all infected individuals because so many asymptomatic or mild cases go undetected. Therefore, a more informative metric is the infection fatality rate (IFR), which compares the known deaths to the estimated number of cases. Meta-analyses have produced estimates of global IFR ranging from as low as 0.1% to as high as 1.04% [195,195,196,197]. All of these estimates note that IFR varies widely around the world. Estimates of infection rates are becoming more feasible as more data becomes available for modeling and will be bolstered as serological testing becomes more common and available.

3.2 Dynamics of Transmission

Disease spread dynamics can be estimated using R0, the basic reproduction number, and Rt, the effective reproduction number. Thus, accurate estimates are crucial to understanding the dynamics of infection and to predicting the effects of different interventions. R0 and the timescale of infection (measured by the infectious period and the exposed period) govern population-level epidemic dynamics, with R0 being one of the most important epidemiological parameters [198]. R0 is the average number of new (secondary) infections caused by one infected person, assuming a wholly susceptible population [199]. A simple mechanistic model used to describe infectious disease dynamics is a susceptible-infected-recovered (SIR) compartmental model. In this formulation individuals move through three states: susceptible, infected, and recovered; two parameters, \(\gamma\) and \(\beta\), specify the rate at which the infectious recover, and the infection transmission rate, respectively. In this simple formulation, R0 is estimated as the ratio of \(\beta\) and \(\gamma\).[198,200]. A pathogen can invade a susceptible population only if R0 > 1 [198,201]. The spread of an infectious disease at a particular time t can be quantified by Rt, the effective reproduction number, which assumes that part of the population has already recovered (and thus gained immunity to reinfection) or that mitigating interventions were put into place. For example, if only a fraction St of the population is still susceptible, Rt = St x R0. When Rt is greater than 1, an epidemic grows (i.e., the proportion of the population that is infectious increases); when Rt is less than 1, the proportion of the population that is infectious decreases. R0 and Rt can be estimated directly from epidemiological data or inferred using mathematical modeling. Modeling approaches are typically based upon a classic epidemiological model structure: the SIR model and its extensions [202,203]. In the context of SARS-CoV-2, more complex modified susceptible-exposed-infectious-recovered (SEIR) models are commonly used.

Estimates of R0 for COVID-19 lie in the range R0=1.4-6.5 [204,205,206]. Variation in R0 is expected between different populations, and the estimated values of R0 discussed below are for specific populations in specific environments. The different estimates of R0 should not necessarily be interpreted as a range of estimates of the same underlying parameter. In one study of international cases, the predicted value was R0=1.7 [207]. In China (both Hubei province and nationwide), the value was predicted to lie in the range R0=2.0-3.6 [204,208,209]. Another estimate based on a cruise ship where an outbreak occurred predicted R0=2.28 [210]. SEIR model-derived estimates of R0 range from 2.0 - 6.5 in China [211,212,213,214] to R0=4.8 in France [215]. Using the same model as for the French population, a study estimated R0=2.6 in South Korea [215], which is consistent with other studies [216]. From a meta-analysis of studies estimating R0, [205] predict the median as R0=2.79.

Inference of the effective reproduction number can provide insight into how populations respond to an infection and the effectiveness of interventions. In China, Rt was predicted to lie in the range 1.6-2.6 in January 2020, before travel restrictions [217]. Rt decreased from 2.35 one week before travel restrictions were imposed (January 23, 2020), to 1.05 one week after. Using their model, the authors also estimated the probability of new outbreaks occurring: the probability of a single individual exporting the virus and causing a large outbreak is 17-25%, assuming MERS-like or SARS-like transmission, and the probability of a large outbreak occurring after ≥4 infections exist at a new location is greater than 50%. An independent study came to similar conclusions, finding Rt=2.38 in the two-week period before January 23 with a decrease to Rt = 1.34 (using data from January 24 to February 3) or Rt=0.98 (using data from January 24 to February 8) [206]. In South Korea, Rt was inferred for February through March 2020 in two cities, Daegu (the center of the outbreak) and Seoul [216]. Metro data was also analyzed to estimate the effects of social distancing measures. Rt decreased in Daegu from around 3 to <1 over the period that social distancing measures were introduced. In Seoul, Rt decreased slightly, but remained close to 1 (and larger than Rt in Daegu). These findings indicate that social distancing measures appeared to be effective in containing the infection in Daegu, but in Seoul, Rt remained above 1, meaning secondary outbreaks remained possible. The study also shows the importance of region-specific analysis: the large decline in case load nationwide was mainly due to the Daegu region and could mask persistence of the epidemic in other regions, such as Seoul and Gyeonggi-do. In Iran, estimates of Rt declined from 4.86 in the first week to 2.1 by the fourth week after the first cases were reported [218]. In Europe, analysis of 11 countries inferred the dynamics of Rt over a time range from the beginning of the outbreak until March 28, 2020, by which point most countries had implemented major interventions (such as school closures, public gathering bans, and stay-at-home orders) [219]. Across all countries, the mean Rt before interventions began was estimated as 3.87; Rt varied considerably, from below 3 in Norway to above 4.5 in Spain. After interventions, Rt decreased by an average of 64% across all countries, with mean Rt=1.43. The lowest predicted value was 0.97 for Norway and the highest was 2.64 for Sweden, which may be in part because Sweden did not implement social distancing measures on the same scale as other countries. The study concludes that while large changes in Rt are observed, it is too early to tell whether the interventions put into place are sufficient to decrease Rt below 1.

More generally, population-level epidemic dynamics can be both observed and modelled [200]. Data and empirically determined biological mechanisms inform models, while models can be used to try to understand data and systems of interest or to make predictions about possible future dynamics, such as the estimation of capacity needs [220] or the comparison of predicted outcomes among prevention and control strategies [221,222]. Many current efforts to model Rt have led to tools that assist the visualization of estimates in real time or over recent intervals [223,224]. While these may be valuable resources, it is important to note that the estimates arise from models containing many assumptions and are dependent on the quality of the data they use, which varies widely by region.

3.3 Molecular Signatures and Transmission

Genetic variation in SARS-CoV-2 has been used to elucidate patterns over time and space. Mutations observed in individual SARS-CoV-2 genome sequences can be used to trace transmission patterns and have provided insights during outbreak investigations [15,159,160]. Similar mutations observed in several patients may indicate that the patients belong to the same transmission group. The tracking of SARS-CoV-2 mutations is recognized as an essential tool for controlling outbreaks that may facilitate tracing the paths of SARS-CoV-2’s spread [225]. Several studies used phylogenetic analysis to determine the source of local COVID-19 outbreaks in Connecticut (USA), [226], the New York City area (USA) [227], and Iceland [228]. There is an ongoing effort to collect SARS-CoV-2 genomes throughout the COVID-19 outbreak, and as of August 7, 2020, more than 78,000 genome sequences have been collected from patients. The sequencing data can be found at GISAID [229], NCBI [230], and COVID-19 data portal [231].

3.4 Factors Influencing Susceptibility

As COVID-19 has spread into communities around the globe, it has become clear that the risks associated with this disease are not equally shared by all individuals or all communities. Significant disparities in outcomes have led to interest in the demographic, biomedical, and social factors that influence COVID-19 severity. Untangling the factors influencing COVID-19 susceptibility is a complex undertaking. Among patients who are admitted to the hospital, outcomes have generally been poor, with rates of admission to the intensive care unit (ICU) upwards of 15% in both Wuhan, China and Italy [35,232,233]. However, hospitalization rates vary by location [234]. This variation may be influenced by demographic (e.g., average age in the area), medical (e.g., the prevalence of comorbid conditions such as diabetes), and social (e.g., income or healthcare availability) factors that vary geographically. Additionally, some of the same factors may influence an individual’s probability of exposure to SARS-CoV-2, their risk of developing a more serious case of COVID-19 that would require hospitalization, and their access to medical support. As a result, quantifying or comparing susceptibility among individuals, communities, or other groups requires consideration of a number of complex phenomena that intersect across many disciplines of research. In this section, the term “risk factors” is used to refer to variables that are statistically associated with more severe COVID-19 outcomes. Some are intrinsic characteristics that have been observed to carry an association with variation in outcomes, whereas others may be more functionally linked to the pathophysiology of COVID-19.

3.4.1 Patient Traits Associated with Increased Risk

Two traits that have been consistently associated with more severe COVID-19 outcomes are male sex and advanced age. In the United States, males and older individuals diagnosed with COVID-19 were found to be more likely to require hospitalization [235,236]. A retrospective study of hospitalized Chinese patients [36] found that a higher probability of mortality was associated with older age, and world-wide, population age structure has been found to be an important variable for explaining differences in outbreak severity [237]. The CFR for adults over 80 has been estimated upwards of 14% or even 20% [238]. Male sex has also been identified as a risk factor for severe COVID-19 outcomes, including death [239,240,241]. Early reports from China and Europe indicated that even though the case rates were similar across males and females, males were at elevated risk for hospital admission, ICU admission, and death [240], although data from some US states indicates more cases among females, potentially due to gender representation in care-taking professions [242]. In older age groups (e.g., age 60 and older), comparable absolute numbers of male and female cases actually suggests a higher rate of occurrence in males, due to increased skew in the sex ratio [240]. Current estimates based on worldwide data suggest that, compared to females, males may be 30% more likely to be hospitalized, 80% more likely to be admitted to the ICU, and 40% more likely to die as a result of COVID-19 [241]. There also may be a compounding effect of advanced age and male sex, with differences time to recovery worst for males over 60 years old relative to female members of their age cohort [243].

Both of these risk factors can be approached through the lens of biology. The biological basis for greater susceptibility with age is likely linked to the prevalence of extenuating health conditions such as heart failure or diabetes [238]. Several hypotheses have been proposed to account for differences in severity between males and females. For example, some evidence suggests that female sex hormones may be protective [240,242]. ACE2 expression in the kidneys of male mice was observed to be twice as high as that of females, and a regulatory effect of estradiol on ACE2 expression was demonstrated by removing the gonads and then supplementing with estradiol [242,244]. Other work in mice has shown an inverse association between mortality due to SARS-CoV and estradiol, suggesting a protective role for the sex hormone [242]. Similarly, evidence suggests that similar patterns might be found in other tissues: preliminary analysis suggested that male patients with aortic valve stenosis may show higher levels of ACE2 expression in the myocardium than females, although this pattern was not found in controls, and research has indicated that females may respond to lower doses of heart medications that act on a pathway shared with ACE2 (Renin angiotensin aldosterone system or RAAS) [240]. Additionally, several components of the immune response, including the inflammatory response, may differ in intensity and timing between males and females [242,244]. This hypothesis is supported by some preliminary evidence showing that female patients who recovered from severe COVID-19 had higher antibody titers than males [242]. Sex steroids can also bind to immune cell receptors to influence cytokine production [240]. Additionally, social factors may influence risks related to both age and sex: for example, older adults are more likely to live in care facilities, which have been a source for a large number of outbreaks [245], and gender roles may also influence exposure and/or susceptibility due to differences in care-taking and/or risky behaviors (e.g., caring for elder relatives and smoking, respectively) [240] among men and women (however, it should be noted that both transgender men and women are suspected to be at heightened risk [246].)

3.4.2 Comorbid Health Conditions

A number of pre-existing or comorbid conditions have repeatedly been identified as risk factors for more severe COVID-19 outcomes. Several underlying health conditions were identified at high prevalence among hospitalized patients, including obesity, diabetes, hypertension, lung disease, and cardiovascular disease [234]. Higher Sequential Organ Failure Assessment (SOFA) scores have been associated with a higher probability of mortality [36], and comorbid conditions such as cardiovascular and lung disease as well as obesity were also associated with an increased risk of hospitalization and death, even when correcting for age and sex [239]. Diabetes may increase the risk of lengthy hospitalization [247] or of death [247,248]. [249] and [250] discuss possible ways in which COVID-19 and diabetes may interact. Obesity also appears to be associated with higher risk of severe outcomes from SARS-CoV-2 [251,252]. Obesity is considered an underlying risk factor for other health problems, and the mechanism for its contributions to COVID-19 hospitalization or mortality is not yet clear [253]. Dementia and cancer were also associated with the risk of death in an analysis of a large number (more than 20,000) COVID-19 patients in the United Kingdom [239]. It should be noted that comorbid conditions are inextricably tied to age, as conditions tend to be accumulated over time, but that the prevalence of individual comorbidities or of population health overall can vary regionally [254]. Several comorbidities that are highly prevalent in older adults, such as COPD, hypertension, cardiovascular disease, and diabetes, have been associated with CFRs upwards of 8% compared to an estimate of 1.4% in people without comorbidities [238,255]. Therefore, both age and health are important considerations when predicting the impact of COVID-19 on a population [254]. However, other associations may exist, such as patients with sepsis having higher SOFA scores – in fact, SOFA was developed for the assessment of organ failure in the context of sepsis, and the acronym originally stood for Sepsis-Related Organ Failure Assessment [256,257]. Additionally, certain conditions are likely to be more prevalent under or exacerbated by social conditions, especially poverty, as is discussed further below.

3.4.3 Ancestry

A number of studies have suggested associations between individuals’ racial and ethnic backgrounds and their COVID-19 risk. In particular, Black Americans are consistently identified as carrying a higher burden of COVID-19 than white Americans [235,236], with differences in the rates of kidney complications from COVID-19 particularly pronounced [90]. Statistics from a number of cities indicate significant discrepancies between the proportion of COVID-19 cases and deaths in Black Americans relative to their representation in the general population [258]. In addition to Black Americans, disproportionate harm and mortality from COVID-19 has also been noted in Latino/Hispanic Americans and in Native American and Alaskan Native communities, including the Navajo nation [259,260,261,262,263]. In Brazil indigenous communities likewise carry an increased burden of COVID-19 [264]. In the United Kingdom, nonwhite ethnicity (principally Black or South Asian) was one of several factors found to be associated with a higher risk of death from COVID-19 [265].

From a genetic standpoint, it is highly unlikely that ancestry itself predisposes individuals to contracting COVID-19 or to experiencing severe COVID-19 outcomes. Examining human genetic diversity indicates variation over a geographic continuum, and that most human genetic variation is associated with the African continent [266]. African-Americans are also a more genetically diverse group relative to European-Americans, with a large number of rare alleles and a much smaller fraction of common alleles identified in African-Americans [267]. Therefore, the idea that African ancestry (at the continent level) might convey some sort of genetic risk for severe COVID-19 contrasts with what is known about worldwide human genetic diversity [268]. The possibility for genetic variants that confer some risk or some protection remains possible, but has not been widely explored, especially at a global level. Research in Beijing of a small number (n=80) hospitalized COVID-19 patients revealed an association between severe COVID-19 outcomes and homozygosity for an allele in the interferon-induced transmembrane protein 3 (IFITM3) gene, which was selected as a candidate because it was previously found to be associated with influenza outcomes in Chinese patients [269]. Genetic factors may also play a role in the risk of respiratory failure for COVID-19 [270,271,272]. However, genetic variants associated with outcomes within ancestral groups are far less surprising than genetic variants explaining outcomes between groups. Alleles in ACE2 and TMPRSS2 have been identified that vary in frequency among ancestral groups [273], but whether these variants are associated with COVID-19 susceptibility has not been explored.

Instead, examining patterns of COVID-19 susceptibility on a global scale that suggest that social factors are of primary importance in predicting mortality. Reports from several sub-Saharan African countries have indicated that the effects of the COVID-19 pandemic have been less severe than expected based on the outbreaks in China and Italy. In Kenya, for example, estimates of national prevalence based on testing blood donors for SARS-CoV-2 antibodies were consistent with 5% of Kenyan adults having recovered from COVID-19 [274]. This high seroprevalence of antibodies lies in sharp contrast to the low number of COVID-19 fatalities in Kenya, which at the time was 71 out of 2093 known cases [274]. Likewise, a serosurvey of health care workers in Blantyre City, Malawi reported an adjusted antibody prevalence of 12.3%, suggesting that the virus had been circulating more widely than thought and that the death rate was up eight times lower than models had predicted [275]. While several possible hypotheses for the apparent reduced impact of COVID-19 on the African continent are being explored, such as young demographics in many places [276], these reports present a stark contrast to the severity of COVID-19 in Americans and Europeans of African descent. Additionally, ethnic minorities in the United Kingdom also tend to be younger than white British living in the same areas, yet the burden of COVID-19 is still more serious for minorities, especially people of Black Caribbean ancestry, both in absolute numbers and when controlling for age and location [277]. Furthermore, the groups in the United States and United Kingdom that have been identified as carrying elevated COVID-19 burden, namely Black American, indigenous American, and Black and South Asian British, are quite distinct in their position on the human ancestral tree. What is shared across these groups is instead a history of disenfranchisement under colonialism and ongoing systematic racism. A large analysis of over 11,000 COVID-19 patients hospitalized in 92 hospitals across U.S. states revealed that Black patients were younger, more often female, more likely to be on Medicaid, more likely to have comorbidities, and came from neighborhoods identified as more economically deprived than white patients [278].i This study reported that when these factors were accounted for, the differences in mortality between Black and white patients were no longer significant. Thus, the current evidence suggests that the apparent correlations between ancestry and health outcomes must be examined in the appropriate social context. We explore the role these social factors have played in shaping the COVID-19 pandemic broadly in the Discussion.

4 Diagnostics

Identifying individuals who have contracted COVID-19 is crucial to slowing down the global pandemic. Given the high transmissibility of SARS-CoV-2, the development of reliable assays to detect SARS-CoV-2 infection even in asymptomatic carriers is vitally important. For instance, the deployment of wide-scale diagnostic testing followed by the isolation of infected people has been a key factor in South Korea’s successful strategy for controlling the spread of the virus. Following the first release of the genetic sequence of the virus by Chinese officials on January 10 2020, the first test was released about 13 days later [279]. A range of diagnostic approaches from a methodological standpoint are being or could possibly be developed.

There are two main classes of diagnostic tests: molecular tests, which can diagnose an active infection by identifying the presence of SARS-CoV-2, and serological tests, which can assess whether an individual was infected in the past via the presence or absence of antibodies against SARS-CoV-2. Molecular tests are essential for identifying individuals for treatment and alerting their contacts to quarantine and be alert for possible symptoms. While serological tests may be of interest to individuals who wish to confirm they were infected with SARS-CoV-2 in the past based on disease symptoms, their potential for false positives means that they are not currently recommended for this use. However, serological tests are critical at the population level from an epidemiological perspective, as they can be used to estimate the extent of the infection in a given area. Thus, they may be used to better understand the percent of infected cases that develop severe disease as well as to guide public health and economic decisions regarding resource allocation and counter-disease measures.

4.1 Molecular Tests

Molecular tests are used to identify distinct genomic subsequences of a viral molecule in a sample and thus to diagnose an active viral infection. This first requires identifying biospecimens that are likely to contain the virus in infected individuals and then acquiring these samples from the patient(s) to be tested. Common sources for a sample used in a molecular test include nasopharyngeal cavity samples, including throat wash and saliva [280], or stool samples [281]. Given a sample from a patient, molecular tests involve a number of steps to analyze a sample and produce results. When testing for RNA viruses like SARS-CoV-2, pre-processing is needed in order to create DNA, which can then be replicated during PCR, from the initial RNA sample. The DNA can then be amplified with PCR. Some tests use the results of the PCR to determine presence or absence of the pathogen, but in other cases, it may be necessary to sequence the amplified DNA. Sequencing requires an additional pre-processing step: library preparation. Library preparation is the process of preparing the sample for sequencing, typically by fragmenting the sequences and adding adapters [282]. In some cases, library preparation can involve other modifications of the sample, such as adding “barcoding” to identify a particular sample in the sequence data, which is useful for pooling samples from multiple sources. There are different reagents used for library preparation that are specific to identifying one or more target sections with PCR [283]. Sequential pattern matching is then used to identify unique subsequences of the virus that identify it in specific. If sufficient subsequences are found, the test is considered positive.

4.1.1 RT-PCR

Real-Time Polymerase Chain Reaction (RT-PCR) tests determine whether a target is present by measuring the rate of amplification during PCR compared to a standard. When the target is RNA, such as in the case of RNA viruses, the RNA must be converted into complementary DNA during pre-processing. There are different reagents used for library preparation that are specific to identifying one or more target sections with PCR [283]. The Drosten Lab, from Germany, was the first lab to establish and validate a diagnostic test to detect SARS-CoV-2. This test uses RT-PCR with reverse transcription [279] to detect several regions of the viral genome: the ORF1b of the RNA dependent RNA polymerase (RdRP), the Envelope protein gene (E), and the Nucleocapsid protein gene (N). In collaboration with several other labs in Europe and in China, the researchers confirmed the specificity of this test with respect to other coronaviruses against specimens from 297 patients infected with a broad range of respiratory agents. Specifically this test utilizes two probes against RdRP of which one is specific to SARS-CoV-2 [279]. Importantly, this assay did not give any false positive results.

4.1.2 qRT-PCR

Chinese researchers developed a quantitative real-time reverse transcription PCR (qRT-PCR) test to identify two gene regions of the viral genome, ORF1b and N [284]. Specifically, this assay was tested on samples coming from two COVID-19 patients, including a panel of positive and negative controls consisting of RNA extracted from several cultured viruses. The assay uses the N gene to screen patients, while the ORF1b gene region is used to confirm the infection [284]. In this case the test was designed to detect sequences conserved across sarbecoviruses, or viruses within the same subgenus as SARS-CoV-2. Considering that no other sarbecoviruses are currently known to infect humans, a positive test indicates that the patient is infected with SARS-CoV-2. However, this test is not able to discriminate the genetics of viruses within the sarbecovirus clade. dPCR

Digital PCR (dPCR) is a new generation of PCR technologies offering an alternative to traditional real-time quantitative PCR. In dPCR, a sample is partitioned into thousands of compartments, such as nanodroplets (droplet dPCR or ddPCR) or nanowells, and a PCR reaction takes place in each compartment. This leads to a digital read-out where each partition is either positive or negative for the nucleic acid sequence being tested for, allowing for much higher throughput. While dPCR equipment is not yet as common as that for RT-PCR, dPCR for DNA targets generally achieves higher sensitivity than other PCR technologies while maintaining high specificity, though sensitivity is slightly lower for RNA targets [285]. High sensitivity is particularly relevant for SARS-CoV-2 detection, since low viral load in clinical samples can lead to false negatives. Suo et al. performed a double-blind evaluation of ddPCR for SARS-CoV-2 detection on 57 samples–43 samples from suspected positive patients, and 14 from supposed convalescents–that had all tested negative for SARS-CoV-2 using RT-PCR. Despite the initial negative results, 33 out of 35 (94.3%) patients were later clinically confirmed positive. All of these individuals tested positive using ddPCR. Additionally, of 14 supposed convalescents who had received two consecutive negative RT-PCR tests, nine (64.2%) tested positive for SARS-CoV-2 using ddPCR. Two symptomatic patients tested negative with both RT-PCR and ddPCR, but were later clinically diagnosed positive, and 5 of the 14 suspected convalescents tested negative by ddPCR [286]. While not a complete head-to-head comparison to RT-PCR in all aspects– e.g. no samples testing positive using RT-PCR were evaluated by ddPCR– the study shows the potential of dPCR for viral detection in highly diluted samples. In a second study, Dong et al. [287] compared the results of qRT-PCR and ddPCR testing for SARS-CoV-2 in 194 samples, including 103 samples from suspected patients, 75 from contacts and close contacts, and 16 from suspected convalescents. Of the 103 suspected patient samples, 29 were reported as positive, 25 as negative, and 49 as suspected by qRT-PCR; all patients were later confirmed to be SARS-CoV-2 positive. Of the qRT-PCR negative or suspected samples, a total of 61 (17 negative and 44 suspected) were later confirmed to be positive by ddPCR, improving the overall detection rate among these patients from 28.2% to 87.4%. Of 75 patient samples from contacts and close contacts, 48 were tested negative with both methods and patients indeed remained healthy. Within the remaining 27 patient samples, 10 tested positive, 1 negative, 16 suspect by qRT-PCR. 15 out of 16 suspect samples and the negative test result were overturned by ddPCR, decreasing the rate of suspect cases from 21% to 1%. Importantly, all samples that tested positive using qRT-PCR also tested positive using ddPCR. Among the 16 convalescent patients, qRT-PCR identified 12 as positive, three as suspect, and one as negative, but RT-dPCR identified all 16 as positive. This evidence further indicates that the lower limit of detection made possible by ddPCR may be useful for identifying when COVID-19 patients are cleared of the virus. Overall, these studies suggest that dPCR is a promising tool for overcoming the problem of false-negative SARS-CoV-2 testing.

4.1.3 Pooled and Automated PCR Testing

Due to limited supplies and the need for more tests, several labs have found ways to pool or otherwise strategically design tests to increase throughput. The first such result came from Yelin et al. [288], who found they could pool up to 32 samples in a single qPCR run. This was followed by larger-scale pooling with slightly different methods [289]. Although these approaches are also PCR based, they allow for more rapid scaling and higher efficiency for testing than the initial PCR-based methods developed. CRISPR-based detection

Two CRISPR-associated nucleases, Cas12 and Cas13, have been used for nucleic acid detection. Multiple assays exploiting these nucleases have emerged as potential diagnostic tools for the rapid detection of SARS-CoV-2 genetic material and therefore SARS-CoV-2 infection.

The SHERLOCK method (Specific High-sensitivity Enzymatic Reporter unLOCKing) from Sherlock Biosciences relies on Cas13a to discriminate between inputs that differ by a single nucleotide at very low concentrations [290]. The target RNA is amplified by RT-RPA and T7 transcription, and the amplified product activates Cas13a. The nuclease then cleaves a reporter RNA, which liberates a fluorescent dye from a quencher. Several groups have used the SHERLOCK method to detect SARS-CoV-2 viral RNA. An early study reported that the method could detect 7.5 copies of viral RNA in all 10 replicates, 2.5 copies in 6 out of 10, and 1.25 copies in 2 out of 10 runs [291]. It also reported 100% specificity and sensitivity on 114 RNA samples from clinical respiratory samples (61 suspected cases, among which 52 were confirmed and 9 ruled out by metagenomic next-generation sequencing, 17 nCoV-/hCoV+ cases and 36 samples from healthy subjects), and a reaction turn-around time of 40 minutes. A separate study screened four designs of SHERLOCK and extensively tested the best-performing assay. They determined the limit of detection to be 10 copies/μl using both fluorescent and lateral flow detection [292]. Lateral flow test strips are simple to use and read, but there are limitations in terms of availability and cost per test. Another group therefore proposed the CREST protocol (Cas13-based, Rugged, Equitable, Scalable Testing), which uses a P51 cardboard fluorescence visualizer, powered by a 9V battery, for the detection of Cas13 activity instead of immunochromatography [293]. CREST can be run, from RNA sample to result, with no need for AC power or a dedicated facility, with minimal handling in approximately 2 hours. Testing was performed on 14 nasopharyngeal swabs. CREST picked up the same positives as the CDC-recommended TaqMan assay with the exception of one borderline sample that displayed low quality RNA.

The DETECTR method (DNA Endonuclease-Targeted CRISPR Trans Reporter) from Mammoth Biosciences involves purification of RNA extracted from patient specimens, amplification of extracted RNAs by loop-mediated amplification, a rapid, isothermal nucleic acid amplification technique, and application of their Cas12-based technology. In their assay, guide RNAs were designed to recognize portions of sequences corresponding to the SARS-CoV-2 genome, specifically the N2 and E regions [294]. In the presence of SARS-CoV-2 genetic material, sequence recognition by the guide RNAs results in double-stranded DNA cleavage by Cas12, as well as cleavage of a single-stranded DNA molecular beacon. The cleavage of this molecular beacon acts as a colorimetric reporter that is subsequently read out in a lateral flow assay and indicates the positive presence of SARS-CoV-2 genetic material and therefore SARS-CoV-2 infection. The 40-minute assay is considered positive if there is detection of both the E and N genes or presumptive positive if there is detection of either of them. The assay had 95% positive predictive agreement and 100% negative predictive agreement with the US Centers for Disease Control and Prevention SARS-CoV-2 real-time RT–PCR assay. The estimated limit of detection was 10 copies per μl reaction, versus 1 copy per μl reaction for the CDC assay. These results have been confirmed by other DETECTR approaches. Using RTRPA for amplification, another group detected 10 copies of synthetic SARS-CoV-2 RNA per μl of input within 60 minutes of RNA sample preparation in a proof-of-principle evaluation [295]. The DETECTR protocol was improved by combining RT-RPA and CRISPR-based detection in a one-pot reaction that incubates at a single temperature, and by using dual crRNAs (which increases sensitivity). This new assay, known as All-In-One Dual CRISPR-Cas12a (AIOD-CRISPR), detected 4.6 copies of SARS-CoV-2 RNA per μl of input in 40 minutes [296]. Another single-tube, constant-temperature approach using Cas12b instead of Cas12a achieved a detection limit of 5 copies/μl in 40-60 minutes [297]. It was also reported that that electric field gradients can be used to control and accelerate CRISPR assays by co-focusing Cas12-gRNA, reporters, and target [298]. The authors generated an appropriate electric field gradient using a selective ionic focusing technique known as isotachophoresis (ITP) implemented on a microfluidic chip. They also used ITP for automated purification of target RNA from raw nasopharyngeal swab samples. Combining this ITP purification with loop-mediated isothermal amplification, their ITP-enhanced assay to achieved detection of SARS-CoV-2 RNA (from raw sample to result) in 30 minutes.

There is an increasing body of evidence that CRISPR-based assays offer a practical solution for rapid, low-barrier testing in areas that are at greater risk of infection, such as airports and local community hospitals. In the largest study to date, DETECTR was compared to qRT-PCR on 378 patient samples [299]. The authors reported a 95% reproducibility. Both techniques were equally sensitive in detecting SARS-CoV-2. Lateral flow strips showed a 100% correlation to the high-throughput DETECTR assay. Importantly, DETECTR was 100% specific for SARS-CoV-2 and did not detect other human coronaviruses.

4.1.4 Limitation of Molecular Tests

Tests that identify SARS-CoV-2 using nucleic-acid-based technologies will identify only individuals with current infections and are not appropriate for identifying individuals who have recovered from a previous infection. Within this category, different types of tests have different limitations. For example, PCR-based test can be highly sensitive, but in high-throughput settings they can show several problems:

  1. False-negative responses, which can present a significant problem to large-scale testing. To reduce occurrence of false negatives, correct execution of the analysis is crucial [300].
  2. Uncertainty surrounding the SARS-CoV-2 viral shedding kinetics, which could affect the result of a test depending on when it was taken [300].
  3. Type of specimen, as it is not clear which clinical samples are best to detect the virus [300].
  4. Expensive machinery, which might be present in major hospitals and/or diagnostic centers but is often not available to smaller facilities [301].
  5. Timing of the test, which might take up to 4 days to give results [301].
  6. The availability of supplies for testing, including swabs and testing media, has been limited [302].
  7. Because the guide RNA can recognize other interspersed sequences on the patient’s genome, false positives and a loss of specificity can occur.

Similarly, in tests that use CRISPR, false positives can occur due to the specificity of the technique, as the guide RNA can recognize other interspersed sequences on the patient’s genome. As noted above, false negatives are a significant concern for several reason. Importantly, clinical reports indicate that it is imperative to exercise caution when interpreting the results of molecular tests for SARS-CoV-2 because negative results do not necessarily mean a patient is virus-free [303].

4.2 Serological Tests

Although diagnostic tests based on the detection of the genetic material can be quite sensitive, they cannot provide information about the extent of the disease over time. Most importantly, they would not work on a patient who has fully recovered from the virus at the time of sample collection. In this context, serological tests, which use serum to test for the presence of antibodies against SARS-CoV-2, are significantly more informative. Additionally, they can help scientists to understand why the disease has a different course among patients, as well as what strategy might work to manage the spread of the infection. Furthermore, serological tests hold significant interest at present because they can provide information relevant to advancing economic recovery and allowing reopenings. For instance, people that have developed antibodies can plausibly return to work prior to the others, based on (still-unproven) protective immunity [304]. On a related note, for some infectious agents an epidemic can be stopped from growing through herd immunity in which enough of the population is immune to infection through vaccination and/or prior experience with infection. A simple SIR model predicts that to achieve the required level of exposure for herd immunity to be effective, at least (1-(1/R0)) fraction of the population must be immune or, equivalently, less than (1/R0) fraction of the population susceptible [201]. However, for SARS-CoV-2 and COVID-19, because of the calculated R0 and mortality and the recorded per-region deaths and accumulated cases with the estimated factor of undetected cases, relying on herd immunity without vaccines and/or proven treatment options and/or strong non-pharmaceutical measures of prevention and control would likely result in a significant loss of life.

4.2.1 Sustained Immunity to COVID-19

In the process of mounting a response to a viral pathogen, the immune system produces antibodies specific to the pathogen. Understanding the acquisition and retention of antibodies is important both to the diagnosis of prior infections that are no longer active and to the development of vaccines. The two immunoglobulin classes most pertinent to these areas of interest are immunoglobulin M (IgM), which are the first antibodies produced in response to an infection, and immunoglobulin G (IgG), which are the most abundant antibodies found in the blood. Following SARS infection, IgM and IgG antibodies were detected in the second week post-infection. IgM titers peaked by the first month post-infection, and then declined to undetectable levels after day 180. IgG titers peaked by day 60, and persisted in all donors through the two-year duration of study [305]. A two-year longitudinal study following convalesced SARS patients with a mean age of 29 found that IgG antibodies were detectable in all 56 patients surveyed for at least 16 months, and remained detectable in all but 4 (11.8%) of patients through the full two-year study period [306]. The persistence of antibodies to SARS-CoV-2 remains under investigation. Circulating antibody titers to other coronaviruses have been reported to decline significantly after 1 year [307]. Autopsies of lymph nodes and spleens from severe acute COVID-19 patients showed loss of T follicular helper cells and germinal centers may explain some of the impaired development of antibody responses [308]. An early study (initially released on medRxiv on February 25, 2020) presented a chemiluminescence immunoassay to a synthetic peptide derived from the amino acid sequence of the SARS_CoV-2 S protein [309]. This method was highly specific to SARS-CoV-2 and detected IgM in 57.2% and IgG in 71.4% and 57.2% of sera samples from 276 confirmed COVID-19 patients. They reported that they could detect IgG within two days of the onset of fever and were not able to detect IgM any earlier, a pattern they compared to findings in MERS.

4.2.2 Current Approaches

Several countries are now focused on implementing antibody tests, and in the United States, the FDA recently approved a serological test by Cellex for use under emergency conditions [310]. Specifically, the Cellex qSARS-CoV-2 IgG/IgM Rapid Test is a chromatographic immunoassay designed to qualitatively detect IgM and IgG antibodies against SARS-CoV-2 in the plasma of patients (blood sample) suspected to have developed the infection [310]. Such tests allow for the progress of the viral disease to be understood, as IgM are the first antibodies produced by the body and indicate that the infection is active. Once the body has responded to the infection, IgG are produced and gradually replace IgM, indicating that the body has developed immunogenic memory [311]. The test cassette contains a pad of SARS-CoV-2 antigens and a nitrocellulose strip with lines for each of IgG and IgM, as well as a control (goat IgG) [310]. In a specimen that contains antibodies against the SARS-CoV-2 antigen, the antibodies will bind to the strip and be captured by the IgM and/or IgG line(s), resulting in a change of color [310]. With this particular assay results can be read within 15-20 minutes [310]. Other research groups, such as the Krammer lab of the Icahn School of Medicine at Mount Sinai proposed an ELISA test that detects IgG and IgM that react against the receptor binding domain (RBD) of the spike proteins (S) of the virus [312]. The authors are now working to get the assay into clinical use [313].

4.2.3 Limitations of Serological Tests

Importantly, false-positives can occur due to the cross-reactivity with other antibodies according to the clinical condition of the patient [310]. Therefore, this test should be used in combination with RNA detection tests [310]. Due to the long incubation times and delayed immune responses of infected patients, serological tests are insufficiently sensitive for a diagnosis in the early stages of an infection. The limitations due to timing make serological tests far less useful for enabling test-and-trace strategies.

4.3 Possible Alternatives to Current Practices for Identifying Active Cases

Clinical symptoms are too similar to other types of pneumonia to be sufficient as a sole diagnostics criterion. In addition, as noted above, identifying asymptomatic cases is critical. Even among mildly symptomatic patients, a predictive model based on clinical symptoms had a sensitivity of only 56% and a specificity of 91% [314]. More problematic is that clinical symptom-based tests are only able to identify already symptomatic cases, not presymptomatic or asymptomatic cases. They may still be important for clinical practice, and for reducing tests needed for patients deemed unlikely to have COVID-19.

X-ray diagnostics have been reported to have high sensitivity but low specificity in some studies [315]. Other studies have shown that specificity varies between radiologists [316], though the sensitivity reported here was lower than that published in the previous paper. However, preliminary machine-learning results have shown far higher sensitivity and specificity from analyzing chest X-rays than was possible with clinical examination [317]. X-ray tests with machine learning can potentially detect asymptomatic or presymptomatic infections that show lung manifestations. This approach would still not recognize entirely asymptomatic cases. Given the above, the widespread use of X-ray tests on otherwise healthy adults is likely inadvisable.

4.4 Challenges to Diagnostic Approaches

4.4.1 Limitations to Implementation of Large-Scale Testing

More information to follow.

4.4.2 Strategies and Considerations for Determining Whom to Test

Currently, Coronavirus tests are limited to people that are in danger of serious illness [318]. Specifically, the individuals at risk include:

However, this method of testing administration does not detect a high proportion of infections and does not allow for test-and-trace methods to be used. Individuals who are asymptomatic (i.e. potential spreaders) and individuals who are able to recover at home are therefore often unaware of their status. For instance, a recent study from Imperial College estimates that in Italy the true number of infections is around 5.9 million in a total population ~60 million, compared to the 70,000 detected as of March 28th [219]. Another analysis, which examined New York state, indicated that as of May 2020, approximately 300,000 cases had been reported in a total population of approximately 20 million, corresponding to ~1.5% of the population, but ~12% of individuals sampled statewide were estimated as positive through antibody tests (along with indications of spatial heterogeneity at higher resolution) [319].

5 Therapeutics and Prophylactics

Given the worldwide spread of COVID-19, the development of prophylactic and therapeutic interventions holds valuable potential for controlling the impact of the disease. Such interventions fall into two categories: therapeutics, which are meant to treat existing disease, and prophylactics, which are meant to prevent a disease from occurring. For infectious diseases such as COVID-19, the main prophylactics of interest are vaccines. Several types of vaccines are currently under development, as detailed below. While vaccines would be expected to save the largest number of lives by bolstering the immune response of the at-risk population broadly to the virus, which would result in a lower rate of infection, the vaccine development process is long, and they fail to provide immediate prophylactic protection or treat ongoing infections [320]. Thus, there is also an immediate need for treatments that palliate symptoms to avoid the most severe outcomes from infection. Therapeutics can generally either be considered for the treatment and reduction of symptoms in order to reduce the severity and risks associated with an active infection or as a more direct way of targeting the virus (e.g., antivirals) to inhibit the development of the virus once an individual is infected. In the context of COVID-19, there is often uncertainty surrounding the exact mechanism of action, as most therapies have secondary or off-target effects. Thus, in this section, we describe some of the early treatments considered and classify both therapeutics and prophylactics according to their biological properties, specifically whether they are biologics (produced from components of organisms) or small molecules. Biologics include antibodies, interferons, and vaccines, while small molecules include drugs targeted at viral particles, drugs targeted at host proteins, and broad-based pharmaceuticals. Broad-based pharmaceuticals include the much-discussed drugs hydroxychloroquine and chloroquine. We also describe nutraceuticals, which are dietary supplement interventions that may prime an individual’s immune system to lessen the impact of RNA virus infections [321,322]. In the following sections, we critically appraise the literature and clinical trials (Figure 3) surrounding the repurposing of existing treatments and development of novel approaches for the prevention, mitigation, and treatment of coronavirus infections.

Figure 3: COVID-19 clinical trials. There are 5,257 COVID-19 clinical trials and 157 trials with results as of September 2, 2020. The recruitment statuses and trial phases are shown only for trials in which the status or phase is recorded. The study types include only types used in at least five trials. The common interventions are all interventions used in at least ten trials. Combinations of interventions, such as Hydroxychloroquine + Azithromycin, are tallied separately from the individual interventions. Trials data are from the University of Oxford Evidence-Based Medicine Data Lab’s COVID-19 TrialsTracker [323].

5.1 Small Molecule Drugs

5.1.1 Small Molecule Drugs Targeting SARS-CoV-2

The replication cycle of a virus within an epithelial host cell includes six basic steps that can be summarized as follows: i) attachment of the virus to the host cell; ii) penetration by endocytosis; iii) uncoating, classically defined as the release of viral contents into the host cell; iv) biosynthesis, during which the viral genetic material enters the nucleus where it gets replicated; v) assembly, where viral proteins are translated and new viral particles are assembled; vi) release, when the new viruses are released into the extracellular environment [324]. Antiviral drugs do not kill the virus, rather they inhibit its amplification by impairing one of these steps. Nowadays, many of these drugs act during the biosynthesis step in order to inhibit the replication of viral genetic material. In contrast to DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depends on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication [325,326]. As noted above, even if a drug is meant to target the virus, it can also impact other processes in the host. Nucleoside and Nucleotide Analogs Favipiravir

Favipiravir (Avigan) was discovered by Toyama Chemical Co., Ltd. [327]. The drug was found to effective at blocking viral amplification in several influenza subtypes as well as other RNA viruses, such as Flaviviridae and Picornaviridae, through a reduction in plaque formation [328] and viral replication in MDCK cells [329]. Furthermore, inoculation of mice with favipiravir was shown to increase survival [328,329]. In 2014, the drug was approved in Japan for the treatment of patients infected with influenza that was resistant to conventional treatments like neuraminidase inhibitors [330]. Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) acts as a purine and purine nucleoside analogue that inhibits viral RNA polymerase in a dose-dependent manner across a range of RNA viruses, including Influenza virus [331,332,333,334,335]. Nucleotide/side are the natural building blocks for RNA synthesis. Because of this, modifications to these nucleotides/sides can disrupt key processes including replication [336]. Biochemical experiments showed that favipiravir was recognized as a purine nucleoside analogue and incorporated into the viral RNA template. A single incorporation does not influence RNA transcription; however, multiple events of incorporation lead to the arrest of RNA synthesis [337]. Evidence for T-705 inhibiting viral RNA polymerase are based on time-of-drug addition studies that found that viral loads were reduced with the addition of Favipiravir in early times post-infection [331,334,335].

The effectiveness of favipiravir for treating patients with COVID-19 is currently under investigation. An open-label, nonrandomized, before-after controlled study was recently conducted [338]. The study included 80 COVID-19 patients (35 treated with favipiravir, 45 control) from the isolation ward of the National Clinical Research Center for Infectious Diseases (The Third People’s Hospital of Shenzhen), Shenzhen, China. The patients in the control group were treated with other antivirals, such as lopinavir and ritonavir. Treatment was applied on days 2-14; treatment stopped either when viral clearance was confirmed or at day 14. The efficacy of the treatment was measured by 1) the time until viral clearance using Kaplan-Meier survival curves, and 2) the improvement rate of chest computed tomography (CT) scans on day 14 after treatment. The study found that favipiravir increased the speed of recovery (measured as viral clearance from the patient by RT-PCR) to 4 days compared to 11 days using other antivirals such as lopinavir and ritonavir. Additionally, the lung CT scans of patients treated with favipiravir showed significantly higher improvement rates (91%) on day 14 compared to control patients (62%). However, there were adverse side effects in 4 (11%) favipiravir-treated patients and 25 (56%) control patients. The adverse side effects included: diarrhea, vomiting, nausea, rash, and liver and kidney injury. Overall, despite the study reporting clinical improvement in favipiravir-treated patients, due to some issues with study design, it cannot be determined whether treatment with favipiravir had an effect or whether these patients would have recovered regardless of any treatment. For example, although there were significant differences between the two treatment groups, follow-up analysis is necessary due to the small sample size. The selection of patients did not take into consideration important factors such as previous clinical conditions or sex, and there was no age categorization. The study was neither randomized nor blinded, and the baseline control group was another antiviral instead of a placebo. Therefore, randomized controlled trials are still required. Remdesivir

Remdesivir (GS-5734) is an intravenous antiviral that was developed by Gilead Sciences to treat Ebola Virus Disease. At the outset of the COVID-19 pandemic, it did not have any have any FDA-approved use. However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients [339]. The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 [340,341,342,343]. Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination [344,345,346]. Although it was developed against Ebola, it also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV in cell culture assays with submicromolar IC50s [347]. It also inhibits SARS-CoV-2, showing synergy with chloroquine in vitro [346].

In addition to the previous work showing remdesivir to be an effective treatment for viral pathogens such as SARS-CoV and MERS-CoV in cultured cells and animal models, a recent study found that administration of remdesivir to non-human primate models resulted in 100% protection against infection by the Ebola virus. Although a clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against Ebola, two antibody preparations were found to be more effective, and remdesivir was not pursued [348]. Remdesivir has also been reported to inhibit SARS-CoV-2 infection in a human cell line sensitive to the virus [346]. The effectiveness of remdesivir for treating patients with COVID-19 is currently under investigation. Remdesivir was first used on some COVID-19 patients under compassionate use guidelines [349,350]. All were in late stages of COVID-19 infection, and these reports were inconclusive about the drug’s efficacy. Gilead Sciences, the maker of remdesivir, led a recent publication that reported outcomes for compassionate use of the drug in 61 patients hospitalized with confirmed COVID-19. Here, 200mg of remdesivir was administered intravenously on day 1, followed by a further 100mg/day for 9 days [343]. There were significant issues with the study design or lack thereof. There was no randomized control group. The inclusion criteria were variable: some patients only required low doses of oxygen, others required ventilation. The study included many sites, potentially with variable inclusion criteria and treatment protocols. Patients analyzed had mixed demographics. There was a short follow-up period of investigation. Some patients worsened, some patients died, and eight were excluded from the analysis mainly due to missing post-baseline information; thus, their health is unaccounted for. Therefore, even though the study reported clinical improvement in 68% of the 53 patients ultimately evaluated, due to the significant issues with study design, it could not be determined whether treatment with remdesivir had an effect or whether these patients would have recovered regardless of treatment. Another study comparing 5 and 10 day treatment regimens had similar results but was also limited because of the lack of a placebo control [352]. The study did not alter our understanding of the efficacy of remdesivir in treating COVID-19, but the encouraging results provided motivation for placebo-controlled studies.

Remdesivir was later tested in a double-blind placebo-controlled phase 3 clinical trial performed at 60 trial sites, 45 of which were in the United states. The trial recruited 1,063 patients and randomly assigned them to placebo treatment or treatment with remdesivir. The treatment was 200 mg on day 1, followed by 100 mg on days 2 through 10. Data was analyzed from 1,059 patients (538 assigned to remdesivir and 521 to placebo). The two groups were well matched demographically and clinically at baseline. Those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Though mortality was lower in the remdesivir group, it was not significant. Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). The median time to recovery in patients in the subgroup receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) could not be established which may indicate that the follow up time was too short for this group (272 patients). Largely on the results of this trial, the FDA issued the Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients. Clinical trials are currently underway to evaluate the use of remdesivir to treat COVID-19 patients at both early and late stages of infection and in combinations with other drugs (Figure 3). These trials include [346,353,354,355,356].

In summary, remdesivir is a first in class to receive FDA approval, currently as an Emergency Use Authorization. It establishes proof of principle that drugs targeting the virus can benefit patients. It also shows proof of principle that the virus can be targeted at the level of viral replication, since remdesivir targets the viral RNA polymerase at high potency. Moreover, one of the most successful therapies for viral diseases is to target the viral replication machinery, which are typically virally encoded polymerases. Small molecule drugs targeting viral polymerases are the backbones of treatments for other viral diseases including HIV and Herpes. Note that the HIV and Herpes polymerases are a reverse transcriptase and a DNA polymerase, respectively, whereas SARS-CoV-2 encodes an RNA-dependent RNA polymerase, so most of the commonly used polymerase inhibitors are not likely to be active against SARS-CoV-2. In clinical use, polymerase inhibitors show short term benefits for HIV patients but for long term benefits they must be part of combination regimens. They are typically combined with protease inhibitors, integrase inhibitors and even other polymerase inhibitors. Additional clinical trials of remdesivir on different patient pools and in combination with other therapies will refine its use in the clinic. Protease Inhibitors

Several studies showed that viral proteases play an important role in the life cycle of viruses, including coronaviruses, by modulating the cleavage of viral polyprotein precursors [357]. Several FDA-approved drugs target proteases, including lopinavir and ritonavir for HIV infection and simeprevir for hepatitis C virus infection. In particular, serine protease inhibitors were suggested for the treatment of SARS and MERS viruses [358]. Recently, a study [65] suggested that camostat mesylate, an FDA-approved protease inhibitor (PI) could block the entry of SARS-CoV-2 into lung cells in vitro. However, to test the efficacy of PIs in patients, randomized clinical trials will need to be conducted on patients and healthy volunteers. Investigation of possible PIs that work against SARS-CoV-2 has been driven by computational predictions, leading to the computer-aided design of a Michael acceptor inhibitor, N3, to target a protease critical to SARS-CoV-2 replication.

Discovery of the N3 mechanism arose from interest in the two polyproteins encoded by the SARS-CoV-2 replicase gene, pp1a and pp1ab, that are critical for viral replication and transcription [359]. These polyproteins must undergo proteolytic processing. This processing is usually conducted by Mpro, a 33.8-kilodaltons (kDa) SARS-CoV-2 protease that is therefore fundamental to viral replication and transcription. N3 was designed computationally [360] to bind in the substrate binding pocket of the Mpro protease of SARS-like coronaviruses [361], therefore inhibiting proteolytic processing. Subsequently, the structure of N3-bound SARS-CoV-2 Mpro was solved [359], confirming the computational prediction. N3 was tested in vitro on SARS-CoV-2-infected Vero cells and was found to inhibit SARS-CoV-2 [359].

Although N3 is a strong inhibitor of SARS-CoV-2 in vitro, its safety and efficacy have to be tested in healthy volunteers and patients. After the design and confirmation of N3 as a highly potent Michael acceptor inhibitor and the identification of Mpro structure [359,362], 10,000 compounds were screened for their in vitro anti-Mpro activity. The six leads that were identified were ebselen, disulfiram, tideglusib, carmofur, and PX-12. In vitro analysis revealed that Ebselen had the strongest potency in reducing the viral load in SARS-CoV-2-infected Vero cells [359]. Ebselen is an organoselenium compound with anti-inflammatory and antioxidant properties [363] It has been proposed as a possible treatment for conditions ranging from bipolar disorder to diabetes to heart disease [363], and a preliminary investigation of ebselen as a treatment for noise-induced hearing loss provided promising reports of its safety [364]. For COVID-19, the NSP5 in SARS-CoV-2 contains a cysteine at the active site of Mpro, and ebselen is able to inactivate the protease by bonding covalently with this cysteine to form a selenosulfide [363,365]. Interestingly there has been some argument that selenium deficiency may be associated with more severe COVID-19 outcomes [366,367,368], possibly indicating that its antioxidative properties are protective [365]. On the other hand, ebselen and the other compounds identified are likely to be promiscuous binders, which could diminish their therapeutic potential [359]. While there is clear computational and in vitro support for ebselen’s potential as a COVID-19 therapeutic, results from clinical trials are not yet available for this compound.

In summary, N3 is a computationally designed molecule that inhibits the viral transcription through inhibiting Mpro. Ebselen is both a strong Mpro inhibitor and strong inhibitor of viral replication in vitro that was found to reduce SARS-CoV-2 viral load even more effectively than N3. Ebselen is a very promising compound since its safety has been demonstrated in other indications. However, Ebselen is likely a false positive since it is a promiscuous compound that can have many targets [369]. Therefore, compounds with higher specificity may be required to effectively translate to clinical trials.

5.1.2 Drugs Targeting Host Proteins

When a virus enters a host, the host becomes the virus’ environment. Therefore, the state of the host can also influence whether a virus is able to replicate and spread. Traditionally, viral targets have been favored because altering host processes is likely to be less specific than targeting the virus directly [370]. On the other hand, targeting the host offers potential for a complementary strategy to anti-virals that could broadly limit the ability of viruses to replicate [370]. As a result, therapeutic approaches that target host proteins have become an area of interest for SARS-CoV-2. Viral entry receptors in particular have emerged as a target of interest. Entry of SARS-CoV-2 into the cell depends on the ACE2 receptor and the enzyme encoded by TMPRSS2 [65]. In principle, drugs that reduce the expression of these proteins or sterically hinder viral interactions with them might reduce viral entry into cells. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are among the most commonly prescribed medications [371,372]. In the United States, for example, they are prescribed well over 100,000,000 times annually. Data from some animal models suggest that several, but not all, ACE inhibitors and several ARBs increase ACE2 expression in the cells of some organs [373]. Clinical studies have not established whether plasma ACE2 expression is increased in humans treated with these medications [374]. While randomized clinical trials are ongoing, a variety of observational studies have examined the relationship between exposure to ACE inhibitors or ARBs and outcomes in patients with COVID-19. An observational study of the association of ACE inhibitor or ARB exposure on outcomes in COVID-19 was retracted from the New England Journal of Medicine [375]. Moreover, because observational studies are subject to confounding, randomized controlled trials are the standard means of assessing the effects of medications, and the findings of the various observational studies bearing on this topic cannot be interpreted as indicating a protective effect of the drug [376,377]. Clinical trials testing the effects of ACE inhibitors or ARBs on COVID-19 outcomes are ongoing [378,379,380,381,382,383]. These studies of randomized intervention will provide important data for understanding whether exposure to ACEis or ARBs is associated with COVID-19 outcomes. Additional information about ACE2, observational studies of ACE inhibitors and ARBs in COVID-19, and clinical trials on this topic have been summarized [384].

5.1.3 Broad-Spectrum Pharmaceuticals

Due to the urgent nature of the COVID-19 pandemic, many of the pharmaceutical agents that have been widely publicized as having possible therapeutic or prophylactic effects are broad-spectrum pharmaceuticals. These treatments, which in most cases pre-date the COVID-19 pandemic, are not specifically targeted at the virus itself or at the host receptors it relies on, but rather induce broad shifts in host biology that are hypothesized as potential inhibitors of the virus. In most cases, interest in particular candidate medications or nutraceuticals arises because they are already available for other purposes. However, the fact that the targets of these agents are non-specific means that the mechanism of action can sound relevant to COVID-19 without a therapeutic or prophylactic effect being observed in rigorous testing. This category of drugs has received significant attention from the media and general public. Hydroxychloroquine and Chloroquine

Chloroquine (CQ) and hydroxychloroquine (HCQ) are lysosomotropic agents, meaning they are weak bases that can pass through the plasma membrane. Both drugs increase cellular pH by accumulating in their protonated form inside lysosomes [385,386]. This shift in pH inhibits the breakdown of proteins and peptides by the lysosomes during the process of proteolysis [386]. A number of mechanisms have been proposed through which these drugs could influence the immune response to pathogen challenge. For example, CQ/HCQ can interfere with digestion of antigens within the lysosome and inhibit CD4 T-cell stimulation while promoting the stimulation of CD8 T-cells [386]. CQ/HCQ can also decrease the production of certain key cytokines involved in the immune response including IL-6 and inhibit the stimulation of toll-like receptors (TLR) and TLR signaling [386]. The drugs also have anti-inflammatory and photoprotective effects and may also affect rates of cell death, blood clotting, glucose tolerance, and cholesterol levels [386].

Interest in CQ and HCQ for treating COVID-19 was catalyzed by a mechanism observed in in vitro studies of both SARS-CoV and SARS-CoV-2. In one study, CQ inhibited viral entry of SARS-CoV into Vero E6 cells, a cell line derived from the epithelial cells of an African green monkey kidney, through the elevation of endosomal pH and the terminal glycosylation of angiotensin-converting enzyme 2 (ACE2), which is the cellular entry receptor [387]. Increased pH within the cell, as discussed above, inhibits proteolysis, and terminal glycosylation of ACE2 is thought to interfere with virus-receptor binding. An in vitro study of SARS-CoV-2 infection of Vero cells, a line from which the Vero E6 clone has been separated since 1968, found both HCQ and CQ to be effective in inhibiting viral replication, with HCQ being more potent [388]. Additionally, an early case study of three COVID-19 patients reported the presence of antiphospholipid antibodies in all three patients [97]. Antiphospholipid antibodies are central to the diagnosis of the antiphospholipid syndrome, a disorder that HCQ has often been used to treat [389,390,391]. Together, these studies triggered initial enthusiasm about the therapeutic potential for HCQ and CQ against COVID-19. HCQ/CQ has been proposed both as a treatment for COVID-19 and a prophylaxis against SARS-CoV-2 exposure. HCQ/CQ are sometimes administered with azithromycin (AZ) and/or zinc supplementation. Therapeutic Administration of HCQ/CQ

The initial study evaluating HCQ as a treatment for COVID-19 patients was published on March 20, 2020 by Gautret et al. This non-randomized, non-blinded, non-placebo clinical trial compared HCQ to standard of care in 42 hospitalized patients in southern France [392]. They reported that patients who received HCQ showed higher rates of virological clearance by nasopharyngeal swab on Days 3-6 when compared to standard care. This study also treated six patients with both HCQ + AZ and found this combination therapy to be more effective than HCQ alone. However, the design and analyses used showed weaknesses that severely limit interpretability of results, including the lack of randomization, lack of blinding, lack of placebo, lack of Intention-To-Treat analysis, lack of correction for sequential multiple comparisons, trial arms entirely confounded by hospital, false negatives in outcome measurements, lack of trial pre-registration, and small sample size. Two of these weaknesses are due to inappropriate data analysis and can therefore be corrected post hoc by recalculating the p-values (lack of Intention-To-Treat analysis and multiple comparisons.) However, all other weaknesses are fundamental design flaws and cannot be corrected for. Thus, conclusions cannot be generalized outside of the study. The International Society of Antimicrobial Chemotherapy, the scientific organization that publishes International Journal of Antimicrobial Agents where the article appeared, has announced that the article does not meet its expected standard for publications [393], although it has not been officially retracted. Because of the preliminary data presented in this study, the use of HCQ in COVID-19 treatment has subsequently been explored by other researchers. About one week later, a follow-up case study reported that 11 consecutive patients were treated with HCQ + AZ using the same dosing regimen [394]. One patient died, two were transferred to the ICU, and one developed a prolonged QT interval, leading to discontinuation of HCQ + AZ. As in the Gautret et al. study, the outcome assessed was virological clearance at Day 6 post-treatment, as measured in nasopharyngeal swabs. Of the ten living patients on Day 6, eight remained positive for SARS-CoV-2 RNA. Like in the original study, interpretability was severely limited by lack of comparison group and the small sample size. However, these results stand in contrast to the claims by Gautret et al. that all six patients treated with HCQ + AZ tested negative for SARS-CoV-2 RNA by Day 6 post-treatment. This case study illustrated the need for further investigation using robust study design before the original proposed benefits of HCQ could be widely accepted.

On April 10, 2020, a randomized, non-placebo trial of 62 COVID-19 patients at the Renmin Hospital of Wuhan University was released [395]. This study investigated whether HCQ decreased time to fever break or time to cough relief when compared to standard of care [395]. This trial found HCQ decreased both average time to fever break and average time to cough relief, defined as mild or no cough. While this study improved on some of the methodological flaws in Gautret et al. by randomizing patients, it also had several flaws in trial design and data analysis that prevent generalization of the results. These weaknesses include the lack of placebo, lack of correction for multiple primary outcomes, inappropriate choice of outcomes, lack of sufficient detail to understand analysis, drastic disparities between pre-registration and published protocol, and small sample size. The choice of outcomes may be inappropriate as both fevers and cough may break periodically without resolution of illness. Additionally, for these outcomes, the authors reported that 23 of 62 patients did not have a fever and 25 of 62 patients did not have a cough at the start of the study, but the authors failed to describe how these patients were included in a study assessing time to fever break and time to cough relief. It is important to note here that the authors claimed “neither the research performers nor the patients were aware of the treatment assignments.” This blinding seems impossible in a non-placebo trial because at the very least, providers would know whether they were administering a medication or not, and this knowledge could lead to systematic differences in the administration of care. Correction for multiple primary outcomes can be adjusted post hoc by recalculating p-values, but all of the other issues were design and statistical weaknesses that cannot be corrected for. Additionally, the observation of drastic disparities between pre-registration and published protocol could indicate p-hacking. The design limitations mean that the conclusions cannot be generalized outside of the study. A second randomized trial, conducted by the Shanghai Public Health Clinical Center, analyzed whether HCQ increased rates of virological clearance at day 7 in respiratory pharyngeal swabs compared to standard care [396]. This trial was published in Chinese along with an abstract in English, and only the English abstract was read and interpreted for this review. The trial found comparable outcomes in virological clearance rate, time to virological clearance, and time to body temperature normalization between the treatment and control groups. A known weakness is small sample size, with only 30 patients enrolled and 15 in each arm. This problem suggests the study is underpowered to detect potentially useful differences and precludes interpretation of results. Additionally, because only the abstract could be read, other design and analysis issues could be present. Thus, though these studies added randomization to their assessment of HCQ, their conclusions should be interpreted very cautiously. These two studies assessed different outcomes and reached differing conclusions about the efficacy of HCQ for treating COVID-19; the designs of both studies, especially with respect to sample size, meant that no general conclusions can be made about the efficacy of the drug.

Several widely reported studies on HCQ have issues with data integrity and/or provenance. A Letter to the Editor published in BioScience Trends on March 16, 2020 claimed that numerous clinical trials have shown that HCQ is superior to control treatment in inhibiting the exacerbation of COVID-19 pneumonia [397]. This letter has been cited by numerous primary literature, review articles, and media alike [398,399]. However, the letter referred to 15 pre-registration identifiers from the Chinese Clinical Trial Registry. When these identifiers are followed back to the registry, most trials claim they are not yet recruiting patients or are currently recruiting patients. For all of these 15 identifiers, no data uploads or links to publications could be located on the pre-registrations. At the very least, the lack of availability of the primary data means the claim that HCQ is efficacious against COVID-19 pneumonia cannot be verified. Similarly, a recent multinational registry analysis [400] analyzed the efficacy of CQ and HCQ with and without a macrolide, which is a class of antibiotics that includes Azithromycin, for the treatment of COVID-19. The study observed 96032 patients split into a control and four treatment conditions (CQ with and without a macrolide; HCQ with and without a macrolide). They concluded that treatment with CQ and HCQ was associated with increased risk of de novo ventricular arrhythmia during hospitalization. However, this study has since been retracted by The Lancet due to an inability to validate the data used [401]. These studies demonstrate that increased skepticism in evaluation of the HCQ/CQ and COVID-19 literature may be warranted, possible because of the significant attention HCQ and CQ have received as possible treatments for COVID-19 and the politicization of these drugs.

Despite the fact that the study suggesting that CQ/HCQ increased risk of ventricular arrhythmia in COVID-19 patients has now been retracted, previous studies have identified risks with HCQ/CQ. A patient with systemic lupus erythematosus developed a prolonged QT interval that was likely exacerbated by use of HCQ in combination with renal failure [402]. A prolonged QT interval is associated with ventricular arrhythmia [403]. Furthermore, a separate study [404] investigated the safety associated with the use of HCQ with and without macrolides between 2000 and 2020. The study involved 900,000 cases treated with HCQ and 300,000 cases treated with HCQ + AZ. The results indicated that short-term use of HCQ was not associated with additional risk, but that HCQ + AZ was associated with an enhanced risk of cardiovascular complications (15-20% increased risk of chest pain) and a two-fold increased risk of mortality. Therefore, whether studies utilize HCQ alone or HCQ in combination with a macrolide may be an important consideration in assessing risk. As results from initial investigations of these drug combinations have emerged, concerns about the efficacy and risks of treating COVID-19 with HCQ and CQ has led to the removal of CQ/HCQ from standard of care practices in several countries [405,406]. As of May 25, 2020, WHO had suspended administration of HCQ as part of the worldwide Solidarity Trial [407].

As additional research has emerged, HCQ/CQ have increasingly been demonstrated to be ineffective against COVID-19 and to carry a number of significant side effects. A randomized, open-label, non-placebo trial of 150 COVID-19 patients was conducted in parallel at 16 government-designated COVID-19 centers in China to assess the safety and efficacy of HCQ [408]. The trial compared treatment with HCQ in conjunction with standard of care (SOC) to SOC alone in 150 infected patients who were assigned randomly to the two groups (75 per group). The primary endpoint of the study was the negative conversion rate of SARS-CoV-2 in 28 days, and the investigators found no difference in this parameter between the groups. The secondary endpoints were an amelioration of the symptoms of the disease such as axillary temperature ≤36.6°C, SpO2 >94% on room air, and disappearance of symptoms like shortness of breath, cough, and sore throat. The median time to symptom alleviation was similar across different conditions (19 days in HCQ+SOC vs. 21 days in SOC). Additionally, 30% of the patients receiving SOC+HCQ reported adverse outcomes compared to 8.8% of patients receiving only SOC, with the most common adverse outcome in the SOC+HCQ group being diarrhea (10% vs. 0% in the SOC group, p=0.004). Furthermore, there are several factors that limit the interpretability of this study. Most of the enrolled patients had mild-to-moderate symptoms (98%), and the average age was 46. SOC in this study included the use of antivirals (Lopinavir-Ritonavir, Arbidol, Oseltamivir, Virazole, Entecavir, Ganciclovir, and Interferon alfa), which appeared to introduce confounding effects. Thus, to isolate the effect of HCQ, SOC would need to exclude the use of antivirals. In this trial, the samples used to test for the presence of the SARS-CoV-2 virus were collected from the upper respiratory tract, and the authors indicated that the use of upper respiratory samples may have introduced false negatives (e.g., [77]); thus, the identification of biomarkers that can be collected non-invasively would be valuable to studies such as this one. Another limitation of the study that the authors acknowledge was that the HCQ treatment began, on average, at a 16-day delay from the symptom onset. The fact that this study was open-label and lacked a placebo limits interpretation, and additional analysis is required to determine whether HCQ reduces inflammatory response. Therefore, despite some potential areas of investigation identified in post hoc analysis, this study cannot be interpreted as providing support for HCQ as a therapeutic against COVID-19.

Additional evidence comes from a retrospective analysis [409] that examined data from 368 COVID-19 patients across all United States Veteran Health Administration medical centers. The study retrospectively investigated the effect of the administration of HCQ (n=97), HCQ + AZ (n=113), and no HCQ (n=158) on 368 patients. The primary outcomes assessed were death and the need for mechanical ventilation. Standard supportive care was rendered to all patients. Due to the low representation of women (N=17) in the available data, the study included only men, and the median age was 65 years. The rate of death in the HCQ-only treatment condition was 27.8% and in the HCQ + AZ treatment condition, it was 22.1%. In comparison to the 14.1% rate of death in the no-HCQ cohort, these data indicated a statistically significant elevation in the risk of death for the HCQ-only group compared to the no-HCQ group (adjusted hazard ratio: 2.61, p=0.03), but not for the HCQ + AZ group compared to the no-HCQ group (adjusted hazard ratio: 1.14; p=0.72). Further, the risk of ventilation was similar across all three groups (adjusted hazard ratio: 1.43, p=0.48 (HCQ) and 0.43, p=0.09 (HCQ + AZ) compared to no HCQ). The study thus showed evidence of an association between increased mortality and HCQ in this cohort of COVID-19 patients but no change in rates of mechanical ventilation among the treatment conditions. The study had a few limitations: it was not randomized, and the baseline vital signs, laboratory tests, and prescription drug use were significantly different among the three groups. All of these factors could potentially influence treatment outcome. Furthermore, the authors acknowledge that the effect of the drugs might be different in females and pediatric subjects, since these subjects were not part of the study. The reported result that HCQ + AZ is safer than HCQ contradicts the findings of the previous large-scale analysis of twenty years of records that found HCQ + AZ to be more frequently associated with cardiac arrhythmia than HCQ alone [404]; whether this discrepancy is caused by the pathology of COVID-19, is influenced by age or sex, or is a statistical artifact is not presently known.

Finally, findings from the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial were released on October 8, 2020. This study used a randomized, open-label design to study the effects of HCQ compared to standard care at 176 hospitals in the United Kingdom [410]. This large study enrolled 11,197 hospitalized patients whose physicians believed it would not harm them to participate. Patients were randomized into either the control group or one of the treatment arms, with twice as many patients enrolled in the control group as any treatment group. Of the patients eligible to receive HCQ, 1561 were randomized into the HCQ arm while 3155 were randomized into the control arm. The demographics of the HCQ and control groups were similar in terms of average age (65 years), proportion female (approximately 38%), ethnic make-up (73% versus 76% white), and prevalence of pre-existing conditions (56% versus 57% overall). In the HCQ arm of the study, patients received 800 mg at baseline and again after 6 hours, then 400 mg at 12 hours and every subsequent 12 hours. The primary outcome analyzed was all-cause mortality, and patient vital statistics were reported by physicians upon discharge or death, or else at 28 days following HCQ administration if they remained hospitalized. The secondary outcome assessed was the combined risk of progression to invasive mechanical ventilation or death within 28 days. By the advice of an external data monitoring committee, the HCQ arm of the study was reviewed early, leading to it being closed due a lack of support for HCQ as a treatment for COVID-19. Patients who received HCQ had a longer duration of hospitalization than patients receiving usual care, were less likely to be discharged alive within 28 days, and were more likely to progress to mechanical ventilation. This large-scale study thus builds upon studies in the United States and China to suggest that HCQ is not an effective treatment, and in fact may negatively impact COVID-19 patients due to its side effects. The rates of COVID-19-related reported in the RECOVERY trial did not differ between the control and HCQ arms, but patients receiving HCQ were more likely to die due to cardiac events. Therefore, though none of the studies have been blinded, taken together it becomes clear that all of the available evidence points to significant concerns about the administration of HCQ to hospitalized COVID-19 patients, without providing any support for its efficacy. HCQ for the Treatment of Mild Cases

One additional possible therapeutic application considered was the treatment of mild COVID-19 cases in otherwise healthy individuals. This possibility was assessed in a randomized, open-label, multi-center analysis conducted in Catalonia (Spain) [411]. This analysis enrolled adults 18 and older who had been experiencing mild symptoms of COVID-19 for fewer than five days. Participants were randomized into an HCQ arm (N=136) and a control arm (N=157), and those in the treatment arm were administered 800 mg of HCQ on the first day of treatment followed by 400 mg on each of the subsequent six days. The primary outcome assessed was viral clearance at days 3 and 7 following the onset of treatment, and secondary outcomes were clinical progression and time to complete resolution of symptoms. They found no significant differences between the two groups. This study thus suggests that COVID-19 does not improve recovery from COVID-19, even in otherwise healthy adult patients with mild symptoms. Prophylactic Administration of HCQ

An initial study of the possible prophylactic application of HCQ utilized a randomized, double-blind, placebo-controlled design to analyze the administration of HCQ prophylactically [412]. Asymptomatic adults in the United States and Canada who had been exposed to SARS-CoV-2 within the past four days were enrolled in an online study to see whether administration of HCQ over five days would influence the probability of developing COVID-19 symptoms over a 14-day period. Of the participants, 414 received HCQ and 407 received a placebo. The participants averaged 40 years of age and 51.6% were women. They found no significant difference in the rate of symptomatic illness between the two groups (11.8% HCQ, 14.3% placebo, p=0.35). The HCQ condition was associated with side effects, with 40.1% of patients reporting side effects compared to 16.8% in the control group (p<0.001). However, likely due to the high enrollment of healthcare workers (66% of participants) and the well-known side effects associated with HCQ, a large number of participants were able to correctly identify whether they were receiving HCQ or a placebo (46.5% and 35.7%, respectively). Furthermore, due to a lack of availability of diagnostic testing, only 20 of the 107 cases were confirmed with a PCR-based test to be positive for SARS-CoV-2. The rest were categorized as “probable” or “possible” cases by a panel of four physicians who were blind to the treatment status. One possible confounder is that a patient presenting one or more symptoms, which included diarrhea, was defined as a “possible” case, but diarrhea is also a common side effect of HCQ. Additionally, four of the twenty PCR-confirmed cases did not develop symptoms until after the observation period had completed, suggesting that the 14-day trial period may not have been long enough or that some participants also encountered secondary exposure events. Finally, in addition to the young age of the participants in this study, which ranged from 32 to 51, there were possible impediments to generalization introduced by the selection process, as 2,237 patients who were eligible but had already developed symptoms by day 4 were enrolled in a separate study. It is therefore likely that asymptomatic cases were over-represented in this sample, which would not have been detected based on the diagnostic criteria used. Therefore, while this study does represent the first effort to conduct a randomized, double-blind, placebo-controlled investigation of HCQ’s effect on COVID-19 symptoms in a large sample, the lack of PCR tests and several other design flaws significantly impedes interpretation of the results. However, in line with the results from therapeutic studies, there is no evidence that HCQ provides protection against COVID-19.

A second study [413] examined the effect of administering HCQ to healthcare workers as a pre-exposure prophylactic. The primary outcome assessed was the conversion from SARS-CoV-2 negative to SARS-CoV-2 positive status over the 8 week study period. This study was also randomized, double-blind, and placebo-controlled and sough to address some of the limitations of the first prophylactic study. They sought to enroll 200 healthcare workers, preferentially those working with COVID-19 patients, at two hospitals within the University of Pennsylvania hospital system in Philadelphia, PA. Participants were randomized 1:1 to receive either 600 mg of HCQ daily or a placebo, and their SARS-CoV-2 infection status and antibody status were assessed using RT-PCR and serological testing, respectively, at baseline, 4 weeks, and 8 weeks following the beginning of the treatment period. The statistical design of the study accounted for interim analyses at 50 and 100 participants in case efficacy or futility of HCQ for prophylaxis became clear earlier than completion of enrollment. The 139 individuals enrolled comprised a study population that was fairly young (average age 33) and made of largely of people who were white, women, and without pre-existing conditions. At the second interim analysis, more individuals in the treatment group than the control group had contracted COVID-19 (4 versus 3), causing the estimate z-score to fall below the pre-established threshold for futility. As a result, the trial was terminated early, offering additional evidence against the use of HCQ for prophylaxis. Summary

Early in vitro evidence indicated that HCQ could be an effective therapeutic against SARS-CoV-2 and COVID-19, leading to early interest in its potential as both a therapeutic and prophylaxis. Because the 90% effective concentration (EC90) of CQ in Vero E6 cells (6.90 μM) can be achieved in and tolerated by rheumatoid arthritis patients, it was hypothesized that it might also be possible to achieve the effective concentration in COVID-19 patients [414]. Additionally, HCQ has been found to be effective in treating HIV [415] and chronic Hepatitis C [416]. Therefore, initially it was hypothesized that CQ/HCQ might be effective against SARS-CoV-2, especially since CQ and HCQ have both been found to inhibit the expression of CD154 in T-cells and to reduce toll-like receptor signaling that leads to the production of pro-inflammatory cytokines [417]. Clinical trials for COVID-19 have more often used HCQ rather than CQ because it offers the advantages of being cheaper and having fewer side effects than CQ. Several countries have removed CQ from their standard of care for COVID-19 due to the frequency of adverse effects. However, a large analysis of patients receiving HCQ from January 2000 through March 2020 reported that the combination of HCQ and azithromycin, but not other macrolides, was associated with an elevated risk of cardiovascular complications and mortality. Multiple clinical studies have already been carried out to assess HCQ as a therapeutic agent for COVID-19, and many more are in progress. To date, none of these studies have used randomized, double-blind, placebo-controlled designs with a large sample size, which would be the gold standard. Despite the design limitations (which would be more likely to produce false positives than false negatives), initial optimism about HCQ has not been substantiated by these studies. The most methodologically rigorous analysis to date [412] evaluated the prophylactic potential of HCQ and found no significant differences between the treatment and control groups. Thus, HCQ/CQ are not likely to be effective therapeutic or prophylactic agents against COVID-19. Additionally, one study identified an increased risk of mortality in older men receiving HCQ, and administration of HCQ and HCQ+AZ did not decrease the use of mechanical ventilation in these patients [409]. HCQ use for COVID-19 also leads to shortages for anti-malarial or anti-rheumatic use, where it has been definitively proven to be effective. Despite significant attention, these drugs appear to be ineffective against COVID-19. Dexamethasone

Dexamethasone (9α-fluoro-16α-methylprednisolone) is a synthetic corticosteroid that binds to the glucocorticoid receptors [418,419]. It was first synthesized in the late 1950s as an anti-inflammatory and has been used to treat rheumatoid arthritis and other inflammatory conditions [420,421]. Steroids such as dexamethasone are widely available and affordable, and they are often used to treat community-acquired pneumonia [422]. A clinical trial that began in 2012 recently reported that dexamethasone may improve outcomes for patients with ARDS [423]. However, meta-analysis of a small amount of available data regarding the use of dexamethasone to treat SARS suggested that it may, in fact, be associated with patient harm [424], although these findings may have been biased by the fact that all of the studies examined were observational and a large number of inconclusive studies were not included [425]. Dexamethasone works as an anti-inflammatory by binding to glucocorticoid receptors with higher affinity than endogenous cortisol [426]. In order to understand how dexamethasone works to reduce inflammation, it is necessary to consider the stress response more broadly. In response to stress, corticotropin‐releasing hormone stimulates the release of neurotransmitters known as catecholamines, such as epinephrine, and steroid hormones known as glucocorticoids, such as cortisol [427,428]. While catecholamines are often associated with the characteristic fight-or-flight response, the specific role that glucocorticoids play is less clear, although they are thought to be important to restoring homeostasis [429]. Immune challenge is a stressor that is known to interact closely with the stress response. The immune system can therefore interact with the central nervous system; for example, macrophages can both respond to and produce catecholamines [427]. Additionally, the production of both catecholamines and glucocorticoids is associated with inhibition of proinflammatory cytokines such as IL-6, IL-12, and TNF‐α and the stimulation of anti-inflammatory cytokines such as IL-10, meaning that the stress response can regulate inflammatory immune activity [428]. Administration of dexamethasone has been found to correspond to dose-dependent inhibition of IL-12 production, but not to affect IL-10 [430]; the fact that this relationship could be disrupted by administration of a glucocorticoid-receptor antagonist suggests that it is regulated by the receptor itself [430]. Thus, the administration of dexamethasone for COVID-19 is likely to simulate the release of glucocorticoids endogenously during stress, resulting in binding of the synthetic steroid to the glucocorticoid receptor and the associated inhibition of the production of proinflammatory cytokines. In this model, dexamethasone reduces inflammation by stimulating the mechanism used to reduce inflammation following a threat such as immune challenge.

The application of dexamethasone for the treatment of COVID-19 was evaluated as part of the multi-site RECOVERY trial in the United Kingdom [431]. Over 6,000 hospitalized COVID-19 patients were assigned into standard care or treatment (dexamethasone) arms of the trial with a 2:1 ratio. At the time of randomization, some patients were ventilated (16%), others were on non-invasive oxygen (60%), and others were breathing independently (24%). Patients in the treatment arm were administered dexamethasone either orally or intravenously at 6 mg per day for up to 10 days. The primary end-point was the patient’s status at 28-days post-randomization (mortality, discharge, or continued hospitalization), and secondary outcomes analyzed included the progression to invasive mechanical ventilation over the same period. The 28-day mortality rate was found to be lower in the treatment group than in the standard care group (21.6% vs 24.6%, p <0.001). However, this finding was driven by differences in mortality among patients who were receiving mechanical ventilation or supplementary oxygen at the start of the study. The report indicated that dexamethasone reduced 28-day mortality relative to standard care in patients who were ventilated (29.3% vs. 41.4%) and among those who were receiving oxygen supplementation (23.3% vs. 26.2%) at randomization, but not in patients who were breathing independently (17.8% vs. 14.0%). One possible confounder is that patients receiving mechanical ventilation tended to be younger than patients who were not receiving respiratory support (by 10 years on average) and to have had symptoms for a longer period. However, adjusting for age did not change their conclusions, although the duration of symptoms was found to be significantly associated with the effect of dexamethasone administration. These findings also suggested that dexamethasone may have reduced progression to mechanical ventilation, especially among patients who were receiving oxygen support at randomization. Thus, this large, randomized, and multi-site, albeit not placebo-controlled, study suggests that administration of dexamethasone to patients who are unable to breathe independently may significantly improve survival outcomes. Additionally, dexamethasone is a widely available and affordable medication, raising the hope that it could be made available to COVID-19 patients globally.

The results of the RECOVERY trial’s analysis of dexamethasone suggest that this therapeutic is effective primarily in patients who had been experiencing symptoms for at least seven days and patients who were not breathing independently [432]. Thus, it seems likely that dexamethasone is useful for treating inflammation associated with immunopathy or cytokine release syndrome. In fact, corticosteroids such as dexamethasone are sometimes used to treat CRS [433]. It is not surprising that administration of an immunosuppressant would be most beneficial when the immune system was dysregulated towards inflammation. However, it is also unsurprising that care must be taken in administering an immunosuppressant to patients fighting a viral infection. In particular, the concern has been raised that treatment with dexamethasone might increase patient susceptibility to concurrent (e.g., nosocomial) infections [434]. Additionally, the drug could potentially slow viral clearance and inhibit patients’ ability to develop antibodies to SARS-CoV-2 [424,434]. Furthermore, dexamethasone has been associated with side effects that include psychosis, glucocorticoid-induced diabetes, and avascular necrosis [424], and the RECOVERY trial did not report outcomes with enough detail to be able to determine whether they observed similar complications. However, since these results were released, strategies have been proposed for administering dexamethasone alongside more targeted treatments to minimize the likelihood of negative side effects [434]. Given the available evidence, dexamethasone is currently one of the most promising treatments for severe COVID-19.

5.1.4 Nutraceuticals and Dietary Supplements

Given the current pandemic, scientists and the medical community are scrambling to repurpose or discover novel host-directed therapies. For the general public in particular, whether nutraceuticals or dietary supplements can provide any prophylactic or therapeutic benefit has been a topic of interest. Nutraceuticals are classified as supplements with health benefits beyond their basic nutritional value [435,436]. The key difference between a dietary supplement and a nutraceutical is that nutraceuticals should not only supplement the diet, but also aid in the prophylaxis and/or treatment of a disorder or disease [437]. Unlike pharmaceuticals, nutraceuticals do not fall under the responsibility of the FDA, but they are monitored as dietary supplements according to the Dietary Supplement, Health and Education Act 1994 (DSHEA) [438] and the Drug Administration Modernization Act 1997 [439]. However, there is significant concern that these acts do not adequately protect the consumer as they ascribe responsibility on the manufacturers to ensure safety of the product before manufacturing or marketing [440]. Likewise, manufacturers are not required to register or seek approval from the FDA to produce or sell food supplements or nutraceuticals. Health or nutrient content claims for labeling purposes are approved based on an authoritative statement from the Academy of Sciences or relevant federal authorities once the FDA has been notified and on the basis that the information is known to be true and not deceptive [440]. In Europe, health claims are permitted on a product label only following authorization according to the European Food Safety Authority (EFSA) guidelines on nutrition and health claims [441]. EFSA does not currently distinguish between food supplements and nutraceuticals for health claim applications of new products, as claim authorization is dependent on the availability of clinical data in order to substantiate efficacy [442]. These guidelines seem to provide more protection to consumers. Currently, there is a debate among scientists and regulatory authorities over developing a regulatory framework to deal with the challenges of safety and health claim substantiation for nutraceuticals [440,442]. As a result, studies of nutraceuticals do not necessarily follow the same rigorous clinical trial framework used for pharmaceuticals.

Nutraceuticals purported to ‘boost’ the immune response, reduce immunopathology, exhibit antiviral activities or prevent acute respiratory distress syndrome (ARDS) are being considered for their potential therapeutic value [322]. A host of potential candidates have been highlighted in the literature that target various aspects of the COVID-19 viral pathology, while others are thought to prime the host immune system. These candidates include vitamins and minerals along with extracts and omega-3 polyunsaturated fatty acids (n-3 PUFA) [443]. In vitro and in vivo studies suggest that nutraceuticals containing phycocyanobilin, N-acetylcysteine, glucosamine, selenium or phase 2 inductive nutraceuticals (e.g. ferulic acid, lipoic acid, or sulforaphane) can prevent or modulate RNA virus infections via amplification of the signaling activity of mitochondrial antiviral-signaling protein (MAVS) and activation of toll-like receptor 7 (TLR7) [321]. While promising, further animal and human studies are required to assess the therapeutic potential of these various nutraceuticals against COVID-19. n-3 PUFA

One nutraceutical that has been explored for beneficial effects against various viral infections is n-3 PUFA [443], such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA intake can come from a diet high in fish or through dietary supplementation with fish oils or purified oils [444]. They can mediate inflammation and therefore may have the capacity to modulate the adaptive immune response [436,444,445]. Another potential mechanism that has led to interest in n-3 PUFA for viral infections is its potential as a precursor molecule for the biosynthesis of endogenous specialized proresolving mediators (SPM), such as protectins and resolvins, that actively resolve inflammation and infection [446]. Finally, some COVID-19 patients, particularly those with comorbidities, are at a significant risk of thrombotic complications including arterial and venous thrombosis [102,447]. Therefore, the use of prophylactic and therapeutic anticoagulants and antithrombotic agents is under consideration [448], which could potentially include n-3 PUFA.

SPM have exhibited beneficial effects against a variety of lung infections, including some caused by RNA viruses [449]. Indeed, protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [450]. Several mechanisms for SPM have been proposed, including preventing the release of pro-inflammatory cytokines and chemokines or increasing phagocytosis of cellular debris by macrophages [451]. In influenza, SPM promote antiviral B lymphocytic activities [452], and protectin D1 has been shown to increase survival from H1N1 viral infection in mice by affecting the viral replication machinery [450]. It is hypothesized that SPM could aid in the resolution of the cytokine storm and pulmonary inflammation associated with COVID-19 [453]. However, not all studies are in agreement that n-3 PUFA is effective against infections [454]. At a minimum, the effectiveness of n-3 PUFA against infections would be dependent on the dosage, timing, and the specific pathogens responsible [455]. On another level, there is still the question of whether fish oils can raise the levels of SPM levels upon ingestion and in response to acute inflammation in humans [456].

The increased risk of thrombotic complications in COVID-19 infected patients was reported relatively late in comparison to other manifestations of COVID-19 [96,447]. Considering that there is significant evidence that n-3 fatty acids and other fish oil-derived lipids possess antithrombotic properties and anti-inflammatory properties [457,458], they may have therapeutic value against the prothrombotic complications of COVID-19. Based on concern among the medical community that the use of investigational therapeutics on COVID-19 patients already on antiplatelet therapies due to a pre-existing comorbidities may lead to issues with dosing and drug choice, and/or negative drug-drug interactions [448], this supplementation holds particular interest for the treatment of patients already receiving pharmaceutical antiplatelet therapies. As a result, the use of other therapeutics, such as dietary sources of n-3 fatty acids or nutraceuticals with antiplatelet activities, may be beneficial and warrant further investigation. A new clinical trial [459] is currently recruiting COVID-19 positive patients to investigate the anti-inflammatory activity of a recently developed, highly purified derivative of EPA known as icosapent ethyl (Vascepa TM) [460]. Other randomized controlled trials are in the preparatory stages with the intention of investigating the administration of EPA and other bioactive compounds to COVID-19 positive patients to determine whether anti-inflammatory effects or disease state improvements are observed [461,462]. Finally, while there have been studies investigating the therapeutic value of n-3 fatty acids against ARDS in humans, there is still limited evidence of their effectiveness [463]. It should be noted that the overall lack of human studies in this area means there is limited evidence as to whether these nutraceuticals could affect COVID-19 infection. Consequently, clinical trials have been proposed and many are in the preparatory stages. These trials will investigate whether the anti-inflammatory potential of n-3 PUFA and their derivatives is beneficial in the treatment of COVID-19. Therefore, the evidence is not present to draw conclusions about whether n-3 PUFA will be useful in treating COVID-19, but as there is likely little harm associated with a diet rich in fish oils, interest in this nutraceutical by the general public is unlikely to have negative effects. Zinc

There is evidence that certain nutrient supplements may exhibit some benefit against RNA viral infections. Zinc is a trace metal obtained from dietary sources or supplementation that is important for the maintenance of immune cells involved in adaptive and innate immunity [464]. Zinc supplements can be administered orally as a tablet or as a lozenge and they are available in many forms, such as zinc picolinate, zinc acetate, and zinc citrate. Zinc is also available from dietary sources including meat, seafood, nuts, seeds, legumes, and dairy. The role of zinc in immune function has been extensively reviewed [464]. Zinc is an important signaling molecule and zinc levels can alter host defense systems. In inflammatory situations such as an infection, zinc can regulate leukocyte immune responses and it can activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), thus altering cytokine production [465,466]. In particular, zinc supplementation can increase natural killer cell levels, which are important cells for host defense against viral infections [464,467].

Adequate zinc intake has been associated with reduced incidence of infection [468] and antiviral immunity [469]. Similarly, a randomized, double-blind, placebo-controlled trial that administered zinc supplementation to elderly subjects over the course of a year found zinc deficiency to be associated with increased susceptibility to infection and that zinc deficiency could be prevented through supplementation [468]. Clinical trial data supports the utility of zinc to diminish the duration and severity of symptoms associated with common colds when it is provided within 24 hours of the onset of symptoms [470,471]. In coronaviruses specifically, in vitro evidence demonstrates that the combination of zinc (Zn2+) and zinc ionophores (pyrithione) can interrupt the replication mechanisms of SARS-CoV-GFP (a fluorescently tagged SARS-CoV) and a variety of other RNA viruses [472,473]. Currently, there are over twenty clinical trials registered with the intention to use zinc in a preventative or therapeutic manner. However, many of these trials proposed the use of zinc in conjunction with hydroxychloroquine and azithromycin [474,475,476,477], and it is not known how the lack of evidence supporting the use of hydroxychloroquine will affect investigation of zinc. Other trials, however, are investigating zinc in conjunction with other nutrients such as vitamin C or n-3 PUFA [462,478]. Though there is, overall, encouraging data for zinc supplementation against the common cold and viral infections, there is currently limited evidence to suggest zinc supplementation has any beneficial effects against the current novel COVID-19; thus, the clinical trials that are currently underway will provide vital information on the efficacious use of zinc in COVID-19 prevention and/or treatment. However, given the limited risk, maintaining a healthy diet to ensure an adequate zinc status may be advisable for individuals seeking to reduce their likelihood of infection. Vitamin C

Vitamins B, C, D, and E have also been suggested as potential nutrient supplement interventions for COVID-19 [443,479]. In particular vitamin C has been proposed as a potential therapeutic agent against COVID-19. Vitamin C can be obtained via dietary sources such as fruit and vegetable or via supplementation. Vitamin C plays a significant role in promoting immune function due to its effects on various immune cells. It affects inflammation by modulating cytokine production, decreasing histamine levels, enhancing the differentiation and proliferation of T- and B-lymphocytes, increasing antibody levels, and protecting against the negative effects of reactive oxygen species amongst other effects [480,481,482]. Vitamin C is utilized by the body during viral infections, as evinced by lower concentrations in leukocytes and lower concentrations of urinary vitamin C. Post-infection, these levels return to baseline ranges [483,484,485,486,487].

A recent meta-analysis found consistent support for regular vitamin C supplementation reducing the duration of the common cold, but that supplementation with vitamin C (> 200 mg) failed to reduce the incidence of colds [488]. Individual studies have found Vitamin C to reduce the susceptibility of patients to lower respiratory tract infections such as pneumonia [489]. Another meta-analysis has demonstrated in twelve trials that vitamin C supplementation reduced the length of stay of patients in intensive care units (ICUs) by 7.8% (95% CI: 4.2% to 11.2%; p = 0.00003). Furthermore, high doses (1-3 g/day) significantly reduced the length of an ICU stay by 8.6% in six trials (p = 0.003). Vitamin C also shortened the duration of mechanical ventilation by 18.2% in three trials in which patients required intervention for over 24 hours (95% CI 7.7% to 27%; p = 0.001) [490]. Despite these findings, the CITRUS ALI study failed to show a benefit of a 96-hour infusion of vitamin C to treat ARDS, which is a severe complication of COVID-19 infection [491]. Nevertheless, a randomized placebo-controlled trial [492] has begun in Wuhan, China to investigate the intravenous infusion of vitamin C to treat pneumonia in 140 severe COVID-19 infected patients. As summarized by Carr [493] the trial will not be completed until September 2020. Another trial in Italy [494] intends to deliver a 10 g infusion of vitamin C to 500 severe COVID-19 patients with pneumonia to assess in-hospital mortality over a 72 hr period as the primary outcome. The trial is currently recruiting and is due to run until March 2021. We will not know how effective vitamin C is as a therapeutic for quite some time due to the length of both trials. These are not the only trials investigating the potential value of vitamin C, as there are currently (as of October 2020) over twenty trials registered with that are either recruiting or are currently in preparation. When completed, the trials will provide crucial evidence on the efficacy of vitamin C as a therapeutic for COVID-19 infection. Thus, some evidence suggests that vitamin C supplementation or infusion can shorten the duration of a cold, reduce an individual’s susceptibility to infections, and shorten a patient’s stay in an ICU when administered at high doses, but we don’t yet understand if these findings apply to COVID-19. There are ongoing trials in China and Italy that will inform our understanding of the therapeutic value of vitamin C supplementation for COVID-19. Once again, vitamin C intake is likely to be part of a healthy diet and the vitamin likely presents minimal risk, but its potential prophylactic or therapeutic effects against COVID-19 are unknown. Vitamin D

In terms of other dietary supplements, vitamin D can modulate the adaptive and innate immune system and has been associated with various aspects of health. Vitamin D can be sourced through diet or supplementation, but it is mainly biosynthesized by the body on exposure to sunlight. Vitamin D deficiency is associated with an increased susceptibility to infection [495]. In particular, vitamin D deficient patients are at risk of developing acute respiratory infections [496] and ARDS [496]. 1,25-dihydroxyvitamin D3 is the more active form of vitamin D that is involved in adaptive and innate responses, however, due to a short half life of a few hours, it is measured by its longer lasting precursor 25-hydroxyvitamin D. The vitamin D receptor is expressed in various immune cells and vitamin D is an immunomodulator of antigen presenting cells, dendritic cells, macrophages, monocytes, and T- and B-lymphocytes [495,497]. Due to its potential immunomodulating properties, vitamin D supplementation may be advantageous to maintain a healthy immune system.

One influential review postulated that an individual’s vitamin D status may significantly affect their risk of developing COVID-19 [498]. This hypothesis was derived from the fact that the current pandemic emerged in winter in Wuhan China when 25-hydroxyvitamin D concentrations are at their lowest due to a lack of sunlight, whereas in the Southern Hemisphere, where it was nearing the end of the summer and higher 25-hydroxyvitamin D concentrations would be higher, the number of cases was low. The authors suggested that people at risk of developing COVID-19 should increase their vitamin D3 intake to reach 25-hydroxyvitamin D plasma concentrations above 40–60 ng/ml. The authors also suggest high-dose supplementation of vitamin D to treat infected patients and to prevent infection in hospital staff [498]. While vitamin D is relatively inexpensive and safe to consume, caution is warranted when interpreting this review as it has yet to be determined whether vitamin D levels affect COVID-19 outside of this geographic/climatic correlation. Likewise, though it is assumed that COVID-19 may be seasonal, multiple other factors that can affect vitamin D levels should also be considered. These factors include an individual’s nutritional status, their age, their occupation, skin pigmentation, potential comorbidities, and the variation of exposure to sunlight due to latitude amongst others. As the pandemic evolves, further research has investigated some of the potential links identified in the Grant et al. review [498] between vitamin D and COVID-19 and sought to shed light on whether there is any prophylactic and/or therapeutic relationship. A study in Switzerland demonstrated that 27 SARS-CoV-2 positive patients exhibited 25-hydroxyvitamin D plasma concentrations that were significantly lower (11.1 ng/ml) than those of SARS-CoV-2 negative patients (24.6 ng/ml; p = 0.004), an association that held when stratifying for patients greater than 70 years old [499]. These findings seem to be supported by a Belgian observational study of 186 SARS-CoV-2 positive patients exhibiting symptoms of pneumonia, where 25-hydroxyvitamin D plasma concentrations were measured and a CT scan of the lungs was obtained upon hospitalization [500]. A significant difference in 25-hydroxyvitamin D levels was observed between the SARS-CoV-2 patients and 2,717 season-matched diseased controls. Both female and male patients possessed lower median 25-hydroxyvitamin D concentrations than the control group (18.6 ng/ml versus 21.5 ng/ml; p = 0.0016) and a higher rate of vitamin D deficiency (58.6% versus 42.5%). Evidence of sexual dimorphism was apparent, as female patients had equivalent levels of 23-hydroxyvitamin D to the control group, whereas male patients were deficient in 25-hydroxyvitamin D relative to male controls (67% versus 49%; p = 0.0006). Notably, vitamin D deficiency was progressively lower in males with advancing radiological disease stages (p = 0.001). These studies are supported by several others that indicate that vitamin D status may be an independent risk factor for the severity of COVID-19 [501,502,503,504]. Indeed, serum concentrations of 25-hydroxyvitamin D above 30 ng/ml, which indicate vitamin D sufficiency, seems to be associated with a reduction in serum C-reactive protein (CRP), an inflammatory marker, along with increased lymphocyte levels, which suggests that vitamin D levels may modulate the immune response by reducing risk for cytokine storm in response to SARS-CoV-2 infection. Despite these studies potentially linking vitamin D status with COVID-19 severity, an examination of the UK Biobank did not support this thesis [505]. This analysis examined 25-hydroxyvitamin D concentrations in 348,598 UK Biobank participants, of which 449 were SARS-CoV-2 positive. However, this study has caused considerable debate that will likely be settled following further studies [506; 10.1016/j.dsx.2020.05.046]. There is significant interest in the link between vitamin D and COVID-19, hence the multitude of studies published in the literature of varying quality and the clinical trials underway. One trial is currently investigating the utility of vitamin D as an immune-modulating agent by monitoring whether administration of vitamin D precipitates an improvement of health status in non-severe symptomatic patients infected with COVID-19 or whether vitamin D prevents patient deterioration [507]. Other trials are also underway examining various factors including mortality, symptom recovery, severity of disease, rates of ventilation, inflammatory markers such as CRP and IL-6, blood cell counts, and the prophylactic capacity of vitamin D administration [507,508,509,510]. Concomitant administration of vitamin D with pharmaceuticals such as aspirin [511] and bioactive molecules such as resveratrol [512] are also under investigation.

While there is increasing evidence that vitamin D status is linked to COVID-19 outcomes, the effectiveness of its supplementation remains open for debate. Once again, supplementation of vitamin D and maintaining a healthy diet for optimum vitamin D status is unlikely to carry major health risks while the possible link between vitamin D status and COVID-19 is investigated. However, pursuing to elevate vitamin D levels through sunlight exposure does carry additional risks, as many densely populated cities around the world are utilizing ‘stay in place’ orders to enforce social distancing guidelines. Given the lack of conclusive evidence in support of vitamin D supplementation, it is not clear that these guidelines present additional risk. However, to the extent that people are able to maintain safe exposure to sunlight, there is a possibility that it could improve endogenous synthesis of vitamin D, potentially strengthening the immune system. Probiotics

Probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” [513]. Some studies suggest that probiotics are beneficial against common viral infections and there is modest evidence to suggest that they can modulate the immune response [514,515], and as a result it has been hypothesized that probiotics may have therapeutic value worthy of investigation against SARS-CoV-2 [516]. Probiotics and next-generation probiotics, which are more akin to pharmacological-grade supplements, have been associated with multiple potential beneficial effects for allergies, digestive tract disorders, and even metabolic diseases through their anti-inflammatory and immunomodulatory effects [517,518]. However, the mechanisms by which probiotics affect these various conditions would likely differ among strains, with the ultimate effect of the probiotic depending on the heterogeneous set of bacteria present [518]. Some of the beneficial effects of probiotics include reducing inflammation by promoting the expression of anti-inflammatory mediators, inhibiting toll-like receptors (TLR) 2 and 4, direct competition with pathogens, the synthesis of antimicrobial substances or other metabolites, improving intestinal barrier function, and/or favorably altering the gut microbiota and the brain-gut axis [518,519,520]. However, there is also a bi-directional relationship between the lungs and gut microbiota known as the gut-lung axis [521], whereby gut microbial metabolites and endotoxins may affect the lungs via the circulatory system and the lung microbiota in return may affect the gut [522]. Therefore, the gut-lung axis may play role in our future understanding of COVID-19 pathogenesis and become a target for probiotic treatments [523].

Probiotics have tentatively been associated with the reduction of risk and duration of viral upper respiratory tract infections [524,525,526]. Some meta-analyses that have assessed the efficacy of probiotics in viral respiratory infections have reported moderate reductions in the incidence and duration of infection [525,527]. Indeed, randomized controlled trials have shown that administering Bacillus subtilis and Enterococcus faecalis [528], Lactobacillus rhamnosus GG [529], or Lactobacillus casei and Bifidobacterium breve with galactooligosaccharides [530] via the nasogastric tube to ventilated patients reduced the occurrence of ventilator-associated pneumonia in comparison to the respective control groups in studies of viral infections and sepsis. These findings are supported by a recently published meta-analysis [531]. There is a significant risk of ventilator-associated bacterial pneumonia in COVID-19 patients [532], but it can be challenging for clinicians to diagnose this infection due to the fact that severe COVID-19 infection presents with the symptoms of pneumonia [533]. Therefore, an effective prophylactic therapy for ventilator-associated pneumonia in severe COVID-19 patients would be of significant therapeutic value.

Probiotics are generally synonymous with the treatment of gastrointestinal issues due to their supposed anti-inflammatory and immunomodulatory effects [534]. Notably, gastrointestinal symptoms commonly occur in COVID-19 patients [535], and the ACE2 receptor is highly expressed in enterocytes of the ileum and colon, suggesting that these organs may be a potential route of infection [536,537]. Indeed, SARS-CoV-2 viral RNA has been detected in human feces [538], and fecal-oral transmission of the virus has not yet been ruled out [539]. Rectal swabs of some SARS-CoV-2 positive pediatric patients persistently tested positive for several days despite negative nasopharyngeal tests, indicating the potential for fecal viral shedding [540]. However, there is conflicting evidence for the therapeutic value of various probiotics against the incidence or severity of gastrointestinal symptoms in viral or bacterial infections such as gastroenteritis [541,542]. Nevertheless, it has been proposed that the administration of probiotics to COVID-19 patients and healthcare workers may prevent or ameliorate the gastrointestinal symptoms of COVID-19, a hypothesis that several clinical trials are now preparing to investigate [543,544]. Other studies are investigating whether probiotics may affect patient outcomes following SARS-CoV-2 infection [545].

Generally, the efficacy of probiotic use is a controversial topic among scientists. In Europe, EFSA has banned the term probiotics on products labels, which has elicited either criticism for EFSA or support for probiotics from researchers in the field [513,546,547]. This is due to the hyperbolic claims placed on the labels of various probiotic products, which lack rigorous scientific data to support their efficacy. Overall, the data supporting probiotics in the treatment or prevention of many different disorders and diseases is not conclusive as the quality of the evidence is generally considered low [524]. However, in the case of probiotics and respiratory infections, the evidence seems to be supportive of their potential therapeutic value. Consequently, several investigations are underway to investigate the prophylactic and therapeutic potential of probiotics for COVID-19. However, blind use of conventional probiotics for COVID-19 is cautioned against until the pathogenesis of SARS-CoV-2 is further established [548]. Until clinical trials investigating the prophylactic and therapeutic potential of probiotics for COVID-19 are complete, it is not possible to provide an evidence-based recommendation for their use. Nutraceutical Conclusions

Despite all the potential benefits of nutraceutical and dietary supplement interventions presented, currently there is a paucity of clinical evidence to support their use for the prevention or mitigation of COVID-19 infections. Nevertheless, optimal nutritional status will undoubtedly prime an individual’s immune system to protect against the effects of acute respiratory viral infections by supporting normal maintenance of the immune system [549,550]. Nutritional strategies and the use of nutraceuticals will also undoubtedly play a role in the treatment of hospitalized patients, as malnutrition is a risk to COVID-19 patients [551]. Overall, supplementation of vitamin C, vitamin D, and zinc may be an effective method of ensuring their adequate intake to maintain optimal immune function, which may also convey beneficial effects against viral infections due to their immunomodulatory effects. However, many supplements and nutraceuticals designed for various ailments are available in the United States and beyond that are not strictly regulated [552]. Indeed, there can be safety and efficacy concerns associated with many of these products. Often, the vulnerable members of society can be exploited in this regard and unfortunately the COVID-19 pandemic is no different. The Food and Drug Administration (FDA) has issued warnings to several companies for advertising falsified claims in relation to the preventative and therapeutic capabilities of their products against COVID-19 [553]. In light of these serious occurrences, it is pertinent to clarify that the nutraceuticals discussed in this review have been selected because of their possible relevance to the biological mechanisms that can beneficially affect viral and respiratory infections and because they are currently under clinical investigation. Therefore, further intensive investigation is required to establish the effects of these nutraceuticals, if any, against COVID-19. Until effective therapeutics are established, the most effective mitigation strategies consist of encouraging standard public health practices such as regular hand washing with soap, wearing a face mask, and covering a cough with your elbow [554], along with following social distancing measures, “stay in place” guidelines, expansive testing, and contact tracing [555,556].

5.2 Biologics

Biologics are produced from components of living organisms or viruses. They include treatments such as humanized monoclonal antibodies (mAb) tocilizumab (TCZ), and neutralizing antibodies (nAbs), and prophylactics such as vaccines. Historically produced from animal tissue, biologics have become increasingly feasible to produce as recombinant DNA technologies have advanced [557]. Often, they are glycoproteins or peptides [558], but whole viruses can also be used therapeutically or prophylactically, not only for vaccines but also as vectors for gene therapy or therapeutic proteins or for oncolytic virotherapy [559]. They are typically catabolized by the body to their amino acid components [558]. There are many differences on the development side between biologics and synthesized pharmaceuticals, such as small molecule drugs. Biologics are typically orders of magnitude larger than small molecule drugs and their physiochemical properties are often much less understood [558]. They are often heat-sensitive and the toxicity can vary, as it is not directly associated with the primary effects of the drug [558]. However, this class includes some extremely significant medical breakthroughs, including insulin for the management of diabetes and the smallpox vaccine. As a result, it is another possible avenue through which the pharmacological management of SARS-CoV-2 infection can be explored.

5.2.1 Tocilizumab

TCZ is a receptor antibody that was developed to manage chronic inflammation caused by the continuous synthesis of the cytokine interleukin-6 (IL-6) [560]. IL-6 is a pro-inflammatory cytokine belonging to the interleukin family, immune system regulators that are primarily responsible for immune cell differentiation. Often used to treat conditions such as rheumatoid arthritis [560], TCZ has become a pharmaceutical of interest for the treatment of COVID-19. While secretion of IL-6 can be associated with chronic conditions, it is a key player in the innate immune response and is secreted by macrophages in response to the detection of PAMPs or DAMPs [560]. An analysis of 191 in-patients at two Wuhan hospitals revealed that blood concentrations of IL-6 differed between patients who did and did not recover from COVID-19. Patients who ultimately deceased had higher IL-6 levels at admission than those who recovered [36]. Additionally, IL-6 levels remained higher throughout the course of hospitalization in the patients who ultimately deceased [36]. This finding provided some early evidence that COVID-19 deaths may be induced by the hyperactive immune response, which can be either the cytokine release syndrome (CRS) or cytokine storm syndrome (CSS), as IL-6 plays a key role in this response [109]. In this context, the observation of elevated IL-6 in patients who died may reflect an over-production of proinflammatory interleukins, suggesting that TCZ may palliate some of the most severe symptoms of COVID-19 associated with increased cytokine production.

Human IL-6 is a 26-kDa glycoprotein that consists of 184 amino acids and contains two potential N-glycosylation sites and four cysteine residues. It binds to a type I cytokine receptor (IL-6Rα or glycoprotein 80) that exists in both membrane-bound (IL-6Rα) and soluble (sIL-6Rα) forms [561]. It is not the binding of IL-6 to the receptor that initiates pro- and/or anti-inflammatory signaling, but rather the binding of the complex to another subunit, known as IL-6Rβ or glycoprotein 130 (gp13) [561,562]. Unlike membrane-bound IL-6Rα, which is only found on hepatocytes and some types of leukocytes, gp130 is found on most cells [563]. When IL-6 binds to sIL-6Rα, the complex can then bind to a gp130 protein on any cell [563]. The binding of IL-6 to IL-6Rα is termed classical signaling, while its binding to sIL-6Rα is termed trans-signaling [563,564,565]. These two signaling processes are thought to play different roles in health and illness. For example, trans-signaling may play a role in the proliferation of mucosal T-helper TH2 cells associated with asthma, while an earlier step in this proliferation of process may be regulated by classical signaling [563]. Similarly, IL-6 is known to play a role in Crohn’s Disease via trans-, but not classical, signaling [563]. Both classical and trans-signaling can occur through three independent pathways: the Janus-activated kinase (JAK)-STAT3 pathway, the Ras/Mitogen-Activated Protein Kinases (MAPK) pathway and the Phosphoinositol-3 Kinase (PI3K)/Akt pathway [561]. These signaling pathways are involved in a variety of different functions, including cell type differentiation, immunoglobulin synthesis, and cellular survival signaling pathways, respectively [561]. The ultimate result of the IL-6 cascade is to direct transcriptional activity of various promoters of pro-inflammatory cytokines, such as IL-1, TFN, and even IL-6 itself, through the activity of NF-κB [561]. IL-6 synthesis is tightly regulated both transcriptionally and post-transcriptionally, and it has been shown that viral proteins can enhance transcription of the IL-6 gene by strengthening the DNA-binding activity between several transcription factors and IL-6 gene-cis-regulatory elements [566]. Therefore, drugs inhibiting the binding of IL-6 to IL-6Rα or sIL-6Rα are of interest for combating the hyperactive inflammatory response characteristic of CRS and CSS. TCZ is a humanized monoclonal antibody that binds both to the insoluble and soluble receptor of IL-6, providing de facto inhibition of the IL-6 immune cascade.

Tocilizumab is being administered either as an intervention or as concomitant medication in 77 COVID-19 clinical trials (Figure 3). No randomized, placebo-controlled studies have been released yet for TCZ. Therefore, no conclusions can be drawn about its efficacy for the treatment of COVID-19. However, early interest in TCZ as a possible treatment for COVID-19 emerged from a very small retrospective study in China that examined 20 patients with severe symptoms in early February 2020 and reported rapid improvement in symptoms following treatment with TCZ [567]. Subsequently, a number of retrospective studies have been conducted in several countries. Many studies use a retrospective, observational design, where they compare outcomes for COVID-19 patients who received TCZ to those who did not over a set period of time. For example, one of the largest retrospective, observational analysis released to date [568] compared the rates at which patients who received TCZ deceased or progressed to invasive medical ventilation over a 14-day period compared to patients receiving only SOC.

Under this definition, SOC could include other drugs such as HCQ, azithromycin, lopinavir-ritonavir or darunavir-cobicistat, or heparin. While this study was not randomized, a subset of patients who were eligible to receive TCZ were unable to obtain it due to shortages; however, these groups were not directly compared in the analysis. After adjusting for variables such as age, sex, and SOFA score, they found that patients treated with TCZ were less likely to progress to invasive medical ventilation and/or death (adjusted hazard ratio = 0.61, CI 0.40-0.92, p=0.020), although analysis of death and ventilation separately suggests that this effect may have been driven by differences in the death rate (20% of control versus 7% of TCZ-treated patients). They reported particular benefits for patients whose PaO2/FiO2 (P/F) ratio, also known as the Horowitz Index for Lung Function, fell below a 150 mm Hg threshold. They found no differences between groups administered subcutaneous versus intravenous TCZ. Another retrospective observational analysis of interest examined the charts of patients at a hospital in Connecticut, USA where 64% of all 239 COVID-19 patients in the study period were administered TCZ based on assignment by a standardized algorithm [569]. They found that TCZ administration was associated with more similar rates of survivorship in patients with severe versus nonsevere COVID-19 at intake, defined based on the amount of supplemental oxygen needed. They therefore proposed that their algorithm was able to identify patients presenting with or likely to develop CRS as good candidates for TCZ. This study also reported higher survivorship in Black and Hispanic patients compared to white patients when adjusted for age. The major limitation with interpretation for these studies is that there may be clinical characteristics that influenced medical practitioners decisions to administer TCZ to some patients and not others. One interesting example therefore comes from an analysis of patients at a single hospital in Brescia, Italy, where TCZ was not available for a period of time [570]. This study compared COVID-19 patients admitted to the hospital before and after March 13, 2020, when the hospital received TCZ. Therefore, patients who would have been eligible for TCZ prior to this arbitrary date did not receive it as treatment, making this retrospective analysis something of a natural experiment. Despite this design, demographic factors did not appear to be consistent between the two groups, and the average age of the control group was older than the TCZ group. The control group also had a higher percentage of males and a higher incidence of comorbidities such as diabetes and heart disease. All the same, the multivariate hazard ratio, which adjusted for these clinical and demographic factors, found a significant difference between survival in the two groups (HR=0.035, CI=0.004-0.347, p = 0.004). They reported improvement of survival outcomes after the addition of TCZ to their SOC regime, with 11 of 23 patients (47.8%) admitted prior to March 13th dying compared to 2 of 62 (3.2%) admitted afterwards. They also reported a reduced progression to mechanical ventilation in the TCZ group. However, this study also holds a significant limitation: the time delay between the two groups means that knowledge about how to treat the disease likely improved over this timeframe as well. All the same, the results of these observational retrospective studies provide support for TCZ as a pharmaceutical of interest for follow-up in clinical trials.

In addition to the retrospective observational studies, other analysis have utilized a retrospective case-control design to match pairs of patients with similar baseline characteristics, only one of whom received TCZ for COVID-19. In one such study, TCZ was significantly associated with a reduced risk of progression to ICU admission or death [571]. This study examined only 20 patients treated with TCZ compared (all but one of the patients treated with TCZ in the hospital during the study period) to 25 patients receiving standard of care. For the combined primary endpoint of death and/or ICU admission, only 25% of patients receiving TCZ progressed to an endpoint compared to 72% in the SOC group (p = 0.002 presumably based on a chi-square test). When the two endpoints were examined separately, progression to invasive medical ventilation remained significant (32% SOC compared to 0% TCZ, p = 0.006) but not for mortality (48% SOC compared to 25% TCZ, p = 0.066). In contrast, a study that compared 96 patients treated with TCZ to 97 patients treated with SOC only in New York City found that differences in mortality did not differ between the two groups, but that this difference did become significant when intubated patients were excluded from the analysis [572]. Taken together, these findings suggest that future clinical trials of TCZ may want to include intubation as an endpoint. However, these studies should be approached with caution, not only because of the small number of patients enrolled and retrospective design, but also because they performed a large number of statistical tests and did not account for multiple hypothesis testing. These last findings highlight the need to search for a balance between impairing a harmful immune response, such as the one generated during CRS and CSS, and preventing the worsening of the clinical picture of the patients by potential new viral infections.

Though data about TCZ for COVID-19 is still only just emerging, some meta-analyses and systematic reviews have investigated the available data. One meta-analysis [573] evaluated 19 studies published or released as preprints prior to July 1, 2020 and found that the overall trends supportive of the frequent conclusion that TCZ does improve survivorship, with a significant hazard ratio of 0.41. This trend improved when they excluded studies that administered a steroid alongside TCZ, with a significant hazard ratio of 0.04. They also found some evidence for reduced IMV or ICU admission, but only when excluding all studies except a small number reporting estimates that were adjusted for possible bias introduced by the challenges of stringency during the enrollment process. A systematic analysis of nine case-control studies estimated a hazard ratio of 0.482, which was also significant [574]. Although these estimates are similar, it is important to note that they are drawing from the same literature and are therefore likely to be affected by the same biases in publication. A second systematic review of studies investigating TCZ treatment for COVID-19 analyzed 31 studies that had been published or released as pre-prints and reported that none carried a low risk of bias (RoB) [575]. Therefore, the present evidence is not likely to be sufficient for conclusions about the efficacy of TCZ.

TCZ has been used for over a decade to treat RA [576], and a recent study shows that the drug is safe for pregnant and breastfeeding women [577]. However, TCZ may increase the risk of developing infections [576], and RA patients with chronic hepatitis B (HB) infections had a high risk of HB virus reactivation when TCZ was administered in combination with other RA drugs [578]. As a result, TCZ is contraindicated in patients with active infections such as tuberculosis [579]. Previous studies have investigated, with varying results, a possible increased risk of infection in RA patients administered TCZ [580,581], although another study reported that the incidence rate of infections was higher in clinical practice RA patients treated with TCZ than in the rates reported by clinical trials [582]. In the investigation of 544 Italian COVID-19 patients, the group treated with TCZ was found to be more likely to develop secondary infections, with 24% compared to 4% in the control group [568]. Reactivation of hepatitis B and herpes simplex virus 1 was also reported in a small number of patients in this study, all of whom were receiving TCZ. A July 2020 case report described negative outcomes of two COVID-19 patients after receiving TCZ, including one death; however, both patients were intubated and had entered septic shock prior to receiving TCZ [583], likely indicating a severe level of cytokine production. Additionally, D-dimer and sIL2R levels were reported by one study to increase in patients treated with TCZ, which raised concerns because of the potential association between elevated D-dimer levels and thrombosis and between sIL2R and diseases where T-cell regulation is compromised [569]. An increased risk of bacterial infection was also identified in a systematic review of the literature, based on the unadjusted estimates reported [573]. In summary, TCZ administration to COVID-19 patients is not without risks, may introduce additional risk of developing secondary infections, and should be approached especially cautiously for patients who have latent viral infections.

In summary, approximately 25% of coronavirus patients develop ARDS, which is caused by an excessive early response of the immune system which can be a component of cytokine release syndrome [569] and cytokine storm syndrome [579]. This overwhelming inflammation is triggered by IL-6. TCZ is an inhibitor of IL-6 and therefore may be able to neutralize the inflammatory pathway that leads to the cytokine storm. While the mechanism suggests TCZ may be beneficial for the treatment of COVID-19 patients experiencing excessive immune activity, no randomized controlled trials are available assessing its effect. However, small initial studies have found preliminary indications that TCZ may reduce progression to invasive medical ventilation and/or death. It should be noted that SOC varied widely across retrospective studies, with one study administering HCQ, lopinavir-ritonavir, antibiotics, and/or heparin as part of standard care. Interest in TCZ as a treatment for COVID-19 was supported by two meta-analyses that converged on a hazard ratio estimate of approximately 0.45 [573,574], but a third meta-analysis found that all of the available literature carries a risk of bias, with even the largest available TCZ studies to date carrying a moderate risk of bias under the ROBINS-I criteria [575]. Additionally, different studies used different dosages, number of doses, and methods of administration; ongoing research may be needed to optimize administration of TCZ [584], although similar results were reported by one study for intravenous and subcutaneous administration [568]. Clinical trials that are in progress are likely to provide additional insight into the effectiveness of this drug for the treatment of COVID-19 along with how it should be administered.

5.2.2 Neutralizing Antibodies

Monoclonal antibodies have revolutionized the way we treat human diseases. They have become some of the best-selling drugs in the pharmaceutical market in recent years [585]. There are currently 79 FDA approved mAbs on the market including antibodies for viral infections (e.g. Ibalizumab for HIV and Palivizumab for RSV) [585,586]. Virus-specific neutralizing antibodies commonly target viral surface glycoproteins or host structures, thereby inhibiting viral entry through receptor binding interference [587,588]. This section discusses current efforts in developing neutralizing antibodies against SARS-CoV-2 and how expertise gained from previous approaches for MERS-CoV and SARS-CoV may benefit antibody development. Spike (S) Neutralizing Antibody

During the first SARS epidemic in 2002, nAbs were found in SARS-CoV infected patients [589,590]. Several studies following up on these findings identified various S-glycoprotein epitopes as the major targets of neutralizing antibodies against SARS-CoV [591]. The passive transfer of immune serum containing nAbs from SARS-CoV-infected mice resulted in protection of naïve mice from viral lower respiratory tract infection upon intranasal challenge [592]. Similarly, a meta-analysis suggested that administration of plasma from recovered SARS-CoV patients reduced mortality upon SARS-CoV infection [593]. Similar results were observed in MERS-CoV infection during the second coronavirus-related epidemic of the 21st century. In these cases, neutralizing antibodies were identified against various epitopes of the RBD of the S glycoprotein [594; doi:10.1128/JVI.00912-14]. Coronaviruses use trimeric spike (S) glycoproteins on their surface to bind to host cell receptors, such as ACE2, allowing for cell entry [62,65]. Each S glycoprotein protomer is comprised of an S1 domain, also called the receptor binding domain (RBD), and an S2 domain. The S1 domain binds to host cell receptors while the S2 domain facilitates the fusion between the viral envelope and host cell membranes [591]. Although targeting of the host cell receptor ACE2 shows efficacy in inhibiting SARS-CoV-2 infection [73], given the physiological relevance of ACE2 [595], it would be favorable to target virus-specific structures rather than host receptors. This forms the rationale of developing neutralizing antibodies against the S glycoprotein, disrupting its interaction with ACE2 and other receptors and thereby inhibiting viral entry.

The first human neutralizing antibody against SARS-CoV-2 targeting the trimeric spike (S) glycoproteins was developed using hybridoma technology [596], where antibody-producing B-cells developed by mice can be inserted into myeloma cells to produce a hybrid cell line (the hybridoma) that is grown in culture. The 47D11 clone was able to cross-neutralize SARS-CoV and SARS-CoV2 by a mechanism that is different from receptor binding interference. The exact mechanism of how this clone neutralizes SARS-CoV-2 and inhibits infection in vitro remains unknown, but a potential mechanism might be antibody-induced destabilization of the membrane prefusion structure [596,597]. The ability of this antibody to prevent infection at a feasible dose needs to be validated in vivo, especially since in vitro neutralization effects have been shown to not be reflective of in vivo efficacy [598]. Only a week later, a different group successfully isolated multiple nAbs targeting the RBD of the S glycoprotein from blood samples taken from COVID-19 patients in China [143]. Interestingly, the patient-isolated antibodies did not cross-react with RBDs from SARS-CoV and MERS-CoV, although cross-reactivity to the trimeric spike proteins of SARS-CoV and MERS-CoV was observed. This finding suggests that the RBDs between the three coronavirus species are immunologically distinct and that the isolated nAbs targeting the RBD of SARS-CoV-2 are species specific. While this specificity is desirable, it also raises the question of whether these antibodies are more susceptible to viral escape mechanisms. Viral escape is a common resistance mechanism to nAbs therapy due to selective pressure from neutralizing antibodies [599,600]. For HIV, broadly neutralizing antibodies (bnAbs) targeting the CD4 binding site (CD4bs) show greater neutralization breadth than monoclonal antibodies, which target only specific HIV strains [601]. For MERS-CoV, a combination of multiple neutralizing antibodies targeting different antigenic sites prevented neutralization escape [602]. It was found that the different antibody isolates did not target the same epitopes, suggesting that using them in combination might produce a synergistic effect that prevents viral escape [143]. It was also demonstrated that binding affinity of the antibodies does not reflect their capability to compete with ACE2 binding. Furthermore, no conclusions about correlations between the severity of disease and the ability to produce neutralizing antibodies can be drawn at this point. Rather, higher neutralizing antibody titers were more frequently found in patients with severe disease. Correspondingly, higher levels of anti-spike IgG were observed in patients that deceased from infection compared to patient that recovered [603].

Results from the SARS and MERS epidemics thus provide valuable lessons for the design of neutralizing antibodies for the current outbreak. The findings for SARS-CoV and MERS-CoV can aid in identifying which structures constitute suitable targets for nAbs, despite the fact that the RBD appears to be distinct between the three coronavirus species. These studies also suggest that a combination of nAbs targeting distinct antigens might be necessary to provide protection [602]. The biggest challenge remains identifying antibodies that not only bind to their target, but also prove to be beneficial for disease management. On that note, a recently published study indicates that anti-spike antibodies could make the disease worse rather than eliminating the virus [603]. These findings underscores our current lack of understanding the full immune response to SARS-CoV-2.

5.2.3 Interferons

Interferons (IFNs) are a family of cytokines crucial to activating the innate immune system response against viral infections. Interferons are classified into three categories based on their receptor specificity: types I, II and III [109]. Specifically, IFNs I (IFN-𝛼 and 𝛽) and II (IFN-𝛾) induce the expression of antiviral proteins that bring the viral RNA to degradation [604]. Among these IFNs, IFN-𝛽 has already been found to strongly inhibit the replication of other coronaviruses, such as SARS-CoV, in cell culture, while IFN-𝛼 and 𝛾 were shown to be less effective in this context [604]. There is evidence that patients with higher susceptibility to ARDS indeed show deficiency in IFN- 𝛽. For instance, infection with other coronaviruses impairs IFN-𝛽 expression and synthesis, allowing the virus to escape the innate immune response [605]. On March 18 2020, Synairgen plc received approval to start a phase II trial for SNG001, an IFN-𝛽-1a formulation to be delivered to the lungs via inhalation. SNG001 was already shown to be effective in reducing viral load in an in vivo model of swine flu and in vitro models of other coronavirus infections [606-.pdf’. In July, a press release from Synairgen stated that SNG001 reduced progression to ventilation in a double-blind, placebo-controlled, multi-center study of 101 patients with an average age in the late 50s [607]. They also reported that patients in the treatment group showed greater recovery and lower breathlessness. However, given that this information was released in a press release rather than in a manuscript and thus cannot be thoroughly reviewed, these findings should be considered preliminary.

5.2.4 Vaccines Vaccine Development

Flu-like illnesses caused by viruses are a common target of vaccine development, and influenza vaccine technology in particular has made many strides. During the H1N1 influenza outbreak, vaccine development was accelerated because of the existing infrastructure, along with the fact that regulatory agencies had already decided that vaccines produced using egg- and cell-based platforms could be licensed under the regulations used for a strain change. Critiques of the production and distribution of the H1N1 vaccine have stressed the need for alternative development-and-manufacturing platforms that can be readily adapted to new pathogens. Although a monovalent H1N1 vaccine was not available before the pandemic peaked in the United States and Europe, it was available soon afterward as a stand-alone vaccine that was eventually incorporated into commercially available seasonal influenza vaccines [608]. If H1N1 vaccine development provides any indication, considering developing and manufacturing platforms for promising COVID-19 vaccine trials early could hasten the emergence of an effective prophylactic vaccine against SARS-CoV-2.

The first critical step towards developing a vaccine against SARS-CoV-2 was characterizing the target, which fortunately happened early in the COVID-19 outbreak with the sequencing and dissemination of the viral genome [609]. The Coalition for Epidemic Preparedness Innovations (CEPI) is coordinating global health agencies and pharmaceutical companies to develop vaccines against SARS-CoV-2. There are over 100 vaccine candidates against SARS-CoV-2 in clinical trials. Of the 78 active vaccine programs, 73 were in the preclinical or exploratory stage [610]. Unlike many global vaccine development programs previously, such as with H1N1, the vaccine development landscape for COVID-19 includes vaccines produced by a wide array of technologies. Experience in the field of oncology is encouraging COVID-19 vaccine developers to use next-generation approaches to vaccine development, which have led to the great diversity of vaccine development programs [611]. Diverse technology platforms include DNA, RNA, virus-like particle, recombinant protein, both replicating and non-replicating viral vectors, live attenuated virus, and inactivated virus approaches. Given the wide range of vaccines under development, it is possible that some vaccine products may eventually be shown to be more effective in certain subpopulations, such as children, pregnant women, immunocompromised patients, the elderly, etc. The requirements for a successful vaccine trial and deployment are complex and may require coordination between government, industry, academia, and philanthropic entities [612]. While little is currently known about immunity to SARS-CoV-2, vaccine development typically tests for serum neutralizing activity, as this has been established as a biomarker for adaptive immunity in other respiratory illnesses [613]. DNA Vaccines

This vaccination method involves the direct introduction of a plasmid containing a DNA sequence encoding the antigen(s) against which an immune response is sought into appropriate tissues [614]. This approach may offer several advantages over traditional vaccination approaches, such as the stimulation of both B- as well as T-cell responses and the absence of any infectious agent. Currently, a Phase I safety and immunogenicity clinical trial of INO-4800, a prophylactic vaccine against SARS-CoV-2, is underway [615]. The vaccine developer Inovio Pharmaceuticals Technology is overseeing administration of INO-4800 by intradermal injection followed by electroporation with the CELLECTRA® device to healthy volunteers. Electroporation is the application of brief electric pulses to tissues in order to permeabilize cell membranes in a transient and reversible manner. It has been shown that electroporation can enhance vaccine efficacy by up to 100-fold, as measured by increases in antigen-specific antibody titers [616]. The safety of the CELLECTRA® device has been studied for over seven years, and these studies support the further development of electroporation as a safe vaccine delivery method [617]. The temporary formation of pores through electroporation facilitates the successful transportation of macromolecules into cells, allowing cells to robustly take up INO-4800 for the production of an antibody response.

Approved by the U.S. Food and Drug Administration (FDA) on April 6, 2020, the Phase I study is enrolling up to 40 healthy adult volunteers in Philadelphia, PA at the Perelman School of Medicine and at the Center for Pharmaceutical Research in Kansas City, MO. The trial has two experimental arms corresponding to the two locations. Participants in Experimental Group 1 will receive one intradermal injection of 1.0 milligram (mg) of INO-4800 followed by electroporation using the CELLECTRA® 2000 device twice, administered at Day 0 and Week 4. Participants in Experimental Group 2 will receive two intradermal injections of 1.0 mg (total 2.0 mg per dosing visit) of INO-4800 followed by electroporation using the CELLECTRA® 2000 device, administered at Day 0 and Week 4. Safety data and the initial immune responses of participants from the trial are expected by the end of the summer of 2020. The development of a DNA vaccine against SARS-CoV-2 by Inovio could be an important step forward in the world’s search for a COVID-19 vaccine. Although exciting, the cost of vaccine manufacturing and electroporation may make scaling the use of this technology for prophylactic use for the general public difficult. RNA Vaccines

RNA vaccines are nucleic-acid based modalities that code for viral antigens against which the human body elicits a humoral and cellular immune response. The mRNA technology is transcribed in vitro and delivered to cells via lipid nanoparticles (LNP) [618]. They are recognized by ribosomes in vivo and then translated and modified into functional proteins [619]. The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses [619]. Naturally, mRNA is not very stable and can degrade quickly in the extracellular environment or the cytoplasm. The LNP covering protects the mRNA from enzymatic degradation outside of the cell [620]. Codon optimization to prevent secondary structure formation and modifications of the poly-A tail as well as the 5’ untranslated region to promote ribosomal complex binding can increase mRNA expression in cells. Furthermore, purifying out dsRNA and immature RNA with FPLC (fast performance liquid chromatography) and HPLC (high performance liquid chromatography) technology will improve translation of the mRNA in the cell [619,621]. Vaccines based on mRNA delivery confer many advantages over traditional viral vectored vaccines and DNA vaccines. In comparison to live attenuated viruses, mRNA vaccines are non-infectious and can be synthetically produced in an egg-free, cell-free environment, thereby reducing the risk of a detrimental immune response in the host [622]. Unlike DNA vaccines, mRNA technologies are naturally degradable and non-integrating, and they do not need to cross the nuclear membrane in addition to the plasma membrane for their effects to be seen [619]. Furthermore, mRNA vaccines are easily, affordably, and rapidly scalable.

Although mRNA vaccines have been developed for therapeutic and prophylactic purposes, none have been licensed or commercialized thus far. Nevertheless, they have shown promise in animal models and preliminary clinical trials for several indications, including rabies, coronavirus, influenza, and cytomegalovirus [623]. Preclinical data from Pardi et al. identified effective antibody generation against full-length FPLC-purified influenza hemagglutinin stalk-encoding mRNA in mice, rabbits, and ferrets [624]. Similar immunological responses for mRNA vaccines were observed in humans in Phase I and II clinical trials operated by the pharmaceutical-development companies Curevac and Moderna for rabies, flu, and zika [621]. Positively charged bilayer LNPs carrying the mRNA attract negatively charged cell membranes, endocytose into the cytoplasm [620], and facilitate endosomal escape. LNPs can be coated with modalities recognized and engulfed by specific cell types. LNPs 150nm or less effectively enter into lymphatic vessels.

There are three types of RNA vaccines: non-replicating, in vivo self-replicating, and in vitro dendritic cell non-replicating [625]. Non-replicating mRNA vaccines consist of a simple open reading frame (ORF) for the viral antigen flanked by the 5’ UTR and 3’ poly-A tail. In vivo self-replicating vaccines encode a modified viral genome derived from single-stranded, positive sense RNA alphaviruses [619,621]. The RNA genome encodes the viral antigen along with proteins of the genome replication machinery, including an RNA polymerase. Structural proteins required for viral assembly are not included in the engineered genome [619]. Self-replicating vaccines produce more viral antigens over a longer period of time, thereby evoking a more robust immune response [625]. Finally, in vitro dendritic cell non-replicating RNA vaccines limit transfection to dendritic cells. Dendritic cells are potent antigen-presenting immune cells that easily take up mRNA and present fragments of the translated peptide on their MHC proteins, which can then interact with T cell receptors. Ultimately, primed T follicular helper cells can stimulate germinal center B cells that also present the viral antigen to produce antibodies against the virus [626]. These cells are isolated from the patient, grown and transfected ex vivo, and reintroduced to the patient [627].

mRNA-1273 was the first COVID-19 vaccine to enter a phase I clinical in the United States. ModernaTX, Inc. is currently spearheading an investigation on the immunogenicity and reactogenicity of mRNA-1273, a conventional lipid nanoparticle encapsulated RNA encoding a full-length prefusion stabilized spike (S) protein for SARS-CoV-2 [628]. In a study that is ongoing, forty-five participants were enrolled and given intramuscular injections of mRNA-1273 in their deltoid muscle on day 1 and day 29, and then followed for the next twelve months. Healthy males and non-pregnant females aged 18-55 years were recruited for this study and divided into three groups receiving 25, 100, or 250 micrograms (μg) of mRNA-1273. IgG ELISA assays on patient serology samples are being used to examine the immunogenicity of the vaccine [628].

A preliminary report describing initial safety and immunogenicity findings is now available [613]. Binding antibodies were observed at two weeks after the first dose at all concentrations. At the time point one week after the second dose was administered on day 29, the pseudotyped lentivirus reporter single-round-of-infection neutralization assay (PsVNA), which was used to assess neutralizing activity, reached a median level similar to the median observed in convalescent plasma samples. Participants reported mild and moderate systemic adverse events after the day 1 injection, and one severe local event was observed in each of the two highest dose levels. The second injection led to severe systemic adverse events for three of the participants at the highest dose levels, with one participant in the group being evaluated at an urgent care center on the day after the second dose. The reported localized adverse events from the second dose were similar to those from the first.

In summary, mRNA vaccines are promising tools in the prevention and control of pandemics because they may sidestep many challenges associated with traditional vaccine design and manufacturing. mRNA-1273 is the only RNA vaccine for SARS-CoV-2 for which preliminary results are available. This early in the development process, placebo-blinded and randomized results are not yet available, but the initial results are promising. In the dose ranging study, even the lowest dose of 25 μg of mRNA-1273 appeared to be sufficient to induce an immunogenicity profile comparable to that observed in convalescent plasma and appeared to be well tolerated among the population of healthy, non-pregnant participants from 18-55 years of age. Based on the preliminary results from mRNA-1273 [613], a new trial aims to enroll 30,000 participants who will be randomized for two injections of 100 μg of mRNA-1273 or placebo, again spaced 28 days apart [629]. Adjuvants for Vaccines

Adjuvants include a variety of molecules or larger microbial-related products that have an effect on the immune system or an immune response of interest. They can either be comprised of or contain immunostimulants or immunomodulators. Adjuvants are sometimes included within vaccines, especially vaccines other than live-attenuated and inactivated viruses, in order to enhance the immune response. A review on the development of SARS-CoV-2 vaccines [630] also included a brief summary of the potential of adjuvants for these vaccines, including a brief description of some already commonly used adjuvants. Different adjuvants can regulate different types of immune responses, so the type or combination of adjuvants used in a vaccine will depend on both the type of vaccine and concern related to efficacy and safety. A variety of possible mechanisms for adjuvants have been researched [631,632,633], including the following: induction of DAMPs (damage-associated molecular patterns) that can be recognized by certain pattern recognition receptors (PRRs) of the innate immune system; functioning as PAMPs (pathogen-associated molecular patterns) that can also be recognized by certain pattern recognition receptors (PRRs); and more generally enhancing the humoral or cellular immune responses. Selection of one or more adjuvants requires considering how to promote the advantageous effects of the components and/or immune response and, likewise, to inhibit possible deleterious effects. There are also considerations related to the method of delivering (or co-delivering) the adjuvant and antigen components of a vaccine.

6 Discussion

As the COVID-19 pandemic continues to develop, the scientific community has responded by rapidly collecting and disseminating information about the SARS-CoV-2 virus and its ability to infect humans and other animals. This fundamental information has allowed for innovations in the areas of diagnostics and therapeutics that continue to be proposed and developed upon. In this review, we seek to explain the scientific rationale underlying these technologies and to critically evaluate the literature available about them.

6.1 Current State of Diagnostics

6.2 Current State of Therapeutics

The majority of current clinical trials and lines of investigation have focused on repurposing existing therapies to counter SARS-CoV-2 and treat its symptoms. This approach is necessary given the urgency of the situation as well as the extensive time required for developing and testing new therapies. However, in the long-term, new drugs specific for treatment of COVID-19 may also enter development. There is thus value in investigating two lines of inquiry for treatment of COVID-19: 1) new therapeutics specific for treatment of COVID-19 or its symptoms, and 2) repurposing of existing therapeutics for treatment of COVID-19 or its symptoms. Here we consider further avenues that scientific investigators may explore in the development of therapies for COVID-19.

While studies of hydroxychloroquine (HCQ) have not supported the early theoretical interest in this antiviral treatment, it may be of interest to explore alternatives with similar mechanisms. For example, hydroxyferroquine derivatives of HCQ have been described as a class of bioorganometallic compounds that exert antiviral effects with some selectivity for SARS-CoV [634]. Future work could explore whether these compounds exert antiviral effects against SARS-CoV-2 and whether they are safe for use in animals and humans.

The tocilizumab trial described in an above section [36] studies the possibility of using an anti-inflammatory agent typically used for the treatment of autoimmune disease to counter the effects of the “cytokine storm” induced by the virus. Another anti-IL-6 antibody, sarilumab, is also being investigated [635,636]. Typically, immunosuppressive drugs such as these are contraindicated in the setting of infection [637]. However, COVID-19 results in hyperinflammation that appears to contribute to mortality via lung damage, suggesting that immunosuppression may be a helpful approach to treatment [120]. The decision of whether and/or when to counter hyperinflammation with immunosuppression in the setting of COVID-19 remains in debate as the risks of inhibiting antiviral immunity continue to be weighed against the beneficial anti-inflammatory effects [638]. If the need to curtail the “cytokine storm” inflammatory response to the virus transcends the risks of immunosuppression, exploration of more anti-inflammatory agents may be warranted; these agents are considered here. While tocilizumab targets IL-6, several other inflammatory markers could be potential targets, including TNF-alpha. Inhibition of TNF-alpha by an inhibitor such as Etanercept has been previously suggested for treatment of SARS-CoV [639] and may be relevant for SARS-CoV-2 as well. Baricitinib and other small molecule inhibitors of the JAK kinase pathway also curtail the inflammatory response and have been suggested as potential options for SARS-CoV-2 infections [640]. Baricitinib in particular may be able to reduce the ability of SARS-CoV-2 to infect lung cells [641]. Clinical trials studying baricitinib in COVID-19 have already begun in the US and in Italy [642,643]. Identification and targeting of further inflammatory markers that are relevant in SARS-CoV-2 infection may be of value for curtailing the inflammatory response and lung damage. Lastly, it is also worth noting the high costs of tocilizumab therapy and other biologics: at doses used for rheumatoid arthritis patients, the cost for tocilizumab ranges from $179.20 to $896 per dose for the IV form and $355 for the pre-filled syringe [644]. Cyclosporine may be a more cost-effective and readily-available alternative than biologics [645], if it proves effective against the cytokine storm induced by SARS-CoV-2.

Another approach is the development of antivirals, which could be broad-spectrum, specific to coronaviruses, or targeted to SARS-CoV-2. Given the increasingly apparent role of the cytokine storm in disease pathogenesis, it is possible that antivirals could be less effective in more severe cases of COVID-19, but this is not yet known; regardless, it is likely that early-stage patients could benefit from antiviral therapy. The potential for remdesivir as an antiviral has already been described in an above section. Development of new antivirals is complicated by the fact that none have yet been approved for human coronaviruses. Intriguing new options are emerging, however. Beta-D-N4-hydroxycytidine (NHC) is an orally bioavailable ribonucleotide analog showing broad-spectrum activity against RNA viruses, which may inhibit SARS-CoV-2 replication [646]. Various other antivirals are in development. Development of antivirals will be further facilitated as research reveals more information about the interaction of SARS-CoV-2 with the host cell and host cell genome, mechanisms of viral replication, mechanisms of viral assembly, and mechanisms of viral release to other cells; this can allow researchers to target specific stages and structures of the viral life cycle.

Antibodies against viruses, also known as antiviral monoclonal antibodies, could be an alternative as well and are described in detail in an above section. The goal of antiviral antibodies is to neutralize viruses through either cell-killing activity or blocking of viral replication [647]. They may also engage the host immune response, encouraging the immune system to hone in on the virus. Given the cytokine storm that results from immune system activation in response to the virus, which has been implicated in worsening of the disease, a neutralizing antibody (nAb) may be preferable. Upcoming work may explore the specificity of nAbs for their target, mechanisms by which the nAbs impede the virus, and improvements to antibody structure that may enhance the ability of the antibody to block viral activity.

There is also some research into possible potential therapeutics or prophylactics which interact with components of the innate immune response. For example, there are a variety of toll-like receptors (TLRs) which are examples of pattern recognition receptors (PRRs), innate immune response components which recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Note that TLRs form a part of innate immune recognition and can more generally contribute to promoting both innate and adaptive responses [105]. In mouse models, poly(I:C) and CpG, which are agonists of toll-like receptors TLR3 and TLR9, respectively, showed protective effects when administered prior to SARS-CoV infection [648]. Therefore, TLR agonists hold some potential for broad-spectrum prophylaxis. Another type of approach which is being investigated is the possible use of what is termed trained immunity, in particular as elicited by non-SARS-CoV-2 whole-microorganism vaccines (or other microbial stimuli), as a tool which might be shown to generate heterologous protective effects with respect to SARS-CoV-2 susceptibility or severity [649]. In a recent review [650], trained immunity was defined as forms of memory which are temporary (e.g., months or years, and reversible), displayed by innate immune cells and innate immune features of other cells, displayed as increased responsiveness to future same or heterologous pathogen infection or sometimes decreased responsiveness or immunological tolerance, and established through epigenetic and metabolic mechanisms. One type of stimulus which research indicates can induce trained immunity is bacillus Calmette-Guerin (BCG) vaccination. BCG is an attenuated form of bacteria Mycobacterium bovis. The vaccine is most commonly administered for the prevention of tuberculosis in humans. With respect to SARS-CoV-2 specifically, clinical trials in non-SARS-CoV-2-infected adults have been setup to assess the possible efficacy of BCG vaccination – e.g., to assess if it may be effective as a potential prophylactic or potential partial prophylactic in (1) reducing susceptibility / preventing infection and (2) reducing disease severity (for descriptions of trials with BCG vaccine or the related vaccine VPM1002, see [649,651,652,653,654,655,656,657,658,659,660,661,662,663,664]). Some trials enroll healthcare workers, other trials hospitalized elderly adults without immunosuppression who get vaccinated with placebo or BCG at hospital discharge, and yet another set of trials older adults (>50 years) under chronic care for conditions like hypertension and diabetes. One set of trials, for example, uses time until first infection as the primary study endpoint; more generally, outcomes measured in some of these trials are related to incidence of disease and disease severity or symptoms. An article [649] that very briefly summarizes the setup of these trials also mentions some data analyses which showed possible correlations between countries which have more BCG vaccination (or BCG vaccination policies) and the severity of COVID-19 in those countries, but (1) it is unclear whether this correlation indicates an interaction because for example of many other possible factors or confounding factors (country age distribution, detection efficiency, stochastic epidemic dynamic effects, differences in healthcare capacity over time in relation to epidemic dynamics, and various other factors) and (2) also it is unclear what is the relation between BCG vaccination at different ages and at longer times before the start of the SARS-CoV-2 epidemic and BCG vaccination at different ages during the SARS-CoV-2 epidemic at shorter times before the risk of possible infection; at least some of these considerations are also made or pointed out in the data analyses sited and in the article. The article [649] also includes various related considerations such as efficacy in related animal and human studies and the safety of the vaccine, both generally and specifically with respect to SARS-CoV-2. Additionally, we review here one of the most important considerations: severe SARS-CoV-2 has been characterized so far to possibly exhibit dysregulated immune responses and whether or when some immune responses are protective or pathogenic is still under research (e.g., [107,649,665,666]); also, trained immunity itself may sometimes be related to either balanced, or too much or too little, or useful or harmful immunological responses. The article [649] proposes that trained immunity might lead to an earlier stronger response which could reduce viremia and avoid (possibly with the additional support of another therapeutic administered later) the later detrimental immunopathology seen with severe cases; while this is a possibility, additional research is required to assess its validity.

In the longer term, as more information becomes available about the structures of SARS-CoV-2 components, small molecule inhibitors of those components may become candidates for drug discovery. For example, crystal structures of the SARS-CoV-2 main protease have recently been resolved [667,668]. Efforts have already been in place to perform screens for small molecule inhibitors of the main protease, yielding potential hits [667]. Much work remains to be done to determine further crystal structures of other viral components, understand the relative utility of targeting different viral components, perform additional small molecule inhibitor screens, and determine the safety and efficacy of the potential inhibitors. While still nascent, work in this area is promising.

6.3 Social Factors Influencing COVID-19 Outcomes

The evidence clearly indicates that social environmental factors are critical determinants of individuals’ and communities’ risks related to COVID-19. There are distinct components to COVID-19 susceptibility, and an individual’s risk can be elevated at one or all stages from exposure to recovery/mortality: an individual may be more likely to be exposed to the virus, more likely to get infected once exposed, more likely to have serious complications once infected, be less likely to receive adequate care once they are seriously ill. The fact that differences in survival between Black and white patients were no longer significant after controlling for comorbidities and socioeconomic status (type of insurance, neighborhood deprivation score, and hospital where treatment was received) in addition to sex and age [278] underscores the relevance of social factors to understanding mortality differences between racial and ethnic groups. Moreover, the Black patients were younger and more likely to be female than white patients, yet still had a higher mortality rate without correction for the other variables [278]. Here, we outline a few systemic reasons that may exacerbate the COVID-19 pandemic in communities of color.

6.3.1 Exposure to COVID-19

Social distancing has emerged as one of the main social policies used to manage the COVID-19 epidemic in many countries. Many governments issued stay-at-home orders, especially in the initial months of the crisis. However, data clearly indicates that these orders impacted different socioeconomic groups differently. In U.S. counties with and without stay-at-home orders, smartphone tracking indicated a significant decrease in the general population’s mobility in April relative to February through March of 2020 (-52.3% and -60.8%, respectively) [669]. A linear relationship was observed between counties’ reduction in mobility and their wealth and health, as measured by access to health care, food security, income, space, and other factors [669]. Counties with greater reductions in mobility were also found to have much lower child poverty and household crowding and to be more racially segregated, and to have fewer youth and more elderly residents [669]. Similar associations between wealth and decreased mobility were observed in cellphone GPS data from Colombia, Indonesia, and Mexico collected between January and May 2020 [670]. These disparities in mobility are likely to be related to the role that essential workers have played during the pandemic. Essential workers are disproportionately likely to be female, people of color, immigrants, and to have an income below 200% of the poverty line [671]. Black Americans in particular are over-represented among front-line workers and in professions where social distancing is infeasible [672]. Health care work in particular presents an increased risk of exposure to SARS-CoV-2 [672,673,674,675,676]. In the United Kingdom, (South) Asians are more likely than their white counterparts to be medical professionals [277], although BAME medical professionals are still disproportionately represented in the proportion of National Health Service staff deaths [677]. Similar trends have been reported for nurses, especially nurses of color, in the United States [678]. Furthermore, beyond the risks associated with work itself, use of public transportation may also impact COVID-19 risk [679]. The socioeconomic and racial/ethnic gaps in who is working on the front lines of the pandemic make it clear that socioeconomic privilege is likely to decrease the probability of exposure to SARS-CoV-2.

Increased risk of exposure can also arise outside the workplace. Nursing homes and skilled nursing facilities received attention early on as high-risk locations for COVID-19 outbreaks [680]. Prisons and detention centers also confer a high risk of exposure or infection [681,682]. Populations in care facilities are largely older adults, and in the United States, incarcerated people are more likely to be male and persons of color, especially Black [683]. Additionally, multi-generational households are less common among non-Hispanic white Americans than people of other racial and ethnic backgrounds [684], increasing the risk of exposure for more susceptible family members. Analysis suggests that household crowding may also be associated with increased risk of COVID-19 exposure [669], and household crowding is associated with poverty [685]. Forms of economic insecurity like housing insecurity, which is associated with poverty and more pronounced in communities subjected to racism [686,687], would be likely to increase household crowding and other possible sources of exposure. As a result, facets of systemic inequality such as mass incarceration of Black Americans and poverty are likely to increase the risk of exposure outside of the workplace.

6.3.2 Severity of COVID-19 Following Exposure

Following exposure to SARS-CoV-2, the likelihood that an individual develops COVID-19 and the severity of the disease presentation can be influenced by a number of social factors. As discussed above, a number of patient characteristics are associated with the likelihood of severe COVID-19 symptoms. In some cases, these trends run counter to those expected given rates of exposure: for example, although women are more likely to be exposed, men are more likely to be diagnosed with, hospitalized from, or die from COVID-19 [242]. In the case of comorbid conditions and racial/ethnic demographics, however, social factors are highly likely to modulate or at least influence the apparent association between these traits and the increased risk from COVID-19. In particular, the comorbidities and racial/ethnic correlates of severe COVID-19 outcomes suggest that poverty confers additional risk for COVID-19.

In order to explore the relationship between poverty and COVID-19 outcomes, it is necessary to consider how poverty impacts biology. In particular, we focus on the United States and the United Kingdom. Comorbidities that increase risk for COVID-19, including obesity, type II diabetes, hypertension, and cardiovascular disease, are known to be intercorrelated [688]. Metabolic conditions related to heightened inflammation, like obesity, type II diabetes, and hypertension, are more strongly associated with negative COVID-19 outcomes than other comorbid conditions, such as chronic heart disease [689]. As discussed above, dysregulated inflammation characteristic of cytokine release syndrome is one of the greatest concerns for COVID-19-related death. Therefore, it is possible that chronic inflammation characteristic of these metabolic conditions predisposes patients to COVID-19-related death [689]. The association between these diseases and severe COVID-19 outcomes is a concern from a health equity perspective because poverty exposes people to “obesogenic” conditions [690] and is therefore unsurprisingly associated with higher incidence of obesity and associated disorders [691]. Furthermore, cell phone GPS data suggests that lower socioeconomic status may also be associated with decreased access to healthy food choices during the COVID-19 pandemic [692,693], suggesting that health-related risk factors for COVID-19 may be exacerbated as the pandemic continues [694]. Chronic inflammation is a known outcome of chronic stress (e.g., [695,696,697,698]). Therefore, the chronic stress of poverty is likely to influence health broadly (as summarized in [???]) and especially during the stress of the ongoing pandemic.

A preprint [699] provided observational evidence that geographical areas in the United States that suffer from worse air pollution by fine particulate matter have also suffered more COVID-19 deaths per capita, after adjusting for demographic covariates. Although lack of individual-level exposure data and the impossibility of randomization make it difficult to elucidate the exact causal mechanism, this finding would be consistent with similar findings for all-cause mortality (e.g., [700]). Exposure to air pollution is associated with both poverty (e.g., [701]) and chronic inflammation [702]. Taken together, the evidence suggests that low-income workers who face greater exposure to SARS-CoV-2 due to their home or work conditions are also more likely to face environmental and social stressors associated with increased inflammation, and therefore with increased risk from COVID-19. In particular, structural racism can play an important role on disease severity after SARS-CoV-2 exposure, due to consequences of racism which include an increased likelihood of poverty and its associated food and housing instability. COVID-19 can thus be considered a “syndemic”, or a synergistic interaction between several epidemics [703]. As a result, it is not surprising that people from minoritized backgrounds and/or with certain pre-existing conditions are more likely to suffer severe effects of COVID-19, but these “risk factors” are likely to be causally linked to poverty.

6.3.3 Access to Treatment

Finally, COVID-19 outcomes can be influenced by access to healthcare. Receiving care for COVID-19 can, but does not always, include receiving a positive test for the SARS-CoV-2 virus. For example, it is common to see treatment guidelines for suspected cases regardless of whether the presence of SARS-CoV-2 has been confirmed (e.g., [704]). Whether and where a patient is diagnosed can depend on their access to testing, which can vary both between and within countries. In the United States, it is not always clear whether an individual will have access to free testing [705,706]. The concern has been raised that more economic privilege is likely to correspond to increased access to testing, at least within the United States [707]. This is supported by the fact that African Americans seem to be more likely to be diagnosed in the hospital, while individuals from other groups were more likely to have been diagnosed in ambulatory settings in the community [235]. Any delays in treatment are a cause for concern [708], which could potentially be increased by an inability to acquire testing because in the United States, insurance coverage for care received can depend on a positive test [709].

Another important question is whether patients with moderate to severe cases are able to access hospital facilities and treatments, to the extent that they have been identified. Early findings from China as of February 2020 suggested the COVID-19 mortality rate to be much lower in the most developed regions of the country [710], although reported mortality is generally an estimate of CFR, which is dependent on rates of testing. Efforts to make treatment accessible for all confirmed and suspected cases of COVID-19 in China are credited with expanding care to people with fewer economic resources [711]. In the United States, access to healthcare varies widely, with certain sectors of the workforce less likely to have health insurance; many essential workers in transportation, food service, and other frontline fields are among those likely to be uninsured or underinsured [708]. As of 2018, Hispanic Americans of all races were much less likely to have health insurance than people from non-Hispanic backgrounds [712]. Therefore, access to diagnostics and care prior to the development of severe COVID-19 is likely to vary depending on socioeconomic and social factors, many of which overlap with the risks of exposure and of developing more severe COVID-19 symptoms. This discrepancy ties into concerns about broad infrastructural challenges imposed by COVID-19. A major concern in many countries has been the saturation of healthcare systems due to the volume of COVID-19 hospitalizations (e.g., [220]). Similarly, there have been shortages of supplies such as ventilators that are critical to the survival of many COVID-19 patients, leading to extensive ethical discussions about how to allocate limited resources among patients [713,714,715,716]. Although it is generally considered unethical to consider demographic factors such as age, sex, race, or ethnicity while making such decisions, and ideally this information would not be shared with triage teams tasked with allocating limited resources among patients [717], there are substantial concerns about implicit and explicit biases against older adults [718], premature infants [719], and people with disabilities or comorbidities [717,720,721]. Because of the greater burden of chronic disease in populations subjected to systemic racism, algorithms intended to be blind to race and ethnicity could, in fact, reinforce systemic inequalities caused by structural racism [??? 10.1056/NEJMp2023616,722,723]. Because of this inequality, it has been argued that groups facing health disparities should be prioritized by these algorithms [724]. This approach would carry its own ethical concerns, including the fact that many resources that need to be distributed do not have well-established risks and benefits [724].

As the pandemic has progressed, it has become clear that ICU beds and ventilators are not the only limited resources that needs to be allocated, and, in fact, the survival rate for patients who receive mechanical ventilation is lower than these discussions would suggest [725]. Allocation of interventions that may reduce suffering, including palliative care, has become critically important [725,726]. The ambiguities surrounding the risks and benefits associated with therapeutics that have been approved under emergency use authorizations also present ethical concerns related to the distribution of resources [724]. For example, remdesivir, discussed below, is an antiviral produced by Gilead that has shown some promise for alleviating symptoms and reducing the duration of hospitalization. Remdesivir is currently available for the treatment of COVID-19 under compassionate use guidelines and through expanded access programs, and in many cases has been donated to hospitals by Gilead [727,728]. Regulations guiding the distribution of drugs in situations like these typically do not address how to determine which patients receive them [728]. Prioritizing marginalized groups for treatment with a drug like remdesivir would also be unethical because it would entail disproportionately exposing these groups to a therapeutic that may or not be beneficial [724]. On the other hand, given that the drug is one of the most promising treatments available for many patients, using a framework that tacitly feeds into structural biases would also be unethical. At present, the report prepared for the Director of the CDC by Ethics Subcommittee of the CDC fails to address the complexity of this ethical question given the state of structural racism in the United States, instead stating that “prioritizing individuals according to their chances for short-term survival also avoids ethically irrelevant considerations, such as race or socioeconomic status” [729]. In many cases, experimental therapeutics are made available only through participation in clinical trials [730]. However, given the history of medical trials abusing minority communities, especially Black Americans, there is a history of unequal representation in clinical trial enrollment [730]. As a result, the standard practice of requiring enrollment in a clinical trial in order to receive experimental treatment may also reinforce patterns established by systemic racism.

6.3.4 Access to and Representation in Clinical Trials


7 Methods

In an effort to keep pace as new information about COVID-19 and SARS-CoV-2 becomes available, this project is an open, collaborative effort that invited contributions the scientific community broadly, similar to previous efforts to develop collaborative reviews [731,732]. Contributors were recruited by word of mouth and on Twitter. Several efforts to work with existing efforts to train early-career scientists were also integrated: Appendix A contains summaries written by the students, post-docs, and faculty of the Immunology Institute at the Mount Sinai School of Medicine [733] and two of the authors were recruited through the American Physician Scientist Association’s Virtual Summer Research Program [734]. The project was managed through GitHub [735] using Manubot [7] to continuously generate a version of the manuscript online [736]. Contributors developed text that was proposed through GitHub’s pull request system and then reviewed and approved by at least one other author. While this document reflects the current version of record, the online version will continue to be developed as information about the pandemic emerges. Below, we will describe the processes used to synthesize the literature.

7.1 Technical Infrastructure

7.1.1 Collaborative Writing and Manuscript Generation

Manubot [7] is a collaborative writing framework developed to adapt open-source software development techniques and version control for manuscript development. Here, Manubot was used to generate a manuscript from text maintained using GitHub, a popular, online version control interface. The GitHub implementation allowed users to contribute either using git on the command line or using the GitHub user interface, and we developed documentation for users with less experience with this platform. Manubot also provides a functionality to create a bibliography using digital object identifiers (DOIs), website URLs, or other identifiers such as PubMed identifiers and arXiv IDs [7]. Due to the needs of this project, project contributors also submitted pull requests to add support for clinical trial identifiers. Finally, the use of Manubot and GitHub allowed for scripted updates to be run each time the manuscript was generated. These updates were used to check that the manuscript was complete and to dynamically update information in the manuscript.

7.1.2 Data Analysis and Visualization

The combination of Manubot and GitHub Actions made it possible to integrate up-to-date analyses and visualizations of online data sources into the manuscript. Data about worldwide cases and deaths from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University [5] read using a Python script to generate Figure 1. Similarly, Figure 3 was generated based on data from the University of Oxford Evidence-Based Medicine (EBM) Data Lab’s COVID-19 TrialsTracker [323]. In both cases, frequency data was plotted using MatPlotLib in Python. Figure ?? was generated using the countries associated with the trials listed in the EBM’s COVID-19 TrialsTracker, converting the country names to 3-letter ISO codes using pycountry or manual adjustment when necessary, and visualizing the geographic distribution of trial recruitment using geopandas. Current version information for packages and software is available in

7.2 Article Selection and Evaluation

Relevant articles were identified and submitted as issues on GitHub for review. Articles were classified as diagnostic, therapeutic, or other, and a template was developed to guide the review of papers and preprints in each category. Following a framework often used for assessing medical literature, the review consisted of examining methods used in each relevant article, assignment (whether the study was observational or randomized), assessment, results, interpretation, and how well the study extrapolates [737]. For examples of each template, please see Appendices B-D.

7.2.1 Diagnostic Papers Methods

Reviewers began by describing the study question(s) being investigated by the article. They then described the study population, the sample size, the prevalence of the disease in the study population, countries / regions considered in case of human subjects, demographics of participants, the setting, and any remaining inclusion / exclusion criteria considered. They then described the reference test or “gold standard,” if one was utilized. Assignment

Reviewers described how new and reference tests were assigned, including additional relevant details about the study design. For example, reviewers were asked whether the diagnostic test resulted in rigorous assignments of case status or was biased towards sicker or healthier individuals. Assessment

Reviewers described how the test was performed. For example, for both standard and reference tests, reviewers described technical details of assays used, when measurements were taken and by whom. Subsequently, they described how individuals were classified as positive or negative cases and whether results were precise and reproducible with repeated tests. Reviewers described whether there were any missing data, whether some participants underwent only one test, or whether there were individuals with inconclusive results. Results

Reviewers reported the estimated sensitivity, specificity, positive predictive value (PPV), and negative predicted value (NPV), as well as confidence bounds around these measures, if provided. Interpretation

Reviewers reported how well the test ruled in or ruled out disease based on the population, if there were identified side effects, and patient adherence. Extrapolation

Reviewers described how well this test will extrapolate outside the measured population.

7.2.2 Therapeutic Papers Methods

Reviewers began by describing the study question(s) being investigated by the article. They then described the study population, the sample size, the prevalence of the disease in the study population, countries / regions considered in case of human subjects, demographics of participants, the setting, and any remaining inclusion / exclusion criteria considered. Assignment

Reviewers described how the treatment is assigned, whether it was an interventional or observational study, whether randomization took place, etc. Assessment Outcome Assessment

Reviewers described the outcome that was assessed and evaluated whether it was appropriate given the underlying study question. They described whether there were any missing data such as whether there were individuals lost to follow up. They then describe whether there were any potential sources of bias such as lack of blinding in a randomized controlled trial. Statistical Methods Assessment

Reviewers described which statistical methods were used for inference and whether applied methods were appropriate for the study. They then described whether adjustments were made for possible confounders. Results

Reviewers described the estimated association between the treatment and outcome. They described measures of confidence or statistical significance, if provided. Interpretation

Reviewers described whether a causal claim could be made. They described whether any side effects or interactions with other drugs were identified, as well as any subgroup findings. Extrapolation

Reviewers describe how the study may extrapolate to a different species or population.

8 Additional Items

8.1 Competing Interests

Author Competing Interests Last Reviewed
Halie M. Rando None 2020-03-22
Casey S. Greene None 2020-08-13
Michael P. Robson None 2020-03-23
Simina M. Boca None 2020-08-12
Nils Wellhausen None 2020-03-22
Ronan Lordan None 2020-08-13
Christian Brueffer Employee and shareholder of SAGA Diagnostics AB. 2020-04-14
Sadipan Ray None 2020-03-25
Lucy D'Agostino McGowan None 2020-03-26
Anthony Gitter Filed a provisional patent application with the Wisconsin Alumni Research Foundation related to classifying activated T cells 2020-08-12
Ronnie M. Russell None 2020-04-07
Anna Ada Dattoli None 2020-03-26
Ryan Velazquez None 2020-04-04
John P. Barton None 2020-04-06
Jeffrey M. Field None 2020-03-30
Bharath Ramsundar None 2020-04-06
Adam L. MacLean None 2020-04-06
Alexandra J. Lee None 2020-04-07
Immunology Institute of the Icahn School of Medicine None 2020-04-07
Fengling Hu None 2020-04-08
Nafisa M. Jadavji None 2020-04-09
Elizabeth Sell None 2020-04-10
Jinhui Wang None 2020-04-13
Diane N. Rafizadeh None 2020-04-14
Ashwin N. Skelly None 2020-04-16
Marouen Ben Guebila None 2020-04-17
Likhitha Kolla None 2020-04-23
David Manheim None 2020-04-28
Soumita Ghosh None 2020-04-28
Matthias Fax None 2020-04-30
James Brian Byrd Funded by FastGrants to conduct a COVID-19-related clinical trial 2020-04-23
YoSon Park None 2020-04-30
Vikas Bansal None 2020-05-26
Stephen Capone None 2020-08-12
John J. Dziak None 2020-08-12
YuCheng Sun None 2020-07-09
Yanjun Qi None 2020-07-09
Lamonica Shinholster None 2020-07-22
Sergey Knyazev None 2020-08-03
Dimitri Perrin None 2020-08-11
Serghei Mangul None 2020-08-07
Shikta Das None 2020-08-13
Gregory L Szeto None 2020-09-04

8.2 Author Contributions

Author Contributions
Halie M. Rando Project Administration, Writing - Original Draft, Writing - Review & Editing, Methodology
Casey S. Greene Conceptualization, Software, Writing - Review & Editing
Michael P. Robson Software
Simina M. Boca Methodology, Writing - Review & Editing
Nils Wellhausen Writing - Original Draft, Writing - Review & Editing, Project Administration, Visualization
Ronan Lordan Writing - Original Draft, Writing - Review & Editing
Christian Brueffer Writing - Original Draft, Writing - Review & Editing, Project Administration
Sadipan Ray Writing - Original Draft
Lucy D'Agostino McGowan Methodology, Writing - Original Draft
Anthony Gitter Methodology, Software, Project Administration, Writing - Original Draft, Writing - Review & Editing, Visualization
Ronnie M. Russell Writing - Original Draft, Writing - Review & Editing
Anna Ada Dattoli Writing - Original Draft
Ryan Velazquez Methodology, Software
John P. Barton Writing - Original Draft, Writing - Review & Editing
Jeffrey M. Field Writing - Original Draft
Bharath Ramsundar Investigation, Writing - Review & Editing
Adam L. MacLean Writing - Original Draft
Alexandra J. Lee Writing - Original Draft
Immunology Institute of the Icahn School of Medicine Data Curation
Fengling Hu Writing - Original Draft, Writing - Review & Editing
Nafisa M. Jadavji Writing - Original Draft, Writing - Review & Editing
Elizabeth Sell Writing - Original Draft, Writing - Review & Editing
Jinhui Wang Writing - Revising & Editing
Diane N. Rafizadeh Writing - Original Draft, Writing - Review & Editing
Ashwin N. Skelly Writing - Original Draft, Writing - Review & Editing
Marouen Ben Guebila Writing - Original Draft
Likhitha Kolla Writing - Original Draft
David Manheim Writing - Original Draft, Investigation
Soumita Ghosh Writing - Original Draft
Matthias Fax Writing - Review & Editing
James Brian Byrd Writing - Original Draft, Writing - Review & Editing
YoSon Park Writing - Original Draft, Writing - Review & Editing, Investigation
Vikas Bansal Writing - Original Draft, Investigation
Stephen Capone Writing - Review & Editing, Writing - Original Draft
John J. Dziak Writing - Original Draft
YuCheng Sun Visualization
Yanjun Qi Visualization
Lamonica Shinholster Writing - Original Draft
Sergey Knyazev Writing - Original Draft, Writing - Review & Editing
Dimitri Perrin Writing - Original Draft, Writing - Review & Editing
Serghei Mangul Writing - Review & Editing
Shikta Das Writing - Review & Editing
Gregory L Szeto Writing - Review & Editing

8.3 Acknowledgements

We thank Nick DeVito for assistance with the Evidence-Based Medicine Data Lab COVID-19 TrialsTracker data. We thank Yael Evelyn Marshall who contributed writing (original draft) as well as reviewing and editing of pieces of the text but who did not formally approve the manuscript. We are grateful to the following contributors for reviewing pieces of the text: Nadia Danilova, James Eberwine and Ipsita Krishnan.

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627. mRNA vaccines — a new era in vaccinology
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628. Phase I, Open-Label, Dose-Ranging Study of the Safety and Immunogenicity of 2019-nCoV Vaccine (mRNA-1273) in Healthy Adults
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629. A Phase 3, Randomized, Stratified, Observer-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in Adults Aged 18 Years and Older
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630. Progress and Prospects on Vaccine Development against SARS-CoV-2
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631. Towards an understanding of the adjuvant action of aluminium
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632. DAMP-Inducing Adjuvant and PAMP Adjuvants Parallelly Enhance Protective Type-2 and Type-1 Immune Responses to Influenza Split Vaccination
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633. Better Adjuvants for Better Vaccines: Progress in Adjuvant Delivery Systems, Modifications, and Adjuvant–Antigen Codelivery
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634. Design and Synthesis of Hydroxyferroquine Derivatives with Antimalarial and Antiviral Activities
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635. Sanofi and Regeneron begin global Kevzara® (sarilumab) clinical trial program in patients with severe COVID-19

636. An Adaptive Phase 3, Randomized, Double-blind, Placebo-controlled Study Assessing Efficacy and Safety of Sarilumab for Hospitalized Patients With COVID19
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637. Prevention of infection caused by immunosuppressive drugs in gastroenterology
Katarzyna Orlicka, Eleanor Barnes, Emma L. Culver
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638. Immunosuppression for hyperinflammation in COVID-19: a double-edged sword?
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The Lancet (2020-04)
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639. TNF-α inhibition for potential therapeutic modulation of SARS coronavirus infection
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640. COVID-19: combining antiviral and anti-inflammatory treatments
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The Lancet Infectious Diseases (2020-04)
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641. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease
Peter Richardson, Ivan Griffin, Catherine Tucker, Dan Smith, Olly Oechsle, Anne Phelan, Justin Stebbing
The Lancet (2020-02)
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642. Lilly Begins Clinical Testing of Therapies for COVID-19 | Eli Lilly and Company

643. Baricitinib Combined With Antiviral Therapy in Symptomatic Patients Infected by COVID-19: an Open-label, Pilot Study
Fabrizio Cantini (2020-04-19)

644. Table 1, Cost-Comparison Table for Biologic Disease-Modifying Drugs for Rheumatoid Arthritis
National Center for Biotechnology Information, U. S. National Library of Medicine 8600 Rockville Pike, Bethesda MD, 20894 Usa

645. A Cost Comparison of Treatments of Moderate to Severe Psoriasis
Cheryl Hankin, Steven Feldman, Andy Szczotka, Randolph Stinger, Leslie Fish, David Hankin
Drug Benefit Trends (2005-05)

646. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice
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647. Antiviral Monoclonal Antibodies: Can They Be More Than Simple Neutralizing Agents?
Mireia Pelegrin, Mar Naranjo-Gomez, Marc Piechaczyk
Trends in Microbiology (2015-10)
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648. Intranasal Treatment with Poly(I{middle dot}C) Protects Aged Mice from Lethal Respiratory Virus Infections
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649. Trained Immunity: a Tool for Reducing Susceptibility to and the Severity of SARS-CoV-2 Infection
Mihai G. Netea, Evangelos J. Giamarellos-Bourboulis, Jorge Domínguez-Andrés, Nigel Curtis, Reinout van Crevel, Frank L. van de Veerdonk, Marc Bonten
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650. Defining trained immunity and its role in health and disease
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651. BCG Vaccination to Reduce the Impact of COVID-19 in Healthcare Workers (BRACE) Trial
Murdoch Childrens Research Institute (2020-10-19)

652. Reducing Health Care Workers Absenteeism in COVID-19 Pandemic by Enhanced Trained Immune Responses Through Bacillus Calmette-Guérin Vaccination, a Randomized Controlled Trial.
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653. Bacillus Calmette-Guerin Vaccination as Defense Against SARS-CoV-2: A Randomized Controlled Trial to Protect Health Care Workers by Enhanced Trained Immune Responses
Texas A&M University (2020-05-24)

654. Application of BCG Vaccine for Immune-prophylaxis Among Egyptian Healthcare Workers During the Pandemic of COVID-19
Adel Khattab (2020-04-17)

655. Performance Evaluation of BCG Vaccination in Healthcare Personnel to Reduce the Severity of SARS-COV-2 Infection in Medellín, Colombia, 2020
Universidad de Antioquia (2020-04-24)

656. COVID-19: BCG As Therapeutic Vaccine, Transmission Limitation, and Immunoglobulin Enhancement
Leonardo Oliveira Reis (2020-08-05)

657. Using BCG Vaccine to Enhance Non-specific Protection of Health Care Workers During the COVID-19 Pandemic. A Randomized Controlled Multi-center Trial
Bandim Health Project (2020-05-03)

658. Reducing Morbidity and Mortality in Health Care Workers Exposed to SARS-CoV-2 by Enhancing Non-specific Immune Responses Through Bacillus Calmette-Guérin Vaccination, a Randomized Controlled Trial
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659. Randomized Controlled Trial Evaluating the Efficacy of Vaccination With Bacillus Calmette and Guérin (BCG) in the Prevention of COVID-19 Via the Strengthening of Innate Immunity in Health Care Workers
Assistance Publique - Hôpitaux de Paris (2020-08-17)

660. A Phase III, Double-blind, Randomized, Placebo-controlled Multicentre Clinical Trial to Assess the Efficacy and Safety of VPM1002 in Reducing Healthcare Professionals’ Absenteeism in the SARS-CoV-2 Pandemic by Modulating the Immune System
Vakzine Projekt Management GmbH (2020-09-29)

661. A Randomized Clinical Trial for Enhanced Trained Immune Responses Through Bacillus Calmette-Guérin Vaccination to Prevent Infections by COVID-19: The ACTIVATE II Trial
Hellenic Institute for the Study of Sepsis (2020-07-10)

662. Reducing Hospital Admission of Elderly in SARS-CoV-2 Pandemic Via the Induction of Trained Immunity by Bacillus Calmette-Guérin Vaccination, a Randomized Controlled Trial
Radboud University (2020-06-03)

663. A Phase III, Randomized, Double-blind, Placebo-controlled, Multicentre, Clinical Trial to Assess the Efficacy and Safety of VPM1002 in Reducing Hospital Admissions and/or Severe Respiratory Infectious Diseases in Elderly in the SARS-CoV-2 Pandemic by Modulating the Immune System
Vakzine Projekt Management GmbH (2020-08-31)

664. A Randomized, Double-blind, Placebo-controlled Phase 3 Study: Efficacy and Safety of VPM1002 in Reducing SARS-CoV-2 Infection Rate and COVID-19 Severity
University Health Network, Toronto (2020-08-18)

665. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure
Evangelos J. Giamarellos-Bourboulis, Mihai G. Netea, Nikoletta Rovina, Karolina Akinosoglou, Anastasia Antoniadou, Nikolaos Antonakos, Georgia Damoraki, Theologia Gkavogianni, Maria-Evangelia Adami, Paraskevi Katsaounou, … Antonia Koutsoukou
Cell Host & Microbe (2020-06)
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666. Type I and Type III Interferons – Induction, Signaling, Evasion, and Application to Combat COVID-19
Annsea Park, Akiko Iwasaki
Cell Host & Microbe (2020-06)
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667. Structure of M pro from COVID-19 virus and discovery of its inhibitors
Zhenming Jin, Xiaoyu Du, Yechun Xu, Yongqiang Deng, Meiqin Liu, Yao Zhao, Bing Zhang, Xiaofeng Li, Leike Zhang, Chao Peng, … Haitao Yang
bioRxiv (2020-03-29)
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668. Main protease structure and XChem fragment screen

669. Quantifying the social distancing privilege gap: a longitudinal study of smartphone movement
Nabarun Dasgupta, Michele Jonsson Funk, Allison Lazard, Benjamin Eugene White, Stephen W. Marshall
Cold Spring Harbor Laboratory (2020-05-08)
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670. Uncovering socioeconomic gaps in mobility reduction during the COVID-19 pandemic using location data
Samuel P. Fraiberger, Pablo Astudillo, Lorenzo Candeago, Alex Chunet, Nicholas K. W. Jones, Maham Faisal Khan, Bruno Lepri, Nancy Lozano Gracia, Lorenzo Lucchini, Emanuele Massaro, Aleister Montfort
arXiv (2020-07-28)

671. A Basic Demographic Profile of Workers in Frontline Industries
Hye Jin Rho;Shawn Fremstad;Hayley Brown

672. Differential occupational risk for COVID‐19 and other infection exposure according to race and ethnicity
Devan Hawkins
American Journal of Industrial Medicine (2020-06-15)
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673. Estimating the burden of United States workers exposed to infection or disease: A key factor in containing risk of COVID-19 infection
Marissa G. Baker, Trevor K. Peckham, Noah S. Seixas
PLOS ONE (2020-04-28)
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674. Coronavirus (COVID-19) related deaths by occupation, England and Wales: deaths registered up to and including 20 April 2020
Ben Windsor-Shellard, Jasveer Kaur

675. Which occupations have the highest potential exposure to the coronavirus (COVID-19)?
Office for National Statistics

676. Disparities in the risk and outcomes from COVID-19
Public Health England

677. Exclusive: deaths of NHS staff from covid-19 analysed
Tim Cook, Emira Kursumovic, Simon Lennane2020-04-22T12:42:00+01:00
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679. Racial Disparity in COVID-19 Deaths: Seeking Economic Roots with Census data.
John McLaren
National Bureau of Economic Research (2020-06-22)

680. Mortality, Admissions, and Patient Census at SNFs in 3 US Cities During the COVID-19 Pandemic
Michael L. Barnett, Lissy Hu, Thomas Martin, David C. Grabowski
JAMA (2020-08-04)
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681. COVID-19 in Prisons and Jails in the United States
Laura Hawks, Steffie Woolhandler, Danny McCormick
JAMA Internal Medicine (2020-08-01)
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682. COVID-19 Cases and Deaths in Federal and State Prisons
Brendan Saloner, Kalind Parish, Julie A. Ward, Grace DiLaura, Sharon Dolovich
JAMA (2020-08-11)
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683. State Rates of Incarceration Race & Ethnicity_updated2

684. Under One Roof: A Review of Research on Intergenerational Coresidence and Multigenerational Households in the United States
Jennifer Reid Keene, Christie D. Batson
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685. Chaos and the macrosetting: The role of poverty and socioeconomic status.
Gary W. Evans, John Eckenrode, Lyscha A. Marcynyszyn
American Psychological Association (APA) (2010-01-12)
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686. Housing insecurity among urban fathers
Marah A. Curtis, Amanda B. Geller
Columbia University (2010)
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687. Housing and Employment Insecurity among the Working Poor
Matthew Desmond, Carl Gershenson
Social Problems (2016-02)
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688. Obesity and its comorbid conditions
Lalita Khaodhiar, Karen C. McCowen, George L. Blackburn
Clinical Cornerstone (1999-01)
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689. Aging, Male Sex, Obesity, and Metabolic Inflammation Create the Perfect Storm for COVID-19
Franck Mauvais-Jarvis
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690. Non-communicable disease syndemics: poverty, depression, and diabetes among low-income populations
Emily Mendenhall, Brandon A Kohrt, Shane A Norris, David Ndetei, Dorairaj Prabhakaran
The Lancet (2017-03)
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691. Obesity and poverty paradox in developed countries
Wioletta Żukiewicz-Sobczak, Paula Wróblewska, Jacek Zwoliński, Jolanta Chmielewska-Badora, Piotr Adamczuk, Ewelina Krasowska, Jerzy Zagórski, Anna Oniszczuk, Jacek Piątek, Wojciech Silny
Annals of Agricultural and Environmental Medicine (2014-09-04)
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692. The Impact of the COVID‐19 Pandemic on Unhealthy Eating in Populations with Obesity
Nathaniel J. S. Ashby
Obesity (2020-06-26)
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693. Fast‐Food Patronage and Obesity Prevalence during the COVID‐19 Pandemic: An Alternative Explanation
Candice A. Myers, Stephanie T. Broyles
Obesity (2020-08-02)
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694. The global food syndemic: The impact of food insecurity, Malnutrition and obesity on the healthspan amid the COVID-19 pandemic
Martha I. Huizar, Ross Arena, Deepika R. Laddu
Progress in Cardiovascular Diseases (2020-07)
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695. Stress, chronic inflammation, and emotional and physical well-being: Concurrent effects and chronic sequelae
George P. Chrousos
Journal of Allergy and Clinical Immunology (2000-11)
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696. Chronic psychological stress and the regulation of pro-inflammatory cytokines: A glucocorticoid-resistance model.
Gregory E. Miller, Sheldon Cohen, A. Kim Ritchey
Health Psychology (2002)
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697. Chronic stress, daily stressors, and circulating inflammatory markers.
Jean-Philippe Gouin, Ronald Glaser, William B. Malarkey, David Beversdorf, Janice Kiecolt-Glaser
Health Psychology (2012-03)
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698. Turning Up the Heat
Gregory E. Miller, Ekin Blackwell
Current Directions in Psychological Science (2016-06-24)
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699. Exposure to air pollution and COVID-19 mortality in the United States: A nationwide cross-sectional study
Xiao Wu, Rachel C. Nethery, Benjamin M. Sabath, Danielle Braun, Francesca Dominici
Cold Spring Harbor Laboratory (2020-04-27)
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700. Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter
Richard Burnett, Hong Chen, Mieczysław Szyszkowicz, Neal Fann, Bryan Hubbell, C. Arden Pope, Joshua S. Apte, Michael Brauer, Aaron Cohen, Scott Weichenthal, … Joseph V. Spadaro
Proceedings of the National Academy of Sciences (2018-09-18)
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701. Early-Life Air Pollution Exposure, Neighborhood Poverty, and Childhood Asthma in the United States, 1990–2014
Nicole Kravitz-Wirtz, Samantha Teixeira, Anjum Hajat, Bongki Woo, Kyle Crowder, David Takeuchi
International Journal of Environmental Research and Public Health (2018-05-30)
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702. Early life stress, air pollution, inflammation, and disease: An integrative review and immunologic model of social-environmental adversity and lifespan health
Hector A. Olvera Alvarez, Laura D. Kubzansky, Matthew J. Campen, George M. Slavich
Neuroscience & Biobehavioral Reviews (2018-09)
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703. Systemic racism, chronic health inequities, and ‐19: A syndemic in the making?
Clarence C. Gravlee
American Journal of Human Biology (2020-08-04)
DOI: 10.1002/ajhb.23482 · PMID: 32754945 · PMCID: PMC7441277

704. Coronavirus Disease (COVID-19): A primer for emergency physicians
Summer Chavez, Brit Long, Alex Koyfman, Stephen Y. Liang
The American Journal of Emergency Medicine (2020-03)
DOI: 10.1016/j.ajem.2020.03.036 · PMID: 32265065 · PMCID: PMC7102516

705. Insurers May Only Pay For Coronavirus Tests When They’re “Medically Necessary”

706. Private Health Insurance Coverage in the COVID-19 Public Health Emergency | Commonwealth Fund

707. COVID-19 and racial disparities
Monica Shah, Muskaan Sachdeva, Roni P. Dodiuk-Gad
Journal of the American Academy of Dermatology (2020-07)

708. COVID-19 and racial disparities
Monica Shah, Muskaan Sachdeva, Roni P. Dodiuk-Gad
Journal of the American Academy of Dermatology (2020-07)
DOI: 10.1016/j.jaad.2020.04.046 · PMID: 32305444 · PMCID: PMC7162783

709. FAQs for COVID-19 Claims Reimbursement to Health Care Providers and Facilities for Testing and Treatment of the Uninsured
Official web site of the U.S. Health Resources & Services Administration

710. Potential association between COVID-19 mortality and health-care resource availability
Yunpeng Ji, Zhongren Ma, Maikel P Peppelenbosch, Qiuwei Pan
The Lancet Global Health (2020-02)
DOI: 10.1016/s2214-109x(20)30068-1 · PMID: 32109372 · PMCID: PMC7128131

711. Combating COVID-19: health equity matters
Zhicheng Wang, Kun Tang
Nature Medicine (2020-03-26)
DOI: 10.1038/s41591-020-0823-6 · PMID: 32284617

712. lockup black

713. An Ethical Dilemma in SARS-Cov-2 Pandemic : Who Gets the Ventilator?
Dumache Raluca, Ciocan Veronica, Muresan Camelia Oana, Enache Alexandra
European Scientific Journal ESJ (2020-07-31)
DOI: 10.19044/esj.2020.v16n21p24

714. Planning Hospital Needs for Ventilators and Respiratory Therapists in the COVID-19 Crisis
John Raffensperger, Marygail Brauner, R. Briggs
Rand Corporation (2020)
DOI: 10.7249/pea228-1

715. Fair Allocation of Vaccines, Ventilators and Antiviral Treatments: Leaving No Ethical Value Behind in Health Care Rationing
Parag A. Pathak, Tayfun Sönmez, M. Utku Ünver, M. Bumin Yenmez
arXiv (2020-08-04)

716. Reallocating ventilators during the coronavirus disease 2019 pandemic: Is it ethical?
Quyen Chu, Ricardo Correa, Tracey L. Henry, Kyle A. McGregor, Hanni Stoklosa, Loren Robinson, Sachin Jha, Alagappan Annamalai, Benson S. Hsu, Rohit Gupta, … SreyRam Kuy
Surgery (2020-09)
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717. Ethics Lessons From Seattle’s Early Experience With COVID-19
Denise M. Dudzinski, Benjamin Y. Hoisington, Crystal E. Brown
The American Journal of Bioethics (2020-06-18)
DOI: 10.1080/15265161.2020.1764137 · PMID: 32552455

718. Rationing Limited Healthcare Resources in the COVID‐19 Era and Beyond: Ethical Considerations Regarding Older Adults
Timothy W. Farrell, Leslie Francis, Teneille Brown, Lauren E. Ferrante, Eric Widera, Ramona Rhodes, Tony Rosen, Ula Hwang, Leah J. Witt, Niranjan Thothala, … Debra Saliba
Journal of the American Geriatrics Society (2020-06-14)
DOI: 10.1111/jgs.16539 · PMID: 32374466 · PMCID: PMC7267288

719. Paediatric ethical issues during the COVID‐19 pandemic are not just about ventilator triage
Marlyse F. Haward, Gregory P. Moore, John Lantos, Annie Janvier
Acta Paediatrica (2020-05-20)
DOI: 10.1111/apa.15334 · PMID: 32364256 · PMCID: PMC7267437

720. Ethical Challenges Arising in the COVID-19 Pandemic: An Overview from the Association of Bioethics Program Directors (ABPD) Task Force
Amy L. McGuire, Mark P. Aulisio, F. Daniel Davis, Cheryl Erwin, Thomas D. Harter, Reshma Jagsi, Robert Klitzman, Robert Macauley, Eric Racine, Susan M. Wolf, … The COVID-19 Task Force of the Association of Bioethics Program Directors (ABPD)
The American Journal of Bioethics (2020-06-08)
DOI: 10.1080/15265161.2020.1764138 · PMID: 32511078

721. Disability, Ethics, and Health Care in the COVID-19 Pandemic
Maya Sabatello, Teresa Blankmeyer Burke, Katherine E. McDonald, Paul S. Appelbaum
American Journal of Public Health (2020-10)
DOI: 10.2105/ajph.2020.305837 · PMID: 32816541 · PMCID: PMC7483109

722. Allocating Ventilators During the COVID-19 Pandemic and Conscientious Objection
Mark Wicclair
The American Journal of Bioethics (2020-07-27)
DOI: 10.1080/15265161.2020.1777347 · PMID: 32716798

723. Colorblind Algorithms: Racism in the Era of COVID-19
J. Corey Williams, Nientara Anderson, Myra Mathis, Ezelle Samford, Jeffrey Eugene, Jessica Isom
Journal of the National Medical Association (2020-06)
DOI: 10.1016/j.jnma.2020.05.010 · PMID: 32563687

724. Allocating Remdesivir Under Scarcity: Social Justice or More Systemic Racism
Eli Weber, Mark J. Bliton
The American Journal of Bioethics (2020-08-25)
DOI: 10.1080/15265161.2020.1795538 · PMID: 32840451

725. Revisiting the equity debate in COVID-19: ICU is no panacea
Angela Ballantyne, Wendy A Rogers, Vikki Entwistle, Cindy Towns
Journal of Medical Ethics (2020-06-22)
DOI: 10.1136/medethics-2020-106460 · PMID: 32571847 · PMCID: PMC7335695

726. Ethical Dilemmas in Covid-19 Medical Care: Is a Problematic Triage Protocol Better or Worse than No Protocol at All?
Sheri Fink
The American Journal of Bioethics (2020-07-27)
DOI: 10.1080/15265161.2020.1788663 · PMID: 32716771

727. Developing an Ethics Framework for Allocating Remdesivir in the COVID-19 Pandemic
Sarah Lim, Debra A. DeBruin, Jonathon P. Leider, Nneka Sederstrom, Ruth Lynfield, Jason V. Baker, Susan Kline, Sarah Kesler, Stacey Rizza, Joel Wu, … Susan M. Wolf
Mayo Clinic Proceedings (2020-09)
DOI: 10.1016/j.mayocp.2020.06.016 · PMID: 32861338 · PMCID: PMC7305893

728. Ethically Allocating COVID-19 Drugs Via Pre-approval Access and Emergency Use Authorization
Jamie Webb, Lesha D. Shah, Holly Fernandez Lynch
The American Journal of Bioethics (2020-08-25)
DOI: 10.1080/15265161.2020.1795529

729. (2011-07-27)

730. Adopting an Anti-Racist Model of COVID-19 Drug Allocation and Prioritization
Akilah A. Jefferson
The American Journal of Bioethics (2020-08-25)
DOI: 10.1080/15265161.2020.1795541

731. Opportunities and obstacles for deep learning in biology and medicine
Travers Ching, Daniel S. Himmelstein, Brett K. Beaulieu-Jones, Alexandr A. Kalinin, Brian T. Do, Gregory P. Way, Enrico Ferrero, Paul-Michael Agapow, Michael Zietz, Michael M. Hoffman, … Casey S. Greene
Journal of The Royal Society Interface (2018-04-04)
DOI: 10.1098/rsif.2017.0387 · PMID: 29618526 · PMCID: PMC5938574

732. Opportunities and obstacles for deep learning in biology and medicine [update in progress]
Casey S. Greene, Daniel C. Elton, Alexander J. Titus, Anthony Gitter, Daniel S. Himmelstein, Brock C. Christensen, Joshua J. Levy
Manubot (2020-08-10)

733. ismms-himc/covid-19_sinai_reviews
Human Immune Monitoring Center at Mount Sinai

734. Undergraduate Mentoring - American Physician Scientists Association

735. greenelab/covid19-review
Greene Laboratory

736. SARS-CoV-2 and COVID-19: An Evolving Review of Diagnostics and Therapeutics
Halie M. Rando, Casey S. Greene, Michael P. Robson, Simina M. Boca, Nils Wellhausen, Ronan Lordan, Christian Brueffer, Sadipan Ray, Lucy D\’Agostino McGowan, Anthony Gitter, … Gregory L. Szeto
Manubot (2020-10-22)

737. Using the MAARIE Framework To Read the Research Literature
M. Corcoran
American Journal of Occupational Therapy (2006-07-01)
DOI: 10.5014/ajot.60.4.367 · PMID: 16915865

738. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody
Xiaolong Tian, Cheng Li, Ailing Huang, Shuai Xia, Sicong Lu, Zhengli Shi, Lu Lu, Shibo Jiang, Zhenlin Yang, Yanling Wu, Tianlei Ying
Cold Spring Harbor Laboratory (2020-01-28)
DOI: 10.1101/2020.01.28.923011

739. Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV
Xiang He, Lei Zhang, Qin Ran, Anying Xiong, Junyi Wang, Dehong Wu, Feng Chen, Guoping Li
Cold Spring Harbor Laboratory (2020-02-05)
DOI: 10.1101/2020.02.03.20020206

740. Diarrhea may be underestimated: a missing link in 2019 novel coronavirus
Weicheng Liang, Zhijie Feng, Shitao Rao, Cuicui Xiao, Zexiao Lin, Qi Zhang, Wei Qi
Cold Spring Harbor Laboratory (2020-02-17)
DOI: 10.1101/2020.02.03.20020289

741. Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection
Xiaoqiang Chai, Longfei Hu, Yan Zhang, Weiyu Han, Zhou Lu, Aiwu Ke, Jian Zhou, Guoming Shi, Nan Fang, Jia Fan, … Fei Lan
bioRxiv (2020-02-04)
DOI: 10.1101/2020.02.03.931766

742. Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids
Bing Zhao, Chao Ni, Ran Gao, Yuyan Wang, Li Yang, Jinsong Wei, Ting Lv, Jianqing Liang, Qisheng Zhang, Wei Xu, … Xinhua Lin
Cold Spring Harbor Laboratory (2020-03-17)
DOI: 10.1101/2020.03.16.990317

743. ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism
Jun Wang, Shanmeizi Zhao, Ming Liu, Zhiyao Zhao, Yiping Xu, Ping Wang, Meng Lin, Yanhui Xu, Bing Huang, Xiaoyu Zuo, … Yuxia Zhang
Cold Spring Harbor Laboratory (2020-02-07)
DOI: 10.1101/2020.02.05.20020545

744. The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice
Linlin Bao, Wei Deng, Baoying Huang, Hong Gao, Jiangning Liu, Lili Ren, Qiang Wei, Pin Yu, Yanfeng Xu, Feifei Qi, … Chuan Qin
bioRxiv (2020-02-28)
DOI: 10.1101/2020.02.07.939389

745. Caution on Kidney Dysfunctions of COVID-19 Patients
Zhen Li, Ming Wu, Jiwei Yao, Jie Guo, Xiang Liao, Siji Song, Jiali Li, Guangjie Duan, Yuanxiu Zhou, Xiaojun Wu, … Anti-2019-nCoV Volunteers
Cold Spring Harbor Laboratory (2020-03-27)
DOI: 10.1101/2020.02.08.20021212

746. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome
Kwok Hong Chu, Wai Kay Tsang, Colin S. Tang, Man Fai Lam, Fernand M. Lai, Ka Fai To, Ka Shun Fung, Hon Lok Tang, Wing Wa Yan, Hilda W. H. Chan, … Kar Neng Lai
Kidney International (2005-02)
DOI: 10.1111/j.1523-1755.2005.67130.x · PMID: 15673319 · PMCID: PMC7112337

747. Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection
Wei Lin, Longfei Hu, Yan Zhang, Joshua D. Ooi, Ting Meng, Peng Jin, Xiang Ding, Longkai Peng, Lei Song, Zhou Xiao, … Yong Zhong
Cold Spring Harbor Laboratory (2020-02-18)
DOI: 10.1101/2020.02.08.939892

748. The immune vulnerability landscape of the 2019 Novel Coronavirus, SARS-CoV-2
James Zhu, Jiwoong Kim, Xue Xiao, Yunguan Wang, Danni Luo, Shuang Jiang, Ran Chen, Lin Xu, He Zhang, Lenny Moise, … Yang Xie
Cold Spring Harbor Laboratory (2020-09-04)
DOI: 10.1101/2020.02.08.939553 · PMID: 32908981 · PMCID: PMC7480032

749. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis
I Hamming, W Timens, MLC Bulthuis, AT Lely, GJ Navis, H van Goor
The Journal of Pathology (2004-06)
DOI: 10.1002/path.1570 · PMID: 15141377 · PMCID: PMC7167720

750. Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection
Yaseen M. Arabi, Ahmed A. Arifi, Hanan H. Balkhy, Hani Najm, Abdulaziz S. Aldawood, Alaa Ghabashi, Hassan Hawa, Adel Alothman, Abdulaziz Khaldi, Basel Al Raiy
Annals of Internal Medicine (2014-03-18)
DOI: 10.7326/m13-2486 · PMID: 24474051

751. Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage
Jingyuan Liu, Yao Liu, Pan Xiang, Lin Pu, Haofeng Xiong, Chuansheng Li, Ming Zhang, Jianbo Tan, Yanli Xu, Rui Song, … Xianbo Wang
medRxiv (2020-02-12)
DOI: 10.1101/2020.02.10.20021584

752. Dysregulation of immune response in patients with COVID-19 in Wuhan, China
Chuan Qin, Luoqi Zhou, Ziwei Hu, Shuoqi Zhang, Sheng Yang, Yu Tao, Cuihong Xie, Ke Ma, Ke Shang, Wei Wang, Dai-Shi Tian
Clinical Infectious Diseases (2020-03-12)
DOI: 10.1093/cid/ciaa248 · PMID: 32161940 · PMCID: PMC7108125

753. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
Suxin Wan, Qingjie Yi, Shibing Fan, Jinglong Lv, Xianxiang Zhang, Lian Guo, Chunhui Lang, Qing Xiao, Kaihu Xiao, Zhengjun Yi, … Yongping Chen
medRxiv (2020-02-12)
DOI: 10.1101/2020.02.10.20021832

754. Longitudinal Characteristics of Lymphocyte Responses and Cytokine Profiles in the Peripheral Blood of SARS-CoV-2 Infected Patients
Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Wei Li, Hua Wang, Qiaoxia Tong, Jianhua Yi, Lei Zhao, … Xin Zheng
SSRN Electronic Journal (2020)
DOI: 10.2139/ssrn.3539682

755. Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China
Jie Li, Shilin Li, Yurui Cai, Qin Liu, Xue Li, Zhaoping Zeng, Yanpeng Chu, Fangcheng Zhu, Fanxin Zeng
Cold Spring Harbor Laboratory (2020-02-12)
DOI: 10.1101/2020.02.11.20022053

756. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection
Caibin Fan, Kai Li, Yanhong Ding, Wei Lu Lu, Jianqing Wang
medRxiv (2020-02-13)
DOI: 10.1101/2020.02.12.20022418

757. Aberrant pathogenic GM-CSF + T cells and inflammatory CD14 + CD16 + monocytes in severe pulmonary syndrome patients of a new coronavirus
Yonggang Zhou, Binqing Fu, Xiaohu Zheng, Dongsheng Wang, Changcheng Zhao, Yingjie qi, Rui Sun, Zhigang Tian, Xiaoling Xu, Haiming Wei
bioRxiv (2020-02-20)
DOI: 10.1101/2020.02.12.945576

758. Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia:A Systemic Review and Meta-analysis
Kai Qian, Yi Deng, Yonghang Tai, Jun Peng, Hao Peng, Lihong Jiang
medRxiv (2020-02-17)
DOI: 10.1101/2020.02.14.20021535

759. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients
Jing Liu, Sumeng Li, Jia Liu, Boyun Liang, Xiaobei Wang, Hua Wang, Wei Li, Qiaoxia Tong, Jianhua Yi, Lei Zhao, … Xin Zheng
medRxiv (2020-02-22)
DOI: 10.1101/2020.02.16.20023671

760. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019
Guang Chen, Di Wu, Wei Guo, Yong Cao, Da Huang, Hongwu Wang, Tao Wang, Xiaoyun Zhang, Huilong Chen, Haijing Yu, … Qin Ning
Cold Spring Harbor Laboratory (2020-02-19)
DOI: 10.1101/2020.02.16.20023903

761. SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development
Chunyun Sun, Long Chen, Ji Yang, Chunxia Luo, Yanjing Zhang, Jing Li, Jiahui Yang, Jie Zhang, Liangzhi Xie
bioRxiv (2020-02-20)
DOI: 10.1101/2020.02.16.951723

762. Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine
Yiyou Chen, Qiang Wei, Ruobing Li, Hong Gao, Hua Zhu, Wei Deng, Linlin Bao, Wei Tong, Zhe Cong, Hong Jiang, Chuan Qin
Cold Spring Harbor Laboratory (2020-02-21)
DOI: 10.1101/2020.02.17.951939

763. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)
Bo Diao, Chenhui Wang, Yingjun Tan, Xiewan Chen, Ying Liu, Lifeng Ning, Li Chen, Min Li, Yueping Liu, Gang Wang, … Yongwen Chen
medRxiv (2020-02-20)
DOI: 10.1101/2020.02.18.20024364

764. Clinical characteristics of 25 death cases infected with COVID-19 pneumonia: a retrospective review of medical records in a single medical center, Wuhan, China
Xun Li, Luwen Wang, Shaonan Yan, Fan Yang, Longkui Xiang, Jiling Zhu, Bo Shen, Zuojiong Gong
Cold Spring Harbor Laboratory (2020-02-25)
DOI: 10.1101/2020.02.19.20025239

765. SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China
Lunwen Wang, Xun Li, Hui Chen, Shaonan Yan, Yan Li, Dong Li, Zuojiong Gong
Cold Spring Harbor Laboratory (2020-02-23)
DOI: 10.1101/2020.02.19.20025288

766. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China
Dawei Wang, Bo Hu, Chang Hu, Fangfang Zhu, Xing Liu, Jing Zhang, Binbin Wang, Hui Xiang, Zhenshun Cheng, Yong Xiong, … Zhiyong Peng
JAMA (2020-02-07)
DOI: 10.1001/jama.2020.1585 · PMID: 32031570 · PMCID: PMC7042881

767. Clinical characteristics of 2019 novel coronavirus infection in China
Wei-jie Guan, Zheng-yi Ni, Yu Hu, Wen-hua Liang, Chun-quan Ou, Jian-xing He, Lei Liu, Hong Shan, Chun-liang Lei, David SC Hui, … Nan-shan Zhong
medRxiv (2020-02-09)
DOI: 10.1101/2020.02.06.20020974

768. Potential T-cell and B-cell Epitopes of 2019-nCoV
Ethan Fast, Russ B. Altman, Binbin Chen
Cold Spring Harbor Laboratory (2020-03-18)
DOI: 10.1101/2020.02.19.955484

769. Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
Alexandra C. Walls, Young-Jun Park, M. Alexandra Tortorici, Abigail Wall, Andrew T. McGuire, David Veesler
bioRxiv (2020-02-20)
DOI: 10.1101/2020.02.19.956581

770. Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19
Irani Thevarajan, Thi HO Nguyen, Marios Koutsakos, Julian Druce, Leon Caly, Carolien E van de Sandt, Xiaoxiao Jia, Suellen Nicholson, Mike Catton, Benjamin Cowie, … Katherine Kedzierska
Cold Spring Harbor Laboratory (2020-02-23)
DOI: 10.1101/2020.02.20.20025841

771. The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing
Minfeng Liao, Yang Liu, Jin Yuan, Yanling Wen, Gang Xu, Juanjuan Zhao, Lin Chen, Jinxiu Li, Xin Wang, Fuxiang Wang, … Zheng Zhang
medRxiv (2020-02-26)
DOI: 10.1101/2020.02.23.20026690

772. Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells
Marlena Scharenberg, Sindhu Vangeti, Eliisa Kekäläinen, Per Bergman, Mamdoh Al-Ameri, Niclas Johansson, Klara Sondén, Sara Falck-Jones, Anna Färnert, Hans-Gustaf Ljunggren, … Nicole Marquardt
Frontiers in Immunology (2019-05-17)
DOI: 10.3389/fimmu.2019.01116 · PMID: 31156653 · PMCID: PMC6534051

773. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
Chaolin Huang, Yeming Wang, Xingwang Li, Lili Ren, Jianping Zhao, Yi Hu, Li Zhang, Guohui Fan, Jiuyang Xu, Xiaoying Gu, … Bin Cao
The Lancet (2020-02)
DOI: 10.1016/s0140-6736(20)30183-5 · PMID: 31986264 · PMCID: PMC7159299

774. Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection
Benoit Allard, Alice Panariti, James G. Martin
Frontiers in Immunology (2018-07-31)
DOI: 10.3389/fimmu.2018.01777 · PMID: 30108592 · PMCID: PMC6079255

775. PPAR-γ in Macrophages Limits Pulmonary Inflammation and Promotes Host Recovery following Respiratory Viral Infection
Su Huang, Bibo Zhu, In Su Cheon, Nick P. Goplen, Li Jiang, Ruixuan Zhang, R. Stokes Peebles, Matthias Mack, Mark H. Kaplan, Andrew H. Limper, Jie Sun
Journal of Virology (2019-04-17)
DOI: 10.1128/jvi.00030-19 · PMID: 30787149 · PMCID: PMC6475778

776. Can routine laboratory tests discriminate 2019 novel coronavirus infected pneumonia from other community-acquired pneumonia?
Yunbao Pan, Guangming Ye, Xiantao Zeng, Guohong Liu, Xiaojiao Zeng, Xianghu Jiang, Jin Zhao, Liangjun Chen, Shuang Guo, Qiaoling Deng, … Xinghuan Wang
Cold Spring Harbor Laboratory (2020-02-25)
DOI: 10.1101/2020.02.25.20024711

777. Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia
Jing Gong, Hui Dong, Song Qing Xia, Yi Zhao Huang, Dingkun Wang, Yan Zhao, Wenhua Liu, Shenghao Tu, Mingmin Zhang, Qi Wang, Fuer Lu
Cold Spring Harbor Laboratory (2020-02-26)
DOI: 10.1101/2020.02.25.20025643

778. An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design
CV Herst, S Burkholz, J Sidney, A Sette, PE Harris, S Massey, T Brasel, E Cunha-Neto, DS Rosa, WCH Chao, … R Rubsamen
Cold Spring Harbor Laboratory (2020-04-06)
DOI: 10.1101/2020.02.25.963546

779. Epitope-based peptide vaccine design and target site characterization against novel coronavirus disease caused by SARS-CoV-2
Lin Li, Ting Sun, Yufei He, Wendong Li, Yubo Fan, Jing Zhang
Cold Spring Harbor Laboratory (2020-02-27)
DOI: 10.1101/2020.02.25.965434

780. The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis
Wenjun Wang, Jianxing He, puyi Lie, liyan Huang, Sipei Wu, yongping lin, xiaoqing liu
Cold Spring Harbor Laboratory (2020-02-27)
DOI: 10.1101/2020.02.26.20026989

781. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China
Ying Huang, Rui Yang, Ying Xu, Ping Gong
Cold Spring Harbor Laboratory (2020-03-05)
DOI: 10.1101/2020.02.27.20029009

782. Risk factors related to hepatic injury in patients with corona virus disease 2019
Lu Li, Shuang Li, Manman Xu, Pengfei Yu, Sujun Zheng, Zhongping Duan, Jing Liu, Yu Chen, Junfeng Li
Cold Spring Harbor Laboratory (2020-03-10)
DOI: 10.1101/2020.02.28.20028514

783. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients
Xiaohua Chen, Binghong Zhao, Yueming Qu, Yurou Chen, Jie Xiong, Yong Feng, Dong Men, Qianchuan Huang, Ying Liu, Bo Yang, … Feng Li
medRxiv (2020-03-03)
DOI: 10.1101/2020.02.29.20029520

784. Prognostic factors in the acute respiratory distress syndrome
Wei Chen, Lorraine B Ware
Clinical and Translational Medicine (2015-07-02)
DOI: 10.1186/s40169-015-0065-2 · PMID: 26162279 · PMCID: PMC4534483

785. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study
Li Tan, Qi Wang, Duanyang Zhang, Jinya Ding, Qianchuan Huang, Yi-Quan Tang, Qiongshu Wang, Hongming Miao
Cold Spring Harbor Laboratory (2020-03-03)
DOI: 10.1101/2020.03.01.20029074

786. The potential role of IL-6 in monitoring coronavirus disease 2019.
Tao Liu, Jieying Zhang, Yuhui Yang, Liling Zhang, Hong Ma, Zhengyu Li, Jiaoyue Zhang, Ji Cheng, Xiaoyu Zhang, Gang Wu, Jianhua Yi
Cold Spring Harbor Laboratory (2020-03-06)
DOI: 10.1101/2020.03.01.20029769

787. Clinical and Laboratory Profiles of 75 Hospitalized Patients with Novel Coronavirus Disease 2019 in Hefei, China
Zonghao Zhao, Jiajia Xie, Ming Yin, Yun Yang, Hongliang He, Tengchuan Jin, Wenting Li, Xiaowu Zhu, Jing Xu, Changcheng Zhao, … Xiaoling Ma
Cold Spring Harbor Laboratory (2020-03-06)
DOI: 10.1101/2020.03.01.20029785

788. Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome
Yang Yang, Chenguang Shen, Jinxiu Li, Jing Yuan, Minghui Yang, Fuxiang Wang, Guobao Li, Yanjie Li, Li Xing, Ling Peng, … Yingxia Liu
medRxiv (2020-03-06)
DOI: 10.1101/2020.03.02.20029975

789. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019
Juanjuan Zhao, Quan Yuan, Haiyan Wang, Wei Liu, Xuejiao Liao, Yingying Su, Xin Wang, Jing Yuan, Tingdong Li, Jinxiu Li, … Zheng Zhang
Cold Spring Harbor Laboratory (2020-03-02)
DOI: 10.1101/2020.03.02.20030189

790. Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients
Xiaoping Chen, Jiaxin Ling, Pingzheng Mo, Yongxi Zhang, Qunqun Jiang, Zhiyong Ma, Qian Cao, Wenjia Hu, Shi Zou, Liangjun Chen, … Yong Xiong
medRxiv (2020-03-06)
DOI: 10.1101/2020.03.03.20030437

791. Effects of Systemically Administered Hydrocortisone on the Human Immunome
Matthew J. Olnes, Yuri Kotliarov, Angélique Biancotto, Foo Cheung, Jinguo Chen, Rongye Shi, Huizhi Zhou, Ena Wang, John S. Tsang, Robert Nussenblatt, The CHI Consortium
Scientific Reports (2016-03-14)
DOI: 10.1038/srep23002 · PMID: 26972611 · PMCID: PMC4789739

792. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis
Giuseppe Lippi, Mario Plebani
Clinica Chimica Acta (2020-06)
DOI: 10.1016/j.cca.2020.03.004 · PMID: 32145275 · PMCID: PMC7094472

793. Clinical findings in critical ill patients infected with SARS-Cov-2 in Guangdong Province, China: a multi-center, retrospective, observational study
Yonghao Xu, Zhiheng Xu, Xuesong Liu, Lihua Cai, Haichong Zheng, Yongbo Huang, Lixin Zhou, Linxi Huang, Yun Lin, Liehua Deng, … Yimin Li
Cold Spring Harbor Laboratory (2020-03-06)
DOI: 10.1101/2020.03.03.20030668

794. Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus (SARS-CoV-2)
Ye Feng, Min Qiu, Liang Liu, Shengmei Zou, Yun Li, Kai Luo, Qianpeng Guo, Ning Han, Yingqiang Sun, Kui Wang, … Fan Mo
Cold Spring Harbor Laboratory (2020-06-30)
DOI: 10.1101/2020.03.03.962332

795. Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China
Min Cao, Dandan Zhang, Youhua Wang, Yunfei Lu, Xiangdong Zhu, Ying Li, Honghao Xue, Yunxiao Lin, Min Zhang, Yiguo Sun, … Longping Peng
Cold Spring Harbor Laboratory (2020-03-06)
DOI: 10.1101/2020.03.04.20030395 · PMID: 32511465 · PMCID: PMC7255784

796. Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing
Jin Zhang, Jianhua Liu, Na Li, Yong Liu, Rui Ye, Xiaosong Qin, Rui Zheng
Cold Spring Harbor Laboratory (2020-03-10)
DOI: 10.1101/2020.03.04.20030916

797. Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection
Bo Diao, Chenhui Wang, Rongshuai Wang, Zeqing Feng, Yingjun Tan, Huiming Wang, Changsong Wang, Liang Liu, Ying Liu, Yueping Liu, … Yongwen Chen
medRxiv (2020-04-10)
DOI: 10.1101/2020.03.04.20031120

798. COVID-19 early warning score: a multi-parameter screening tool to identify highly suspected patients
Cong-Ying Song, Jia Xu, Jian-Qin He, Yuan-Qiang Lu
medRxiv (2020-03-08)
DOI: 10.1101/2020.03.05.20031906

799. LY6E impairs coronavirus fusion and confers immune control of viral disease
Stephanie Pfaender, Katrina B. Mar, Eleftherios Michailidis, Annika Kratzel, Dagny Hirt, Philip V’kovski, Wenchun Fan, Nadine Ebert, Hanspeter Stalder, Hannah Kleine-Weber, … Volker Thiel
Cold Spring Harbor Laboratory (2020-03-07)
DOI: 10.1101/2020.03.05.979260 · PMID: 32511345 · PMCID: PMC7255780

800. A preliminary study on serological assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 238 admitted hospital patients
Lei Liu, Wanbing Liu, Shengdian Wang, Shangen Zheng
Cold Spring Harbor Laboratory (2020-03-08)
DOI: 10.1101/2020.03.06.20031856

801. Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newly-emerged SARS-CoV-2
Zhiqiang Zheng, Vanessa M. Monteil, Sebastian Maurer-Stroh, Chow Wenn Yew, Carol Leong, Nur Khairiah Mohd-Ismail, Suganya Cheyyatraivendran Arularasu, Vincent Tak Kwong Chow, Raymond Lin Tzer Pin, Ali Mirazimi, … Yee-Joo Tan
Cold Spring Harbor Laboratory (2020-03-07)
DOI: 10.1101/2020.03.06.980037

802. Mortality of COVID-19 is Associated with Cellular Immune Function Compared to Immune Function in Chinese Han Population
Qiang Zeng, Yong-zhe Li, Gang Huang, Wei Wu, Sheng-yong Dong, Yang Xu
medRxiv (2020-03-13)
DOI: 10.1101/2020.03.08.20031229

803. Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19
JIan Chen, Hua Fan, Lin Zhang, Bin Huang, Muxin Zhu, Yong Zhou, WenHu Yu, Liping Zhu, Shaohui Cheng, Xiaogen Tao, Huan Zhang
Cold Spring Harbor Laboratory (2020-03-17)
DOI: 10.1101/2020.03.09.20033068

804. Relationship between the ABO Blood Group and the COVID-19 Susceptibility
Jiao Zhao, Yan Yang, Hanping Huang, Dong Li, Dongfeng Gu, Xiangfeng Lu, Zheng Zhang, Lei Liu, Ting Liu, Yukun Liu, … Peng George Wang
Cold Spring Harbor Laboratory (2020-03-27)
DOI: 10.1101/2020.03.11.20031096

805. The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15
Shutoku Matsuyama, Miyuki Kawase, Naganori Nao, Kazuya Shirato, Makoto Ujike, Wataru Kamitani, Masayuki Shimojima, Shuetsu Fukushi
bioRxiv (2020-03-12)
DOI: 10.1101/2020.03.11.987016

806. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19
Bicheng Zhang, Xiaoyang Zhou, Chengliang Zhu, Fan Feng, Yanru Qiu, Jia Feng, Qingzhu Jia, Qibin Song, Bo Zhu, Jun Wang
medRxiv (2020-03-16)
DOI: 10.1101/2020.03.12.20035048

807. Reinfection could not occur in SARS-CoV-2 infected rhesus macaques
Linlin Bao, Wei Deng, Hong Gao, Chong Xiao, Jiayi Liu, Jing Xue, Qi Lv, Jiangning Liu, Pin Yu, Yanfeng Xu, … Chuan Qin
bioRxiv (2020-03-14)
DOI: 10.1101/2020.03.13.990226

808. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV
Meng Yuan, Nicholas C. Wu, Xueyong Zhu, Chang-Chun D. Lee, Ray T. Y. So, Huibin Lv, Chris K. P. Mok, Ian A. Wilson
Cold Spring Harbor Laboratory (2020-03-14)
DOI: 10.1101/2020.03.13.991570

809. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein
Ke Wang, Wei Chen, Yu-Sen Zhou, Jian-Qi Lian, Zheng Zhang, Peng Du, Li Gong, Yang Zhang, Hong-Yong Cui, Jie-Jie Geng, … Zhi-Nan Chen
bioRxiv (2020-03-14)
DOI: 10.1101/2020.03.14.988345

810. CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint
Tomoki Kosugi, Kayaho Maeda, Waichi Sato, Shoichi Maruyama, Kenji Kadomatsu
Nephrology Dialysis Transplantation (2015-07)
DOI: 10.1093/ndt/gfu302 · PMID: 25248362

811. The roles of CyPA and CD147 in cardiac remodelling
Hongyan Su, Yi Yang
Experimental and Molecular Pathology (2018-06)
DOI: 10.1016/j.yexmp.2018.05.001 · PMID: 29772453

812. Cancer-related issues of CD147.
Ulrich H Weidle, Werner Scheuer, Daniela Eggle, Stefan Klostermann, Hannes Stockinger
Cancer genomics & proteomics
PMID: 20551248

813. Blood single cell immune profiling reveals the interferon-MAPK pathway mediated adaptive immune response for COVID-19
Lulin Huang, Yi Shi, Bo Gong, Li Jiang, Xiaoqi Liu, Jialiang Yang, Juan Tang, Chunfang You, Qi Jiang, Bo Long, … Zhenglin Yang
Cold Spring Harbor Laboratory (2020-03-17)
DOI: 10.1101/2020.03.15.20033472

814. Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections
Huibin Lv, Nicholas C. Wu, Owen Tak-Yin Tsang, Meng Yuan, Ranawaka A. P. M. Perera, Wai Shing Leung, Ray T. Y. So, Jacky Man Chun Chan, Garrick K. Yip, Thomas Shiu Hong Chik, … Chris K. P. Mok
Cold Spring Harbor Laboratory (2020-03-17)
DOI: 10.1101/2020.03.15.993097 · PMID: 32511317 · PMCID: PMC7239046

815. The feasibility of convalescent plasma therapy in severe COVID-19 patients: a pilot study
Kai Duan, Bende Liu, Cesheng Li, Huajun Zhang, Ting Yu, Jieming Qu, Min Zhou, Li Chen, Shengli Meng, Yong Hu, … Xiaoming Yang
Cold Spring Harbor Laboratory (2020-03-23)
DOI: 10.1101/2020.03.16.20036145

816. Hydroxychloroquine and Azithromycin as a treatment of COVID-19: preliminary results of an open-label non-randomized clinical trial
Philippe GAUTRET, Jean Christophe LAGIER, Philippe PAROLA, Van Thuan HOANG, Line MEDDED, Morgan MAILHE, Barbara DOUDIER, Johan COURJON, Valerie GIORDANENGO, Vera ESTEVES VIEIRA, … Didier RAOULT
medRxiv (2020-03-20)
DOI: 10.1101/2020.03.16.20037135

817. Chloroquine: Modes of action of an undervalued drug
Rodolfo Thomé, Stefanie Costa Pinto Lopes, Fabio Trindade Maranhão Costa, Liana Verinaud
Immunology Letters (2013-06)
DOI: 10.1016/j.imlet.2013.07.004 · PMID: 23891850

818. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy
B. Lo, K. Zhang, W. Lu, L. Zheng, Q. Zhang, C. Kanellopoulou, Y. Zhang, Z. Liu, J. M. Fritz, R. Marsh, … M. B. Jordan
Science (2015-07-23)
DOI: 10.1126/science.aaa1663 · PMID: 26206937

819. The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2
Erik Procko
Cold Spring Harbor Laboratory (2020-05-11)
DOI: 10.1101/2020.03.16.994236 · PMID: 32511321 · PMCID: PMC7239051

820. Comparative Pathogenesis Of COVID-19, MERS And SARS In A Non-Human Primate Model
Barry Rockx, Thijs Kuiken, Sander Herfst, Theo Bestebroer, Mart M. Lamers, Dennis de Meulder, Geert van Amerongen, Judith van den Brand, Nisreen M. A. Okba, Debby Schipper, … Bart L. Haagmans
bioRxiv (2020-03-17)
DOI: 10.1101/2020.03.17.995639

821. Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus
P. B. McCray, L. Pewe, C. Wohlford-Lenane, M. Hickey, L. Manzel, L. Shi, J. Netland, H. P. Jia, C. Halabi, C. D. Sigmund, … S. Perlman
Journal of Virology (2006-11-01)
DOI: 10.1128/jvi.02012-06 · PMID: 17079315 · PMCID: PMC1797474

822. A Model Describing COVID-19 Community Transmission Taking into Account Asymptomatic Carriers and Risk Mitigation
Jacob B Aguilar, Jeremy Samuel Faust, Lauren M. Westafer, Juan B. Gutierrez
Cold Spring Harbor Laboratory (2020-08-11)
DOI: 10.1101/2020.03.18.20037994

823. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice
Quan-xin Long, Hai-jun Deng, Juan Chen, Jieli Hu, Bei-zhong Liu, Pu Liao, Yong Lin, Li-hua Yu, Zhan Mo, Yin-yin Xu, … Ai-long Huang
Cold Spring Harbor Laboratory (2020-03-20)
DOI: 10.1101/2020.03.18.20038018

824. Heat inactivation of serum interferes with the immunoanalysis of antibodies to SARS-CoV-2
Xiumei Hu, Taixue An, Bo Situ, Yuhai Hu, Zihao Ou, Qiang Li, Xiaojing He, Ye Zhang, Peifu Tian, Dehua Sun, … Lei Zheng
Cold Spring Harbor Laboratory (2020-03-16)
DOI: 10.1101/2020.03.12.20034231

825. SARS-CoV-2 specific antibody responses in COVID-19 patients
NISREEN M. A. OKBA, Marcel A Muller, Wentao Li, Chunyan Wang, Corine H. GeurtsvanKessel, Victor M. Corman, Mart M. Lamers, Reina S. Sikkema, Erwin de Bruin, Felicity D. Chandler, … Bart L. Haagmans
medRxiv (2020-03-20)
DOI: 10.1101/2020.03.18.20038059

826. A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19
Drifa Belhadi, Nathan Peiffer-Smadja, François-Xavier Lescure, Yazdan Yazdanpanah, France Mentré, Cédric Laouénan
Cold Spring Harbor Laboratory (2020-03-27)
DOI: 10.1101/2020.03.18.20038190

827. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19
Janice M Leung, Chen Xi Yang, Anthony Tam, Tawimas Shaipanich, Tillie L Hackett, Gurpreet K Singhera, Delbert R Dorscheid, Don D Sin
Cold Spring Harbor Laboratory (2020-03-23)
DOI: 10.1101/2020.03.18.20038455

828. Dynamic profile of severe or critical COVID-19 cases
Yang Xu
Cold Spring Harbor Laboratory (2020-03-20)
DOI: 10.1101/2020.03.18.20038513

829. Association between Clinical, Laboratory and CT Characteristics and RT-PCR Results in the Follow-up of COVID-19 patients
Hang Fu, Huayan Xu, Na Zhang, Hong Xu, Zhenlin Li, Huizhu Chen, Rong Xu, Ran Sun, Lingyi Wen, Linjun Xie, … Yingkun Guo
Cold Spring Harbor Laboratory (2020-03-23)
DOI: 10.1101/2020.03.19.20038315

830. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus
Timothy P. Sheahan, Amy C. Sims, Shuntai Zhou, Rachel L. Graham, Collin S. Hill, Sarah R. Leist, Alexandra Schäfer, Kenneth H. Dinnon, Stephanie A. Montgomery, Maria L. Agostini, … Ralph S. Baric
Cold Spring Harbor Laboratory (2020-03-20)
DOI: 10.1101/2020.03.19.997890

831. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs
Sangeun Jeon, Meehyun Ko, Jihye Lee, Inhee Choi, Soo Young Byun, Soonju Park, David Shum, Seungtaek Kim
bioRxiv (2020-03-28)
DOI: 10.1101/2020.03.20.999730

832. Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2
Vincent J. Munster, Friederike Feldmann, Brandi N. Williamson, Neeltje van Doremalen, Lizzette Pérez-Pérez, Jonathan Schulz, Kimberly Meade-White, Atsushi Okumura, Julie Callison, Beniah Brumbaugh, … Emmie de Wit
bioRxiv (2020-03-21)
DOI: 10.1101/2020.03.21.001628 · PMID: 32511299 · PMCID: PMC7217148

833. Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in Rhesus macaques
Wei Deng, Linlin Bao, Hong Gao, Zhiguang Xiang, Yajin Qu, Zhiqi Song, Shunran Gong, Jiayi Liu, Jiangning Liu, Pin Yu, … Chuan Qin
Cold Spring Harbor Laboratory (2020-03-30)
DOI: 10.1101/2020.03.13.990036

834. ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19
Bruna GG Pinto, Antonio ER Oliveira, Youvika Singh, Leandro Jimenez, Andre NA Goncalves, Rodrigo LT Ogava, Rachel Creighton, Jean PS Peron, Helder I Nakaya
Cold Spring Harbor Laboratory (2020-03-27)
DOI: 10.1101/2020.03.21.20040261 · PMID: 32511627 · PMCID: PMC7276054

835. Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial
Huijie Bian, Zhao-Hui Zheng, Ding Wei, Zheng Zhang, Wen-Zhen Kang, Chun-Qiu Hao, Ke Dong, Wen Kang, Jie-Lai Xia, Jin-Lin Miao, … Ping Zhu
Cold Spring Harbor Laboratory (2020-09-27)
DOI: 10.1101/2020.03.21.20040691

836. CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A
T. Pushkarsky, G. Zybarth, L. Dubrovsky, V. Yurchenko, H. Tang, H. Guo, B. Toole, B. Sherry, M. Bukrinsky
Proceedings of the National Academy of Sciences (2001-05-15)
DOI: 10.1073/pnas.111583198 · PMID: 11353871 · PMCID: PMC33473

837. CD147/EMMPRIN Acts as a Functional Entry Receptor for Measles Virus on Epithelial Cells
Akira Watanabe, Misako Yoneda, Fusako Ikeda, Yuri Terao-Muto, Hiroki Sato, Chieko Kai
Journal of Virology (2010-05-01)
DOI: 10.1128/jvi.02168-09 · PMID: 20147391 · PMCID: PMC2863760

838. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum
Cécile Crosnier, Leyla Y. Bustamante, S. Josefin Bartholdson, Amy K. Bei, Michel Theron, Makoto Uchikawa, Souleymane Mboup, Omar Ndir, Dominic P. Kwiatkowski, Manoj T. Duraisingh, … Gavin J. Wright
Nature (2011-11-09)
DOI: 10.1038/nature10606 · PMID: 22080952 · PMCID: PMC3245779

839. Function of HAb18G/CD147 in Invasion of Host Cells by Severe Acute Respiratory Syndrome Coronavirus
Zhinan Chen, Li Mi, Jing Xu, Jiyun Yu, Xianhui Wang, Jianli Jiang, Jinliang Xing, Peng Shang, Airong Qian, Yu Li, … Ping Zhu
The Journal of Infectious Diseases (2005-03)
DOI: 10.1086/427811 · PMID: 15688292 · PMCID: PMC7110046

840. CD147 mediates intrahepatic leukocyte aggregation and determines the extent of liver injury
Christine Yee, Nathan M. Main, Alexandra Terry, Igor Stevanovski, Annette Maczurek, Alison J. Morgan, Sarah Calabro, Alison J. Potter, Tina L. Iemma, David G. Bowen, … Nicholas A. Shackel
PLOS ONE (2019-07-10)
DOI: 10.1371/journal.pone.0215557 · PMID: 31291257 · PMCID: PMC6619953

841. Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site
Andrew D. Davidson, Maia Kavanagh Williamson, Sebastian Lewis, Deborah Shoemark, Miles W. Carroll, Kate Heesom, Maria Zambon, Joanna Ellis, Phillip A. Lewis, Julian A. Hiscox, David A. Matthews
Cold Spring Harbor Laboratory (2020-03-24)
DOI: 10.1101/2020.03.22.002204

842. Modifications to the Hemagglutinin Cleavage Site Control the Virulence of a Neurotropic H1N1 Influenza Virus
X. Sun, L. V. Tse, A. D. Ferguson, G. R. Whittaker
Journal of Virology (2010-06-16)
DOI: 10.1128/jvi.00797-10 · PMID: 20554779 · PMCID: PMC2919019

843. The architecture of SARS-CoV-2 transcriptome
Dongwan Kim, Joo-Yeon Lee, Jeong-Sun Yang, Jun Won Kim, V. Narry Kim, Hyeshik Chang
Cold Spring Harbor Laboratory (2020-03-14)
DOI: 10.1101/2020.03.12.988865

844. First Clinical Study Using HCV Protease Inhibitor Danoprevir to Treat Naive and Experienced COVID-19 Patients
Hongyi Chen, Zhicheng Zhang, Li Wang, Zhihua Huang, Fanghua Gong, Xiaodong Li, Yahong Chen, Jinzi J. WU
Cold Spring Harbor Laboratory (2020-03-24)
DOI: 10.1101/2020.03.22.20034041

845. Preclinical Characteristics of the Hepatitis C Virus NS3/4A Protease Inhibitor ITMN-191 (R7227)
S. D. Seiwert, S. W. Andrews, Y. Jiang, V. Serebryany, H. Tan, K. Kossen, P. T. R. Rajagopalan, S. Misialek, S. K. Stevens, A. Stoycheva, … L. M. Blatt
Antimicrobial Agents and Chemotherapy (2008-09-29)
DOI: 10.1128/aac.00699-08 · PMID: 18824605 · PMCID: PMC2592891

846. Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China
Xiaoyuan Xu, Bo Feng, Yujuan Guan, Sujun Zheng, Jifang Sheng, Xingxiang Yang, Yuanji Ma, Yan Huang, Yi Kang, Xiaofeng Wen, … Lai Wei
Journal of Clinical and Translational Hepatology (2019-09-30)
DOI: 10.14218/jcth.2019.00033 · PMID: 31608212 · PMCID: PMC6783683

847. Potentially highly potent drugs for 2019-nCoV
Duc Duy Nguyen, Kaifu Gao, Jiahui Chen, Rui Wang, Guo-Wei Wei
Cold Spring Harbor Laboratory (2020-02-13)
DOI: 10.1101/2020.02.05.936013 · PMID: 32511344 · PMCID: PMC7255774

848. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset
Bin Lou, Tigndong Li, Shufa Zheng, Yingying Su, Zhiyong Li, Wei Liu, Fei Yu, Shengxiang Ge, Qianda Zou, Quan Yuan, … Yu Chen
Cold Spring Harbor Laboratory (2020-03-27)
DOI: 10.1101/2020.03.23.20041707

849. SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems
Daniel Blanco-Melo, Benjamin E. Nilsson-Payant, Wen-Chun Liu, Rasmus Møller, Maryline Panis, David Sachs, Randy A. Albrecht, Benjamin R. tenOever
Cold Spring Harbor Laboratory (2020-03-24)
DOI: 10.1101/2020.03.24.004655

850. A New Predictor of Disease Severity in Patients with COVID-19 in Wuhan, China
Ying Zhou, Zhen Yang, Yanan Guo, Shuang Geng, Shan Gao, Shenglan Ye, Yi Hu, Yafei Wang
Cold Spring Harbor Laboratory (2020-03-27)
DOI: 10.1101/2020.03.24.20042119

851. Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study
Shuke Nie, Xueqing Zhao, Kang Zhao, Zhaohui Zhang, Zhentao Zhang, Zhan Zhang
Cold Spring Harbor Laboratory (2020-03-26)
DOI: 10.1101/2020.03.24.20042283

852. Viral Kinetics and Antibody Responses in Patients with COVID-19
Wenting Tan, Yanqiu Lu, Juan Zhang, Jing Wang, Yunjie Dan, Zhaoxia Tan, Xiaoqing He, Chunfang Qian, Qiangzhong Sun, Qingli Hu, … Guohong Deng
medRxiv (2020-03-26)
DOI: 10.1101/2020.03.24.20042382

853. Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray
He-wei Jiang, Yang Li, Hai-nan Zhang, Wei Wang, Dong Men, Xiao Yang, Huan Qi, Jie Zhou, Sheng-ce Tao
Cold Spring Harbor Laboratory (2020-03-27)
DOI: 10.1101/2020.03.20.20039495

854. COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome
Dan Zhang, Rui Guo, Lei Lei, Hongjuan Liu, Yawen Wang, Yili Wang, Tongxin Dai, Tianxiao Zhang, Yanjun Lai, Jingya Wang, … Jinsong Hu
Cold Spring Harbor Laboratory (2020-03-26)
DOI: 10.1101/2020.03.24.20042655

855. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
Aaron Miller, Mac Josh Reandelar, Kimberly Fasciglione, Violeta Roumenova, Yan Li, Gonzalo H Otazu
medRxiv (2020-03-28)
DOI: 10.1101/2020.03.24.20042937

856. Non-specific effects of BCG vaccine on viral infections
S. J. C. F. M. Moorlag, R. J. W. Arts, R. van Crevel, M. G. Netea
Clinical Microbiology and Infection (2019-12)
DOI: 10.1016/j.cmi.2019.04.020 · PMID: 31055165

857. BCG vaccination to reduce the impact of COVID-19 in healthcare workers (The BRACE Trial)
Murdoch Children’s Research Institute

858. Non-neural expression of SARS-CoV-2 entry genes in the olfactory epithelium suggests mechanisms underlying anosmia in COVID-19 patients
David H. Brann, Tatsuya Tsukahara, Caleb Weinreb, Darren W. Logan, Sandeep Robert Datta
bioRxiv (2020-03-28)
DOI: 10.1101/2020.03.25.009084

859. Cigarette smoke triggers the expansion of a subpopulation of respiratory epithelial cells that express the SARS-CoV-2 receptor ACE2
Joan C Smith, Jason Meyer Sheltzer
bioRxiv (2020-03-31)
DOI: 10.1101/2020.03.28.013672

860. The comparative superiority of IgM-IgG antibody test to real-time reverse transcriptase PCR detection for SARS-CoV-2 infection diagnosis
Rui Liu, Xinghui Liu, Huan Han, Muhammad Adnan Shereen, Zhili Niu, Dong Li, Fang Liu, Kailang Wu, Zhen Luo, Chengliang Zhu
Cold Spring Harbor Laboratory (2020-03-30)
DOI: 10.1101/2020.03.28.20045765

10 Appendix 1

This appendix contains reviews produced by the Immunology Institute of the Icahn School of Medicine

10.1 Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody

Tian et al. Emerg Microbes Infect 2020 [738]

10.1.1 Keywords

10.1.2 Summary

Considering the relatively high identity of the receptor binding domain (RBD) of the spike proteins from 2019-nCoV and SARS-CoV (73%), this study aims to assess the cross-reactivity of several anti-SARS-CoV monoclonal antibodies with 2019-nCoV. The results showed that the SARS-CoV-specific antibody CR3022 can potently bind 2019-nCoV RBD.

10.1.3 Main Findings

The structure of the 2019-nCoV spike RBD and its conformation in complex with the receptor angiotensin-converting enzyme (ACE2) was modeled in silico and compared with the SARS-CoV RBD structure. The models predicted very similar RBD-ACE2 interactions for both viruses. The binding capacity of representative SARS-CoV-RBD specific monoclonal antibodies (m396, CR3014, and CR3022) to recombinant 2019-nCoV RBD was then investigated by ELISA and their binding kinetics studied using biolayer interferometry. The analysis showed that only CR3022 was able to bind 2019-nCoV RBD with high affinity (KD of 6.3 nM), however it did not interfere with ACE2 binding. Antibodies m396 and CR3014, which target the ACE2 binding site of SARS-CoV failed to bind 2019-nCoV spike protein.

10.1.4 Limitations

The 2019-nCoV RBD largely differ from the SARS-CoV at the C-terminus residues, which drastically impact the cross-reactivity of antibodies described for other B beta-coronaviruses, including SARS-CoV. This study claims that CR3022 antibody could be a potential candidate for therapy. However, none of the antibodies assayed in this work showed cross-reactivity with the ACE2 binding site of 2019-nCoV, essential for the replication of this virus. Furthermore, neutralization assays with 2019-nCoV virus or pseudovirus were not performed. Although the use of neutralizing antibodies is an interesting approach, these results suggest that it is critical the development of novel monoclonal antibodies able to specifically bind 2019-nCoV spike protein.

10.1.5 Credit

Review by D.L.O as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.2 Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV

He et al. medRxiv [739]

10.2.1 Keywords

10.2.2 Main Findings

The authors used bioinformatics tools to identify features of ACE2 expression in the lungs of different patent groups: healthy, smokers, patients with chronic airway disease (i.e., COPD) or asthma. They used gene expression data publicly available from GEO that included lung tissues, bronchoalveolar lavage, bronchial epithelial cells, small airway epithelial cells, or SARS-Cov infected cells.

The authors describe no significant differences in ACE2 expression in lung tissues of Healthy, COPD, and Asthma groups (p=0.85); or in BAL of Healthy and COPD (p=0.48); or in epithelial brushings of Healthy and Mild/Moderate/Severe Asthma (p=0.99). ACE2 was higher in the small airway epithelium of long-term smokers vs non-smokers (p<0.001). Consistently, there was a trend of higher ACE2 expression in the bronchial airway epithelial cells 24h post-acute smoking exposure (p=0.073). Increasing ACE2 expression at 24h and 48h compared to 12h post SARS-Cov infection (p=0.026; n=3 at each time point) was also detected.

15 lung samples’ data from healthy participants were separated into high and low ACE2 expression groups. “High” ACE2 expression was associated with the following GO pathways: innate and adaptive immune responses, B cell mediated immunity, cytokine secretion, and IL-1, IL-10, IL-6, IL-8 cytokines. The authors speculate that a high basal ACE2 expression will increase susceptibility to SARS-CoV infection.

In 3 samples SARS-Cov infection was associated with IL-1, IL-10 and IL-6 cytokine production (GO pathways) at 24h. And later, at 48h, with T-cell activation and T-cell cytokine production. It is unclear whether those changes were statistically significant.

The authors describe a time course quantification of immune infiltrates in epithelial cells infected with SARS-Cov infection. They state that in healthy donors ACE2 expression did not correlate with the immune cell infiltration. However, in SARS-Cov samples, at 48h they found that ACE2 correlated with neutrophils, NK-, Th17-, Th2-, Th1- cells, and DCs. Again, while authors claim significance, the corresponding correlation coefficients and p-values are not presented in the text or figures. In addition, the source of the data for this analysis is not clear.

Using network analysis, proteins SRC, FN1, MAPK3, LYN, MBP, NLRC4, NLRP1 and PRKCD were found to be central (Hub proteins) in the regulating network of cytokine secretion after coronavirus infection. Authors conclude this indicates that these molecules were critically important in ACE2-induced inflammatory response. Additionally, authors speculate that the increased expression of ACE2 affected RPS3 and SRC, which were the two hub genes involved in viral replication and inflammatory response.

10.2.3 Limitations

The methods section is very limited and does not describe any of the statistical analyses; and description of the construction of the regulatory protein networks is also limited. For the findings in Figures 2 authors claim significance, which is not supported by p-values or coefficients. For the sample selection, would be useful if sample sizes and some of the patients’ demographics (e.g. age) were described.

For the analysis of high vs low ACE2 expression in healthy subjects, it is not clear what was the cut off for ‘high’ expression and how it was determined. Additionally, further laboratory studies are warranted to confirm that high ACE2 gene expression would have high correlation with the amount of ACE2 protein on cell surface. For the GO pathway analysis significance was set at p<0.05, but not adjusted for multiple comparisons.

There were no samples with SARS-CoV-2 infection. While SARS-Cov and SARS-CoV-2 both use ACE2 to enter the host cells, the analysis only included data on SARS-Cov and any conclusions about SARS-CoV2 are limited.

Upon checking GSE accession numbers of the datasets references, two might not be cited correctly: GSE37758 (“A spergillus niger: Control (fructose) vs. steam-exploded sugarcane induction (SEB)”" was used in this paper as “lung tissue” data) and GSE14700 (“Steroid Pretreatment of Organ Donors to Prevent Postischemic Renal Allograft Failure: A Randomized, Controlled Trial” – was used as SARS-Cov infection data).

10.2.4 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

Liang et al. medRxiv [740]

10.3.1 Keywords

10.3.2 Main Findings

This study examined the incidence of diarrhea in patients infected with SARS-CoV-2 across three recently published cohorts and found that there are statistically significant differences by Fisher’s exact test. They report that this could be due to subjective diagnosis criterion for diarrhea or from patients first seeking medical care from gastroenterologist. In order to minimize nosocomial infections arising from unsuspected patients with diarrhea and gain comprehensive understanding of transmission routes for this viral pathogen, they compared the transcriptional levels of ACE2 of various human tissues from NCBI public database as well as in small intestine tissue from CD57BL/6 mice using single cell sequencing. They show that ACE2 expression is not only increased in the human small intestine, but demonstrate a particular increase in mice enterocytes positioned on the surface of the intestinal lining exposed to viral pathogens. Given that ACE2 is the viral receptor for SARS-CoV-2 and also reported to regulate diarrhea, their data suggests the small intestine as a potential transmission route and diarrhea as a potentially underestimated symptom in COVID19 patients that must be carefully monitored. Interestingly, however, they show that ACE2 expression level is not elevated in human lung tissue.

10.3.3 Limitations

Although this study demonstrates a statistical difference in the incidence of diarrhea across three separate COVID19 patient cohorts, their conclusions are limited by a small sample size. Specifically, the p-value computed by Fisher’s exact test is based on a single patient cohort of only six cases of which 33% are reported to have diarrhea, while the remaining two larger cohorts with 41 and 99 cases report 3% and 2% diarrhea incidence, respectively. Despite showing significance, they would need to acquire larger sample sizes and cohorts to minimize random variability and draw meaningful conclusions. Furthermore, they do not address why ACE2 expression level is not elevated in human lung tissue despite it being a major established route of transmission for SARS-CoV-2. It could be helpful to validate this result by looking at ACE2 expression in mouse lung tissue. Finally, although this study is descriptive and shows elevated ACE2 expression in small intestinal epithelial cells, it does not establish a mechanistic link to SARS-CoV-2 infection of the host. Overall, their claim that infected patients exhibiting diarrhea pose an increased risk to hospital staff needs to be further substantiated.

10.3.4 Significance

This study provides a possible transmission route and a potentially underappreciated clinical symptom for SARS-CoV-2 for better clinical management and control of COVID19.

10.3.5 Credit

Summary generated as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.4 Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection

Chai et al. bioRxiv [741]

10.4.1 Keywords

10.4.2 Summary

Using both publicly available scRNA-seq dataset of liver samples from colorectal patients and scRNA-sequencing of four liver samples from healthy volunteers, the authors show that ACE2 is significantly enriched in the majority of cholangiocytes (59.7 %) but not in hepatocytes (2.6%).

10.4.3 Main Findings

Using bioinformatics approaches of RNASeq analysis, this study reveals that ACE2 dominates in cholangiocytes and is present at very low levels in hepatocytes.

10.4.4 Limitations

The study does not provide mechanistic insights into how SARS-CoV-2 can infect and replicate in cholangiocytes and the types of intrinsic anti-viral responses induced by cholangiocytes when infected. In addition, because the study relies on the assumption that SARS-CoV-2 infects cells only through ACE2, it cannot discount the possibility that the virus can infect hepatocytes through mechanisms other than ACE2-mediated entry. Furthermore, because the scRNA-seq analysis were performed on healthy liver samples, one cannot draw any definitive conclusions about gene expression states (including ACE2 expression in liver cell types) in system-wide inflammatory contexts.

10.4.5 Significance

This article with other studies on liver damage in COVID patients suggests that liver damage observed in COVID patients is more due to inflammatory cytokines than direct infection of the liver. Even if cholangiocytes are infectable by SARS-CoV-2 (which was demonstrated by human liver ductal organoid study ([742]), published clinical data show no significant increase in bile duct injury related indexes (i.e. alkaline phosphatase, gamma-glutamyl transpeptidase and total bilirubin). In sum, it underscores the importance of future studies characterizing cellular responses of extra-pulmonary organs in the context of COVID or at least in viral lung infections..

10.4.6 Credit

Summary generated by Chang Moon as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.5 ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism

Wang et al. medRxiv. [743]

10.5.1 Keywords

10.5.2 Main Findings

Colonic enterocytes primarily express ACE2. Cellular pathways associated with ACE2 expression include innate immune signaling, HLA up regulation, energy metabolism and apoptotic signaling.

10.5.3 Limitations

This is a study of colonic biopsies taken from 17 children with and without IBD and analyzed using scRNAseq to look at ACE2 expression and identify gene families correlated with ACE2 expression. The authors find ACE2 expression to be primarily in colonocytes. It is not clear why both healthy and IBD patients were combined for the analysis. Biopsies were all of children so extrapolation to adults is limited. The majority of genes found to be negatively correlated with ACE2 expression include immunoglobulin genes (IGs). IG expression will almost certainly be low in colonocytes irrespective of ACE2 expression.

10.5.4 Significance

This study performs a retrospective analysis of ACE2 expression using an RNAseq dataset from intestinal biopsies of children with and without IBD. The implications for the CoV-19 epidemic are modest, but do provide support that ACE2 expression is specific to colonocytes in the intestines. The ontological pathway analysis provides some limited insights into gene expression associated with ACE2.

10.5.5 Credit

Summary generated as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.6 The Pathogenicity of 2019 Novel Coronavirus in hACE2 Transgenic Mice

Bao et al. bioRxiv [744]

10.6.1 Keywords

10.6.2 Main Findings

Using a transgenic human Angiotensin-converting enzyme 2 (hACE2) mouse that has previously been shown susceptible to infection by SARS-CoV, Bao et al. create a model of pandemic 2019-nCoV strain coronavirus. The model includes interstitial hyperplasia in lung tissue, moderate inflammation in bronchioles and blood vessels, and histology consistent with viral pneumonia at 3 days post infection. Wildtype did not experience these symptoms. In addition, viral antigen and hACE2 receptor were found to co-localize the lung by immunofluorescence 3-10 days post infection only in the hACE2 infected mice.

10.6.3 Limitations

The characterization of the infection remains incomplete, as well as lacking characterization of the immune response other than the presence of a single antiviral antibody. Though they claim to fulfill Koch’s postulates, they only isolate the virus and re-infect Vero cells, rather than naive mice.

10.6.4 Significance

This paper establishes a murine model for 2019-nCoV infection with symptoms consistent with viral pneumonia. Though not fully characterized, this model allows in vivo analysis of viral entry and pathology that is important for the development of vaccines and antiviral therapeutics.

10.6.5 Credit

Review by Dan Fu Ruan, Evan Cody and Venu Pothula as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.7 Caution on Kidney Dysfunctions of 2019-nCoV Patients

Li et al. medRxiv. [745]

10.7.1 Keywords

CoVID-19, 2019-nCoV, SARS-CoV-2, kidney, clinical, creatinine, proteinuria, albuminuria, CT

10.7.2 Main Findings

10.7.3 Limitations

10.7.4 Significance

10.7.5 Credit

Review by Samarth Hegde as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.8 Profiling the immune vulnerability landscape of the 2019 Novel Coronavirus

Zhu et al. bioRxiv [748]

10.8.1 Keywords

10.8.2 Main Findings

This study harnesses bioinformatic profiling to predict the potential of COV2 viral proteins to be presented on MHC I and II and to form linear B-cell epitopes. These estimates suggest a T-cell antigenic profile distinct from SARS-CoV or MERS-CoV, identify focused regions of the virus with a high density of predicted epitopes, and provide preliminary evidence for adaptive immune pressure in the genetic evolution of the virus.

10.8.3 Limitations

While the study performs a comprehensive analysis of potential epitopes within the virus genome, the analysis relies solely on bioinformatic prediction to examine MHC binding affinity and B-cell epitope potential and does not capture the immunogenicity or recognition of these epitopes. Future experimental validation in data from patients infected with SARS-CoV-2 will be important to validate and refine these findings. Thus some of the potential conclusions stated, including viral evolution toward lower immunogenicity or a dominant role for CD4+ T-cells rather than CD8+ T-cells in viral clearance, require further valiadtion.

10.8.4 Significance

These findings may help direct peptide vaccine design toward relevant epitopes and provide intriguing evidence of viral evolution in response to immune pressure.

10.8.5 Credit

Summary generated as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.9 Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection

Lin et al. bioRxiv [747]

10.9.1 Keywords

10.9.2 Main Findings

10.9.3 Limitations

10.9.4 Significance

10.9.5 Credit

Review by Samarth Hegde as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.10 Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage

Liu et al. medRxiv [751]

10.10.1 Keywords

10.10.2 Main Findings

This study aimed to find prognostic biomarkers of COVID-19 pneumonia severity. Sixty-one (61) patients with COVID-19 treated in January at a hospital in Beijing, China were included. On average, patients were seen within 5 days from illness onset. Samples were collected on admission; and then patients were monitored for the development of severe illness with a median follow-up of 10 days].

Patients were grouped as “mild” (N=44) or “moderate/severe” (N=17) according to symptoms on admission and compared for different clinical/laboratory features. “Moderate/severe” patients were significantly older (median of 56 years old, compared to 41 years old). Whereas comorbidies rates were largely similar between the groups, except for hypertension, which was more frequent in the severe group (p= 0.056). ‘Severe’ patients had higher counts of neutrophils, and serum glucose levels; but lower lymphocyte counts, sodium and serum chlorine levels. The ratio of neutrophils to lymphocytes (NLR) was also higher for the ‘severe’ group. ‘Severe’ patients had a higher rate of bacterial infections (and antibiotic treatment) and received more intensive respiratory support and treatment.

26 clinical/laboratory variables were used to select NLR and age as the best predictors of the severe disease. Predictive cutoffs for a severe illness as NLR ≥ 3.13 or age ≥ 50 years.

10.10.3 Limitations

Identification of early biomarkers is important for making clinical decisions, but large sample size and validation cohorts are necessary to confirm findings. It is worth noting that patients classified as “mild” showed pneumonia by imaging and fever, and in accordance with current classifications this would be consistent with “moderate” cases. Hence it would be more appropriate to refer to the groups as “moderate” vs “severe/critical”. Furthermore, there are several limitations that could impact the interpretation of the results: e.g. classification of patients was based on symptoms presented on admission and not based on disease progression, small sample size, especially the number of ‘severe’ cases (with no deaths among these patients). Given the small sample size, the proposed NLR and age cut offs might not hold for a slightly different set of patients. For example, in a study of >400 patients, ‘non-severe’ and ‘severe’ NLR were 3.2 and 5.5, respectively [752].

10.10.4 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.11 Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)

Wan et. al. medRxiv [753]

10.11.1 Keywords

10.11.2 Main Findings

The authors analyzed lymphocyte subsets and cytokines of 102 patients with mild disease and 21 with severe disease. CD8+T cells and CD4+T cells were significantly reduced in both cohort. particularly in severe patients. The cytokines IL6 and IL10 were significantly elevated in severe patients as compared to mild. No significant differences were observed in frequency of B cells and NK cells.

The authors argue that the measurement of T cell frequencies and cytokine levels of IL6 and IL10 can be used to predict progression of disease from Mild to severe Cov-2 infection.

10.11.3 Limitations

The study demonstrates in a limited cohort similar associations to several other reported studies. The authors didn’t compare the changes in lymphocyte and cytokine with healthy individual (Covid-19 Negative) rather used an internal standard value. The recently preprint in LANCET shows The degree of lymphopenia and a pro-inflammatory cytokine storm is higher in severe COVID-19 patients than in mild cases, and is associated with the disease severity [754].

10.11.4 Significance

This translational data identifies key cytokines and lymphopenia associated with disease severity although mechanism and key cellular players are still unknown. Higher level IL-6 production in severe patient suggests potential role of Tocilizumab (anti-IL6R) biologic although clinical trial will be necessary.

10.11.5 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.12 Epidemiological and Clinical Characteristics of 17 Hospitalized Patients with 2019 Novel Coronavirus Infections Outside Wuhan, China

Li et al. medRxiv [755]

10.12.1 Keywords

10.12.2 Major Findings

These authors looked at 17 hospitalized patients with COVID-19 confirmed by RT-PCR in Dazhou, Sichuan. Patients were admitted between January 22 and February 10 and the final data were collected on February 11. Of the 17 patients, 12 remained hospitalized while 5 were discharged after meeting national standards. The authors observed no differences based on the sex of the patients but found that the discharged patients were younger in age (p = 0.026) and had higher lymphocyte counts (p = 0.005) and monocyte counts (p = 0.019) upon admission.

10.12.3 Limitations

This study is limited in the sample size of the study and the last data collection point was only one day after some of the patients were admitted.

10.12.4 Significance

These findings have been somewhat supported by subsequent studies that show that older age and an immunocompromised state are more likely to result in a more severe clinical course with COVID-19. However, other studies have been published that report on larger numbers of cases.

10.12.5 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.13 ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection


10.13.1 Keywords

10.13.2 Main Findings

10.13.3 Limitations

10.13.4 Significance

10.13.5 Credit

Review by Samarth Hegde as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.14 Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus


10.14.1 Keywords

10.14.2 Main Findings

The authors of this study sought to characterize the immune mechanism causing severe pulmonary disease and mortality in 2019-nCoV (COVID-19) patients. Peripheral blood was collected from hospitalized ICU (n=12) and non-ICU (n=21) patients with confirmed 2019-nCoV and from healthy controls (n=10) in The First Affiliated Hospital of University of Science and Technology China (Hefei, Anhui). Immune analysis was conducted by flow cytometry. 2019-nCoV patients had decreased lymphocyte, monocyte, and CD4 T cell counts compared to healthy controls. ICU patients had fewer lymphocytes than non-ICU patients. CD4 T cells of 2019-nCoV patients expressed higher levels of activation markers (OX40, CD69, CD38, CD44) and exhaustion markers (PD-1 and Tim3) than those of healthy controls. CD4 cells of ICU patients expressed significantly higher levels of OX40, PD-1, and Tim3 than those of non-ICU patients. 2019-nCoV patients had higher percentages of CD4 T cells co-expressing GM-CSF and IL-6 compared to healthy controls, while ICU patients had a markedly higher percentage of GM-CSF+ IFN-γ+ CD4 T cells than non-ICU patients. The CD4 T cells of nCoV patients and healthy controls showed no differences in TNF-α secretion.

The CD8 T cells of 2019-nCoV patients also showed higher expression of activation markers CD69, CD38, and CD44, as well as exhaustion markers PD-1 and Tim3, compared to healthy controls. CD8 T cells of ICU patients expressed higher levels of GM-CSF than those of non-ICU patients and healthy controls. No IL-6 or TNF-α was found in the CD8 T cells of any group. There were no differences in numbers of NK cells or B cells in 2019-nCoV patients and healthy controls, nor was there any GM-CSF or IL-6 secretion from these cells in either group.

Percentages of CD14+ CD16+ GM-CSF+ and CD14+ CD16+ IL-6+ inflammatory monocytes were significantly increased in nCoV patients compared to healthy controls; in particular, patients in the ICU had greater percentages of CD14+ CD16+ IL-6+ monocytes than non-ICU patients. The authors suggest that in 2019-nCoV patients, pathogenic Th1 cells produce GM-CSF, recruiting CD14+ CD16+ inflammatory monocytes that secrete high levels of IL-6. These may enter pulmonary circulation and damage lung tissue while initiating the cytokine storm that causes mortality in severe cases. This is consistent with the cytokine storm seen in similar coronaviruses, as IL-6, IFN-γ, and GM-CSF are key inflammatory mediators seen in patients with SARS-CoV-1 and MERS-CoV.

10.14.3 Limitations

Though the results of this study open questions for further investigation, this is an early study on a small cohort of patients, and as such there are a number of limitations. The study included only 12 ICU patients and 21 non-ICU patients, and ideally would be repeated with a much larger patient cohort. Though the authors make claims about differences in lymphocyte and monocyte counts between patients and healthy controls, they did not report baseline laboratory findings for the control group. Additionally, severity of disease was classified based on whether or not patients were in the ICU. It would be interesting to contextualize the authors’ immunological findings with more specific metrics of disease severity or time course. Noting mortality, time from disease onset, pre-existing conditions, or severity of lung pathology in post-mortem tissue samples would paint a fuller picture of how to assess risk level and the relationship between severity of disease and immunopathology. Another limitation is the selection of cytokines and immune markers for analysis, as the selection criteria were based on the cell subsets and cytokine storm typically seen in SARS-CoV-1 and MERS-CoV patients. Unbiased cytokine screens and immune profiling may reveal novel therapeutic targets that were not included in this study.

10.14.4 Significance

This study identifies potential therapeutic targets that could prevent acute respiratory disease syndrome (ARDS) and mortality in patients most severely affected by COVID-19. The authors propose testing monoclonal antibodies against IL6-R or GM-CSF to block recruitment of inflammatory monocytes and the subsequent cytokine storm in these patients.

10.14.5 Credit

Review by Gabrielle Lubitz as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.15 Clinical Characteristics of 2019 Novel Infected Coronavirus Pneumonia:A Systemic Review and Meta-analysis

Qian et al. medRxiv. [758]

10.15.1 Keywords

10.15.2 Main Findings

The authors performed a meta analysis of literature on clinical, laboratory and radiologic characteristics of patients presenting with pneumonia related to SARSCoV2 infection, published up to Feb 6 2020. They found that symptoms that were mostly consistent among studies were sore throat, headache, diarrhea and rhinorrhea. Fever, cough, malaise and muscle pain were highly variable across studies. Leukopenia (mostly lymphocytopenia) and increased white blood cells were highly variable across studies. They identified three most common patterns seen on CT scan, but there was high variability across studies. Consistently across the studies examined, the authors found that about 75% of patients need supplemental oxygen therapy, about 23% mechanical ventilation and about 5% extracorporeal membrane oxygenation (ECMO). The authors calculated a staggering pooled mortality incidence of 78% for these patients.

10.15.3 Limitations

The authors mention that the total number of studies included in this meta analysis is nine, however they also mentioned that only three studies reported individual patient data. It is overall unclear how many patients in total were included in their analysis. This is mostly relevant as they reported an incredibly high mortality (78%) and mention an absolute number of deaths of 26 cases overall. It is not clear from their report how the mortality rate was calculated.

The data is based on reports from China and mostly from the Wuhan area, which somewhat limits the overall generalizability and applicability of these results.

10.15.4 Significance

This meta analysis offers some important data for clinicians to refer to when dealing with patients with COVID-19 and specifically with pneumonia. It is very helpful to set expectations about the course of the disease.

10.15.5 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.16 Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients

Liu et al. medRxiv [759]

10.16.1 Keywords

10.16.2 Main Findings

Liu et al. enrolled a cohort of 40 patients from Wuhan including 27 mild cases and 13 severe cases of COVID-19. They performed a 16-day kinetic analysis of peripheral blood from time of disease onset. Patients in the severe group were older (medium age of 59.7, compared to 48.7 in mild group) and more likely to have hypertension as a co-morbidity. Lymphopenia was observed in 44.4% of the mild patients and 84.6% of the severe patients. Lymphopenia was due to low T cell count, specially CD8 T cells. Severe patients showed higher neutrophil counts and an increase of cytokines in the serum (IL2, IL6, IL10 and IFNγ). The authors measured several other clinical laboratory parameters were also higher in severe cases compared to mild, but concluded that neutrophil to CD8 T cell ratio (N8R) as the best prognostic factor to identify the severe cases compared to other receiver operating characteristic (ROC).

10.16.3 Limitations

This was a small cohort (N=40), and two of the patients initially included in the severe group (N=13) passed away and were excluded from the analysis due to lack of longitudinal data. However, it would be most important to be able to identify patients with severe disease with higher odds of dying. It seems that the different time points analyzed relate to hospital admission, which the authors describe as disease onset. The time between first symptoms and first data points is not described. It would have been important to analyze how the different measured parameters change according to health condition, and not just time (but that would require a larger cohort). The predictive value of N8R compared to the more commonly used NLR needs to be assessed in other independent and larger cohorts. Lastly, it is important to note that pneumonia was detected in patients included in the “mild” group, but according to the Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment (7th edition) this group should be considered “moderate”.

10.16.4 Significance

Lymphopenia and cytokine storm have been described to be detrimental in many other infections including SARS-CoV1 and MERS-CoV. However, it was necessary to confirm that this dramatic immune response was also observed in the SARS-CoV2 infected patients. These results and further validation of the N8R ratio as a predictor of disease severity will contribute for the management of COVID19 patients and potential development of therapies.

10.16.5 Credit

Review by Pauline Hamon as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.17 Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019

Chen et al. medRxiv [760]

10.17.1 Keywords

10.17.2 Main Findings

This study retrospectively evaluated clinical, laboratory, hematological, biochemical and immunologic data from 21 subjects admitted to the hospital in Wuhan, China (late December/January) with confirmed SARS-CoV-2 infection. The aim of the study was to compare ‘severe’ (n=11, ~64 years old) and ‘moderate’ (n=10, ~51 years old) COVID-19 cases. Disease severity was defined by patients’ blood oxygen level and respiratory output. They were classified as ‘severe’ if SpO2 93% or respiratory rates 30 per min.

In terms of the clinical laboratory measures, ‘severe’ patients had higher CRP and ferritin, alanine and aspartate aminotransferases, and lactate dehydrogenase but lower albumin concentrations.

The authors then compared plasma cytokine levels (ELISA) and immune cell populations (PBMCs, Flow Cytometry). ‘Severe’ cases had higher levels of IL-2R, IL-10, TNFa, and IL-6 (marginally significant). For the immune cell counts, ‘severe’ group had higher neutrophils, HLA-DR+ CD8 T cells and total B cells; and lower total lymphocytes, CD4 and CD8 T cells (except for HLA-DR+), CD45RA Tregs, and IFNy-expressing CD4 T cells. No significant differences were observed for IL-8, counts of NK cells, CD45+RO Tregs, IFNy-expressing CD8 T and NK cells.

10.17.3 Limitations

Several potential limitations should be noted: 1) Blood samples were collected 2 days post hospital admission and no data on viral loads were available; 2) Most patients were administered medications (e.g. corticosteroids), which could have affected lymphocyte counts. Medications are briefly mentioned in the text of the manuscript; authors should include medications as part of Table 1. 3) ‘Severe’ cases were significantly older and 4/11 ‘severe’ patients died within 20 days. Authors should consider a sensitivity analysis of biomarkers with the adjustment for patients’ age.

10.17.4 Significance

Although the sample size was small, this paper presented a broad range of clinical, biochemical, and immunologic data on patients with COVID-19. One of the main findings is that SARS-CoV-2 may affect T lymphocytes, primarily CD4+ T cells, resulting in decreased IFNy production. Potentially, diminished T lymphocytes and elevated cytokines can serve as biomarkers of severity of COVID-19.

10.17.5 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.18 SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development

Sun et al. bioRxiv [761]

10.18.1 Keywords

10.18.2 Main Findings

This study compared the structure of SARS-CoV and SARS-CoV-2 Spike (S) protein receptor binding domain (RBD) and interactions with ACE2 using computational modeling, and interrogated cross-reactivity and cross-neutralization of SARS-CoV-2 by antibodies against SARS-CoV. While SARS-CoV and SARS-CoV-2 have over 70 % sequence homology and share the same human receptor ACE2, the receptor binding motif (RBM) is only 50% homologous.

Computational prediction of the SARS-CoV-2 and ACE2 interactions based on the previous crystal structure data of SARS-CoV, and measurement of binding affinities against human ACE2 using recombinant SARS-CoV and SARS-CoV-2 S1 peptides, demonstrated similar binding of the two S1 peptides to ACE2, explaining the similar transmissibility of SARS-CoV and SARS-CoV-2 and consistent with previous data (Wall et al Cell 2020).

The neutralization activity of SARS-CoV-specific rabbit polyclonal antibodies were about two-order of magnitude less efficient to neutralize SARS-CoV-2 than SARS-CoV, and four potently neutralizing monoclonal antibodies against SARS-CoV had poor binding and neutralizing activity against SARS-CoV-2. In contrast, 3 poor SARS-CoV-binding monoclonal antibodies show some efficiency to bind and neutralize SARS-CoV-2. The results suggest that that antibodies to more conserved regions outside the RBM motif might possess better cross-protective neutralizing activities between two strains.

10.18.3 Limitations

It would have been helpful to show the epitopes recognized by the monoclonal antibodies tested on both SARS-CoV, SARS-CoV-2 to be able to make predictions for induction of broadly neutralizing antibodies. The data on monoclonal antibody competition with ACE2 for binding to SARS-CoV RBD should have also included binding on SARS-CoV2, especially for the three monoclonal antibodies that showed neutralization activity for SARS-CoV2. Because of the less homology in RBM sequences between viruses, it still may be possible that these antibodies would recognize the ACE2 RBD in SARS-CoV-2.

10.18.4 Significance

It is noteworthy that immunization to mice and rabbit with SARS-CoV S1 or RBD protein could induce monoclonal antibodies to cross-bind and cross-neutralize SARS-CoV-2 even if they are not ACE2-blocking. If these types of antibodies could be found in human survivors or in the asymptomatic populations as well, it might suggest that exposure to previous Coronavirus strains could have induced cross-neutralizing antibodies and resulted in the protection from severe symptoms in some cases of SARS-CoV2.

10.18.5 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.19 Protection of Rhesus Macaque from SARS-Coronavirus challenge by recombinant adenovirus vaccine

Chen et al. bioRxiv [762]

10.19.1 Keywords

10.19.2 Main Findings

Rhesus macaques were immunized intramuscularly twice (week 0 and week 4) with SV8000 carrying the information to express a S1-orf8 fusion protein and the N protein from the BJ01 strain of SARS-CoV-1. By week 8, immunized animals had signs of immunological protection (IgG and neutralization titers) against SARS-CoV-1 and were protected against challenge with the PUMC-1 strain, with fewer detectable symptoms of respiratory distress, lower viral load, shorter periods of viral persistence, and less pathology in the lungs compared to non-immunized animals.

10.19.3 Limitations

The authors should write clearer descriptions of the methods used in this article. They do not describe how the IgG titers or neutralization titers were determined. There are some issues with the presentation of data, for example, in Figure 1a, y-axis should not be Vmax; forming cells and 1d would benefit from showing error bars. Furthermore, although I inferred that the animals were challenged at week 8, the authors did not explicitly detail when the animals were challenged. The authors should explain the design of their vaccine, including the choice of antigens and vector. The authors also do not include a description of the ethical use of animals in their study.

10.19.4 Significance

The authors describe a vaccine for SARS-CoV-1 with no discussion of possible implications for the current SARS-CoV-2 pandemic. Could a similar vaccine be designed to protect against SARS-CoV-2 and would the concerns regarding emerging viral mutations that the authors describe as a limitation for SARS-CoV-1 also be true in the context of SARS-CoV-2?

10.19.5 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.20 Reduction and Functional Exhaustion of T cells in Patients with Coronavirus Disease 2019 (COVID-19)


10.20.1 Keywords

10.20.2 Main Findings

Based on a retrospective study of 522 COVID patients and 40 healthy controls from two hospitals in Wuhan, China, authors show both age-dependent and clinical severity-dependent decrease in T cell numbers with elderly patients and patients who are in ICU-care showing the most dramatic decrease in T cell counts. Cytokine profiling of COVID patients reveal that TNF-α, IL-6 and IL-10 are increased in infected patients with patients in the ICU showing the highest levels. Interestingly, these three cytokine levels were inversely correlated with T cell counts and such inverse relationship was preserved throughout the disease progression. Surface staining of exhaustion markers (PD-1 and Tim-3) and flow cytometry of stained peripheral blood of 14 patients and 3 healthy volunteers demonstrate that T cells of COVID patients have increased expression of PD-1 with patients in ICU having the highest number of CD8+PD-1+ cells than their counterparts in non-ICU groups.

10.20.3 Limitations

Compared to the number of patients, number of control (n= 40) is small and is not controlled for age. Additional data linking inflammatory cytokines and the quality of the adaptive response including humoral and antigen specific T cell response is much needed. T cell exhaustion study relies on marker-dependent labeling of T cell functionality of a very limited sample size (n=17)—a functional/mechanistic study of these T cells from PBMCs would have bolstered their claims.

10.20.4 Significance

Limited but contains interesting implications. It is already known in literature that in the context of acute respiratory viral infections CD8 T cells exhibit exhaustion-like phenotypes which further underscores the importance of mechanistic studies that can elucidate how COVID infection leads to lymphopenia and T cell exhaustion-like phenotype.

However, as authors have noted, the data does point to an interesting question: How these inflammatory cytokines (TNF-α, IL-6 and IL-10) correlate with or affect effective viral immunity and what types of cells produce these cytokines? Answering that question will help us refine our targets for immune-modulatory therapies especially in patients suffering from cytokine storms.

10.20.5 Credit

This review by Chang Moon was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.21 Clinical Characteristics of 25 death cases infected with COVID-19 pneumonia: a retrospective review of medical records in a single medical center, Wuhan, China


10.21.1 Keywords

10.21.2 Main Findings

Most common chronic conditions among 25 patients that died from COVID-19 related respiratory failure were hypertension (64%) and diabetes (40%). Disease progression was marked by progressive organ failure, starting first with lung dysfunction, then heart (e.g. increased cTnI and pro-BNP), followed by kidney (e.g. increased BUN, Cr), and liver (e.g. ALT, AST). 72% of patients had neutrophilia and 88% also had lymphopenia. General markers of inflammation were also increased (e.g. PCT, D-Dimer, CRP, LDH, and SAA).

10.21.3 Limitations

The limitations of this study include small sample size and lack of measurements for some tests for several patients. This study would also have been stronger with comparison of the same measurements to patients suffering from less severe disease to further validate and correlate proposed biomarkers with disease severity.

10.21.4 Significance

This study identifies chronic conditions (i.e. hypertension and diabetes) that strongly correlates with disease severity. In addition to general markers of inflammation, the authors also identify concomitant neutrophilia and lymphopenia among their cohort of patients. This is a potentially interesting immunological finding because we would typically expect increased lymphocytes during a viral infection. Neutrophilia may also be contributing to cytokine storm. In addition, PCT was elevated in 90.5% of patients, suggesting a role for sepsis or secondary bacterial infection in COVID-19 related respiratory failure.

10.21.5 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.22 SARS-CoV-2 infection does not significantly cause acute renal injury: an analysis of 116 hospitalized patients with COVID-19 in a single hospital, Wuhan, China


10.22.1 Keywords

10.22.2 Main Findings

10.22.3 Limitations

10.22.4 Significance

10.22.5 Credit

Review by Samarth Hegde as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.23 Potential T-cell and B-Cell Epitopes of 2019-nCoV


10.23.1 Keywords

10.23.2 Main Findings

The authors use 2 neural network algorithms, NetMHCpan4 and MARIA, to identify regions within the COVID-19 genome that are presentable by HLA. They identify 405 viral epitopes that are presentable on MHC-I and MHC-II and validate using known epitopes from SARS-CoV. To determine whether immune surveillance drives viral mutations to evade MHC presentation, the authors analyzed 68 viral genomes from 4 continents. They identified 93 point mutations that occurred preferentially in regions predicted to be presented by MHC-I (p=0.02) suggesting viral evolution to evade CD8 T-cell mediated killing. 2 nonsense mutations were also identified that resulted in loss of presentation of an associated antigen (FGDSVEEVL) predicted to be good antigen for presentation across multiple HLA alleles.

To identify potential sites of neutralizing antibody binding, the authors used homology modeling to the SARS-CoV’s spike protein (S protein) to determine the putative structure of the CoV2 spike protein. They used Discotope2 to identify antibody binding sites on the protein surface in both the down and up conformations of the S protein. The authors validate this approach by first identifying antibody binding site in SARS-CoV S protein. In both the down and up conformation of the CoV2 S protein, the authors identified a potential antibody binding site on the S protein receptor binding domain (RBD) of the ACE2 receptor (residues 440-460, 494-506). While RBDs in both SARS-CoV and CoV2 spike proteins may be important for antibody binding, the authors note that SARS-CoV has larger attack surfaces than CoV2. These results were later validated on published crystal structures of the CoV2 S protein RBD and human ACE2. Furthermore, analysis of 68 viral genomes did not identify any mutations in this potential antibody binding site in CoV2.

Finally, the authors compile a list of potential peptide vaccine candidates across the viral genome that can be presented by multiple HLA alleles. Several of the peptides showed homology to SARS-CoV T-cell and B-cell epitopes.

10.23.3 Limitations

While the authors used computational methods of validation, primarily through multiple comparisons to published SARS-CoV structures and epitopes, future work should include experimental validation of putative T-cell and B-cell epitopes.

10.23.4 Significance

The authors identified potential T-cell and B-cell epitopes that may be good candidates for peptide based vaccines against CoV2. They also made interesting observations in comparing SARS-CoV and CoV2 potential antibody binding sites, noting that SARS-CoV had larger attack surfaces for potential neutralizing antibody binding. One of the highlights of this paper was the authors’ mutation analysis of 68 viral genomes from 4 continents. This analysis not only validated their computational method for identifying T-cell epitopes, but showed that immune surveillance likely drives viral mutation in MHC-I binding peptides. The smaller attack surface may point to potential mechanisms of immune evasion by CoV2. However, absence of mutations in the RBD of CoV2 and the small number of mutations in peptides presentable to T cells suggests that vaccines against multiple epitopes could still elicit robust immunity against CoV2.

10.23.5 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.24 Structure, Function, and Antigenicity of the SARSCoV-2 Spike Glycoprotein

Walls et al. bioRxiv. [769] now [62]

10.24.1 Keywords

10.24.2 Main Findings

The authors highlight a human angiotensin-converting enzyme 2 (hACE2), as a potential receptor used by the current Severe Acute respiratory syndrome coronavirus-2 (SARS-CoV-2) as a host factor that allows the virus target human cells. This virus-host interaction facilitates the infection of human cells with a high affinity comparable with SARS-CoV. The authors propose this mechanism as a probable explanation of the efficient transmission of SARS-CoV-2 between humans. Besides, Walls and colleagues described SARS-CoV-2 S glycoprotein S by Cryo-EM along with neutralizing polyclonal response against SAR-CoV-2 S from mice immunized with SAR-CoV and blocking SAR-CoV-2 S-mediated entry into VeroE6 infected cells.**

10.24.3 Limitations

The SARS-CoV-2 depends on the cell factors ACE2 and TMPRSS2, this last, according to a recent manuscript by Markus Hoffman et al., Cell, 2020. The authors used green monkey (VeroE6) and hamster (BHK) cell lines in the experiments to drive its conclusions to humans; however, it is well known the caucasian colon adenocarcinoma human cell line (CaCo-2), highly express the hACE2 receptor as the TMPRSS2 protease as well. In humans, ACE2 protein is highly expressed in the gastrointestinal tract, which again, makes the CaCo-2 cell line suitable for the following SARS-CoV-2 studies.

10.24.4 Significance

The results propose a functional receptor used by SARS-CoV-2 to infect humans worldwide and defining two distinct conformations of spike (S) glycoprotein by cryogenic electron microscopy (Cryo-EM). This study might help establish a precedent for initial drug design and treatment of the current global human coronavirus epidemic.

10.24.5 Credit

Review by postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.25 Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19

Thevarajan et al. medRxiv [770]

10.25.1 Keywords

10.25.2 Main Findings

The authors characterized the immune response in peripheral blood of a 47-year old COVID-19 patient.

SARS-CoV2 was detected in nasopharyngeal swab, sputum and faeces samples, but not in urine, rectal swab, whole blood or throat swab. 7 days after symptom onset, the nasopharyngeal swab test turned negative, at day 10 the radiography infiltrates were cleared and at day 13 the patient became asymptomatic.

Immunofluorescence staining shows from day 7 the presence of COVID-19-binding IgG and IgM antibodies in plasma, that increase until day 20.

Flow cytometry on whole blood reveals a plasmablast peak at day 8, a gradual increase in T follicular helper cells, stable HLA-DR+ NK frequencies and decreased monocyte frequencies compared to healthy counterparts. The expression of CD38 and HLA-DR peaked on T cells at D9 and was associated with higher production of cytotoxic mediators by CD8+ T cells.

IL-6 and IL-8 were undetectable in plasma.

The authors further highlight the presence of the IFITM3 SNP-rs12252-C/C variant in this patient, which is associated with higher susceptibility to influenza virus.

10.25.3 Limitations

These results need to be confirmed in additional patients.

COVID-19 patients have increased infiltration of macrophages in their lungs [771]. Monitoring monocyte proportions in blood earlier in the disease might help to evaluate their eventual migration to the lungs.

The stable concentration of HLA-DR+ NK cells in blood from day 7 is not sufficient to rule out NK cell activation upon SARS-CoV2 infection. In response to influenza A virus, NK cells express higher levels of activation markers CD69 and CD38, proliferate better and display higher cytotoxicity [772]. Assessing these parameters in COVID-19 patients is required to better understand NK cell role in clearing this infection.

Neutralization potential of the COVID-19-binding IgG and IgM antibodies should be assessed in future studies.

This patient was able to clear the virus, while presenting a SNP associated with severe outcome following influenza infection. The association between this SNP and outcome upon SARS-CoV2 infection should be further investigated.

10.25.4 Significance

This study is among the first to describe the appearance of COVID-19-binding IgG and IgM antibodies upon infection. The emergence of new serological assays might contribute to monitor more precisely the seroconversion kinetics of COVID-19 patients [312]. Further association studies between IFITM3 SNP-rs12252-C/C variant and clinical data might help to refine the COVID-19 outcome prediction tools.

10.25.5 Credit

Review by Bérengère Salomé as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.26 The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing

Liao et al. medRxiv [771]

10.26.1 Keywords

10.26.2 Main Findings

The authors performed single-cell RNA sequencing (scRNAseq) on bronchoalveolar lavage fluid (BAL) from 6 COVID-19 patients (n=3 mild cases, n=3 severe cases). Data was compared to previously generated scRNAseq data from healthy donor lung tissue (n=8).

Clustering analysis of the 6 patients revealed distinct immune cell organization between mild and severe disease. Specifically, they found that transcriptional clusters annotated as tissue resident alveolar macrophages were strongly reduced while monocytes-derived FCN1+SPP1+ inflammatory macrophages dominated the BAL of patients with severe COVID19 diseases. They show that inflammatory macrophages upregulated interferon-signaling genes, monocytes recruiting chemokines including CCL2, CCL3, CCL4 as well as IL-6, TNF, IL-8 and profibrotic cytokine TGF-β, while alveolar macrophages expressed lipid metabolism genes, such as PPARG.

The lymphoid compartment was overall enriched in lungs from patients. Clonally expanded CD8 T cells were enriched in mild cases suggesting that CD8 T cells contribute to viral clearance as in Flu infection, whereas proliferating T cells were enriched in severe cases.

SARS-CoV-2 viral transcripts were detected in severe patients, but considered here as ambient contaminations.

10.26.3 Limitations

These results are based on samples from 6 patients and should therefore be confirmed in the future in additional patients. Longitudinal monitoring of BAL during disease progression or resolution would have been most useful.

The mechanisms underlying the skewing of the macrophage compartment in patients towards inflammatory macrophages should be investigated in future studies.

Deeper characterization of the lymphoid subsets is required. The composition of the “proliferating” cluster and how these cells differ from conventional T cell clusters should be assessed. NK and CD8 T cell transcriptomic profile, in particular the expression of cytotoxic mediator and immune checkpoint transcripts, should be compared between healthy and diseased lesions.

10.26.4 Significance

COVID-19 induces a robust inflammatory cytokine storm in patients that contributes to severe lung tissue damage and ARDS [773]. Accumulation of monocyte-derived inflammatory macrophages at the expense of Alveolar macrophages known to play an anti-inflammatory role following respiratory viral infection, in part through the PPARγ pathway [774,775] are likely contributing to lung tissue injuries. These data suggest that reduction of monocyte accumulation in the lung tissues could help modulate COVID-19-induced inflammation. Further analysis of lymphoid subsets is required to understand the contribution of adaptive immunity to disease outcome.

10.26.5 Credit

Review by Bérengère Salomé and Assaf Magen as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.27 Can routine laboratory tests discriminate 2019 novel coronavirus infected pneumonia from other community-acquired pneumonia?

Pan et al. medRxiv [776]

10.27.1 Keywords

10.27.2 Main Findings

In an attempt to use standard laboratory testing for the discrimination between “Novel Coronavirus Infected Pneumonia” (NCIP) and a usual community acquired pneumonia (CAP), the authors compared laboratory testing results of 84 NCIP patients with those of a historical group of 316 CAP patients from 2018 naturally COVID-19 negative. The authors describe significantly lower white blood- as well as red blood- and platelet counts in NCIP patients. When analyzing differential blood counts, lower absolute counts were measured in all subsets of NCIP patients. With regard to clinical chemistry parameters, they found increased AST and bilirubin in NCIP patients as compared to CAP patients.

10.27.3 Limitations

The authors claim to describe a simple method to rapidly assess a pre-test probability for NCIP. However, the study has substantial weakpoints. The deviation in clinical laboratory values in NCIP patients described here can usually be observed in severely ill patients. The authors do not comment on how severely ill the patients tested here were in comparison to the historical control. Thus, the conclusion that the tests discriminate between CAP and NCIP lacks justification.

10.27.4 Significance

The article strives to compare initial laboratory testing results in patients with COVID-19 pneumonia as compared to patients with a usual community acquired pneumonia. The implications of this study for the current clinical situation seem restricted due to a lack in clinical information and the use of a control group that might not be appropriate.

10.27.5 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.


10.28.1 Keywords

10.28.2 Main Findings

This study is a cross-sectional analysis of 100 patients with COVID-19 pneumonia, divided into mild (n = 34), severe (n = 34), and critical (n = 32) disease status based on clinical definitions.

The criteria used to define disease severity are as follows:

  1. Severe – any of the following: respiratory distress or respiratory rate ≥ 30 respirations/minute; oxygen saturation ≤ 93% at rest; oxygen partial pressure (PaO2)/oxygen concentration (FiO2) in arterial blood ≤ 300mmHg, progression of disease on imaging to >50% lung involvement in the short term.

  2. Critical – any of the following: respiratory failure that requires mechanical ventilation; shock; other organ failure that requires treatment in the ICU.

  3. Patients with pneumonia who test positive for COVID-19 who do not have the symptoms delineated above are considered mild.

Peripheral blood inflammatory markers were correlated to disease status. Disease severity was significantly associated with levels of IL-2R, IL-6, IL-8, IL-10, TNF-α, CRP, ferroprotein, and procalcitonin. Total WBC count, lymphocyte count, neutrophil count, and eosinophil count were also significantly correlated with disease status. Since this is a retrospective, cross-sectional study of clinical laboratory values, these data may be extrapolated for clinical decision making, but without studies of underlying cellular causes of these changes this study does not contribute to a deeper understanding of SARS-CoV-2 interactions with the immune system.

It is also notable that the mean age of patients in the mild group was significantly different from the mean ages of patients designated as severe or critical (p < 0.001). The mean patient age was not significantly different between the severe and critical groups. However, IL-6, IL-8, procalcitonin (Table 2), CRP, ferroprotein (Figure 3A, 3B), WBC count, and neutrophil count (Figure 4A, 4B) were all significantly elevated in the critical group compared to severe. These data suggest underlying differences in COVID-19 progression that is unrelated to age.

10.28.3 Significance

Given the inflammatory profile outlined in this study, patients who have mild or severe COVID-19 pneumonia, who also have any elevations in the inflammatory biomarkers listed above, should be closely monitored for potential progression to critical status.

10.28.4 Credit

This review by JJF was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.29 An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors’ CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design

Herst et al. bioRxiv [778]

10.29.1 Keywords

10.29.2 Main Findings

Vaccination of mice with a single dose of a 9-amino-acid peptide NP44-52 located in a conserved region of ebolavirus (EBOV) nucleocapsid protein (NP) confers CD8+ T-cell-mediated immunity against mouse adapted EBOV (maEBOV). Bioinformatic analyses predict multiple conserved CD8+ T cell epitopes in the SARS-CoV-2 NP, suggesting that a similar approach may be feasible for vaccine design against SARS-CoV-2.

The authors focus on a site within a 20-peptide region of EBOV NP which was commonly targeted by CD8+ T cells in a group of EBOV survivors carrying the HLA-A*30:01:01 allele. To justify the testing of specific vaccine epitopes in a mouse challenge setting, the authors cite known examples of human pathogen-derived peptide antigens that are also recognized by C57BL/6 mice, as well as existing data surrounding known mouse immunogenicity of peptides related to this EBOV NP region. Testing 3 distinct 9mer peptides over an 11 amino-acid window and comparing to vaccination with the 11mer with a T-cell reactivity readout demonstrated that optimizing peptide length and position for immunogenicity may be crucial, likely due to suboptimal peptide processing and MHC-class-I loading.

Vaccines for maEBOV challenge studies were constructed by packaging NP44-52 in d,l poly(lactic-co-glycolic) acid microspheres. CpG was also packaged within the microspheres, while Monophosphoryl Lipid A (a TLR4 ligand) was added to the injectate solution. A second peptide consisting of a predicted MHC-II epitope from the EBOV VG19 protein was added using a separate population of microspheres, and the formulation was injected by intraperitoneal administration. The vaccine was protective against a range of maEBOV doses up to at least 10,000 PFU. Survival was anticorrelated with levels of IL6, MCP-1 (CCL2), IL9, and GM-CSF, which recapitulated trends seen in human EBOV infection.

While HLA-A*30:01:01 is only present in a minority of humans, the authors state that MHC binding algorithms predict NP44-52 to be a strong binder of a set of more common HLA-A*02 alleles. The authors predict that a peptide vaccine based on the proposed formulation could elicit responses in up to 50% of people in Sudan or 30% of people in North America.

SARS-CoV-2 NP, meanwhile, has conserved regions which may provide peptide-vaccine candidates. Scanning the SARS-CoV-2 NP sequence for HLA-binding 9mers identified 53 peptides with predicted binding affinity < 500nM, including peptides that are predicted to bind to HLA-class-I alleles of 97% of humans, 7 of which have previously been tested in-vitro.

The results support previously appreciated correlations between certain cytokines and disease severity, specifically IL6 which relates to multiple trial therapies. Prediction of HLA-class-I binding of SARS-CoV-2 NP peptides suggests the plausibility of a peptide vaccine targeting conserved regions of SARS-CoV-2 NP although further validation in previously infected patient samples will be essential.

10.29.3 Credit

Review by Andrew M. Leader as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.30 Epitope-based peptide vaccines predicted against novel coronavirus disease caused by SARS-CoV-2

Li et al. bioRxiv. [779]

10.30.1 Keywords

10.30.2 Main Findings

This study employs a series of bioinformatic pipelines to identify T and B cell epitopes on spike (S) protein of SARS-CoV-2 and assess their properties for vaccine potential. To identify B cell epitopes, they assessed structural accessibility, hydrophilicity, and beta-turn and flexibility which are all factors that promote their targeting by antibodies. To identify T cell epitopes, they filtered for peptides with high antigenicity score and capacity to bind 3 or more MHC alleles. Using the protein digest server, they also demonstrated that their identified T and B cell epitopes are stable, having multiple non-digesting enzymes per epitope. Epitopes were also determined to be non-allergenic and non-toxin as assessed by Allergen FP 1.0 and ToxinPred, respectively. For T cell epitopes, they assessed the strength of epitope-HLA interaction via PepSite. Overall, they predict four B cell and eleven T cell epitopes (two MHC I and nine MHC II binding) to pass stringent computational thresholds as candidates for vaccine development. Furthermore, they performed sequence alignment between all identified SARS-CoV-2 S protein mutations and predicted epitopes, and showed that the epitopes are conserved across 134 isolates from 38 locations worldwide. However, they report that these conserved epitopes may soon become obsolete given the known mutation rate of related SARS-CoV is estimated to be 4x10-4/site/year, underscoring the urgency of anti-viral vaccine development.

10.30.3 Limitations

While spike (S) protein may have a critical role in viral entry into host cells and their epitope prediction criterion were comprehensive, this study did not examine other candidate SARS-CoV-2 proteins. This point is particularly important given that a single epitope may not be sufficient to induce robust immune memory, and recent approaches involve multi-epitope vaccine design. Furthermore, their study only included a direct implementation of various published methods, but did not validate individual bioinformatic tools with controls to demonstrate robustness. Finally, it is critical that these predicted epitopes are experimentally validated before any conclusions can be drawn about their potential as vaccine candidates or their clinical efficacy.

10.30.4 Significance

This study provides a computational framework to rapidly identify epitopes that may serve as potential vaccine candidates for treating SARS-CoV-2.

10.30.5 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.31 The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis

Wang Jr. et al. medRxiv. [780]

10.31.1 Keywords

10.31.2 Main Findings

This study describes the occurrence of a cytokine release syndrome-like (CRSL) toxicity in ICU patients with COVID-19 pneumonia. The median time from first symptom to acute respiratory distress syndrome (ARDS) was 10 days. All patients had decreased CD3, CD4 and CD8 cells, and a significant increase of serum IL-6. Furthermore, 91% had decreased NK cells. The changes in IL-6 levels preceded those in CD4 and CD8 cell counts. All of these parameters correlated with the area of pulmonary inflammation in CT scan images. Mechanical ventilation increased the numbers of CD4 and CD8 cells, while decreasing the levels of IL-6, and improving the immunological parameters.

10.31.3 Limitations

The number of patients included in this retrospective single center study is small (n=11), and the follow-up period very short (25 days). Eight of the eleven patients were described as having CRSL, and were treated by intubation (7) or ECMO (2). Nine patients were still in the intensive care unit at the time of publication of this article, so their disease outcome is unknown.

10.31.4 Significance

The authors define a cytokine release syndrome-like toxicity in patients with COVID-19 with clinical radiological and immunological criteria: 1) decrease of circulating CD4, CD8 and NK cells; 2) substantial increase of IL-6 in peripheral blood; 3) continuous fever; 4) organ and tissue damage. This event seems to occur very often in critically ill patients with COVID-19 pneumonia. Interestingly, the increase of IL-6 in the peripheral blood preceded other laboratory alterations, thus, IL-6 might be an early biomarker for the severity of COVID-19 pneumonia. The manuscript will require considerable editing for organization and clarity.

10.31.5 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.32 Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China

Huang et al. medRxiv. [781]

10.32.1 Keywords

10.32.2 Main Findings

This is a simple study reporting clinical characteristics of patients who did not survive COVID-19. All patients (mean age=69.22 years) had acute respiratory distress syndrome (ARDS) and their median time from onset to ARDS was 11 days. The median time from onset to death was 17 days. Most patients were older male (70% male) with co-morbidities and only 11 % were smokers. 75% patients showed bilateral pneumonia. Many patients had chronic diseases, including hypertension (58.33%). cardiovascular disease (22.22%) and diabetes (19.44%). Typical clinical feature measured in these patients includes lymphopenia and elevated markers of inflammation.

10.32.3 Limitations

As noted by the authors, the conclusions of this study are very limited because this is single-centered study focusing on a small cohort of patients who did not survive. Many clinical parameters observed by the authors (such* as increase levels of serum CRP, PCT, IL-6) have also been described in other COVID19 patients who survived the infection

10.32.4 Significance

This study is essentially descriptive and may be useful for clinical teams monitoring COVID19 patients.

10.32.5 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.


10.33.1 Keywords

10.33.2 Main Findings

Based on a retrospective study of 85 hospitalized COVID patients in a Beijing hospital, authors showed that patients with elevated ALT levels (n = 33) were characterized by significantly higher levels of lactic acid and CRP as well as lymphopenia and hypoalbuminemia compared to their counterparts with normal ALT levels. Proportion of severe and critical patients in the ALT elevation group was significantly higher than that of normal ALT group. Multivariate logistic regression performed on clinical factors related to ALT elevation showed that CRP \(\geq\) 20mg/L and low lymphocyte count (<1.1*10^9 cells/L) were independently related to ALT elevation—a finding that led the authors to suggest cytokine storm as a major mechanism of liver damage.

10.33.3 Limitations

The article’s most attractive claim that liver damage seen in COVID patients is caused by cytokine storm (rather than direct infection of the liver) hinges solely on their multivariate regression analysis. Without further mechanistic studies a) demonstrating how high levels of inflammatory cytokines can induce liver damage and b) contrasting types of liver damage incurred by direct infection of the liver vs. system-wide elevation of inflammatory cytokines, their claim remains thin. It is also worth noting that six of their elevated ALT group (n=33) had a history of liver disease (i.e. HBV infection, alcoholic liver disease, fatty liver) which can confound their effort to pin down the cause of hepatic injury to COVID.

10.33.4 Significance

Limited. This article confirms a rich body of literature describing liver damage and lymphopenia in COVID patients.

10.33.5 Credit

Review by Chang Moon as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.34 Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients


10.34.1 Keywords

10.34.2 Main Findings

48 adult patients diagnosed with Covid19 according to Chinese guidelines for Covid19 diagnosis and treatment version 6 were included in this study. Patients were further sub-divided into three groups based on clinical symptoms and disease severity: (1) mild, positive Covid19 qPCR with no or mild clinical symptoms (fever; respiratory; radiological abnormalities); (2) severe, at least one of the following: shortness of breath/respiratory rate >30/min, oxygen saturation SaO2<93%, Horowitz index paO2/FiO2 < 300 mmHg (indicating moderate pulmonary damage); and (3) critically ill, at least one additional complicating factor: respiratory failure with need for mechanical ventilation; systemic shock; multi-organ failure and transfer to ICU. Serum samples and throat-swaps were collected from all 48 patients enrolled. SARS-CoV-2 RNA was assessed by qPCR with positive results being defined as Ct values < 40, and serum interleukin-6 (IL-6) was quantified using a commercially available detection kit. Briefly, patient characteristics in this study confirm previous reports suggesting that higher age and comorbidities are significant risk factors of clinical severity. Of note, 5 out of 48 of patients (10.41%), all in the critically ill category, were found to have detectable serum SARS-CoV-2 RNA levels, so-called RNAaemia. Moreover, serum IL-6 levels in these patients were found to be substantially higher and this correlated with the presence of detectable SARS-CoV-2 RNA levels. The authors hypothesize that viral RNA might be released from acutely damages tissues in moribund patients during the course of Covid19 and that RNaemia along with IL-6 could potentially be used as a prognostic marker.

10.34.3 Limitations

While this group’s report generally confirms some of the major findings of a more extensive study, published in early February 2020, [773], there are limitations that should be taken into account. First, the number of patients enrolled is relatively small; second, interpretation of these data would benefit from inclusion of information about study specifics as well as providing relevant data on the clinical course of these patients other than the fact that some were admitted to ICU (i.e. demographics on how many patients needed respiratory support, dialysis, APACHE Ii/III or other standard ICU scores as robust prognostic markers for mortality etc). It also remains unclear at which time point the serum samples were taken, i.e. whether at admission, when the diagnosis was made or during the course of the hospital stay (and potentially after onset of therapy, which could have affected both IL-6 and RNA levels). The methods section lacks important information on the qPCR protocol employed, including primers and cycling conditions used. From a technical point of view, Ct values >35 seem somewhat non-specific (although Ct <40 was defined as the CDC cutoff as well) indicating that serum RNA levels are probably very low, therefore stressing the need for highly specific primers and high qPCR efficiency. In addition, the statistical tests used (t-tests, according to the methods section) do not seem appropriate as the organ-specific data such as BUN and troponin T values seem to be not normally distributed across groups (n= 5 RNAaemia+ vs. n= 43 RNAaemia-). Given the range of standard deviations and the differences in patient sample size, it is difficult to believe that these data are statistically significantly different.

10.34.4 Significance

This study is very rudimentary and lacks a lot of relevant clinical details. However, it corroborates some previously published observations regarding RNAemia and IL-6 by another group. Generally, regarding future studies, it would be important to address the question of IL-6 and other inflammatory cytokine dynamics in relation to Covid19 disease kinetics (high levels of IL-6, IL-8 and plasma leukotriene were shown to have prognostic value at the onset of ARDS ; serum IL-2 and IL-15 have been associated with mortality; reviewed by Chen W & Ware L, Clin Transl Med. 2015 [784]).

10.34.5 Credit

This review was undertaken as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn School of Medicine, Mount Sinai.

10.35 Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study


10.35.1 Keywords

10.35.2 Main Findings

Based on a retrospective study of 162 COVID patients from a local hospital in Wuhan, China, the authors show an inverse correlation between lymphocyte % (LYM%) of patients and their disease severity. The authors have also tracked LYM% of 70 cases (15 deaths; 15 severe; 40 moderate) throughout the disease progression with fatal cases showing no recovery of lymphocytes ( <5%) even after 17-19 days post-onset. The temporal data of LYM % in COVID patients was used to construct a Time-Lymphocyte% model which is used to categorize and predict patients’ disease severity and progression. The model was validated using 92 hospitalized cases and kappa statistic test was used to assess agreement between predicted disease severity and the assigned clinical severity (k = 0.49).

10.35.3 Limitations

Time-Lymphocyte % Model (TLM) that authors have proposed as a predictive model for clinical severity is very simple in its construction and derives from correlative data of 162 patients. In order for the model to be of use, it needs validation using a far more robust data set and possibly a mechanistic study on how COVID leads to lymphopenia in the first place. In addition, it should be noted that no statistical test assessing signifi