key: cord-332153-fczf3lzc
authors: Azkur, Ahmet Kursat; Akdis, Mübeccel; Azkur, Dilek; Sokolowska, Milena; van de Veen, Willem; Brüggen, Marie‐Charlotte; O'Mahony, Liam; Gao, Yadong; Nadeau, Kari; Akdis, Cezmi A.
title: Immune response to SARS‐CoV‐2 and mechanisms of immunopathological changes in COVID‐19
date: 2020-05-12
journal: Allergy
DOI: 10.1111/all.14364
sha: 
doc_id: 332153
cord_uid: fczf3lzc

As a zoonotic disease that has already spread globally to several million human beings and possibly to domestic and wild animals, eradication of coronavirus disease 2019 (COVID‐19) appears practically impossible. There is a pressing need to improve our understanding of the immunology of this disease to contain the pandemic by developing vaccines and medicines for the prevention and treatment of patients. In this review, we aim to improve our understanding on the immune response and immunopathological changes in patients linked to detoriating clinical conditions such as, cytokine storm, acute respiratory distress syndrome, autopsy findings and changes in acute phase reactants and serum biochemistry in COVID‐19. Similar to many other viral infections, asymptomatic disease is present in a significant but currently unknown fraction of the affected individuals.In the majority of the patients, a one‐week, self‐limiting viral respiratory disease typically occurs, which ends with the development of neutralizing anti‐viral T cell and antibody immunity. The IgM, IgA and IgG type virus‐specific antibodies levels are important measurements to predict population immunity against this disease and whether cross‐reactivity with other coronaviruses is taking place.High viral‐load during the first infection and repeated exposure to virus especially in healthcare workers can be an important factor for severity of disease. It should be noted that many aspects of severe patients are unique to COVID‐19 and are rarely observed in other respiratory viral infections, such as severe lymphopenia and eosinopenia, extensive pneumonia and lung tissue damage, a cytokine storm leading to acute respiratory distress syndrome and multiorgan failure. Lymphopenia causes a defect in antiviral and immune regulatory immunity. At the same time, a cytokine storm starts with extensive activation of cytokine‐secreting cells with innate and adaptive immune mechanisms both of with contribute to a poor prognosis. Elevated levels of acute phase reactants and lymphopenia are early predictors of high disease severity. Prevention of development to severe disease, cytokine storm, acute respiratory distress syndrome and novel approachs to prevent their development will be main routes for future research areas. As we learn to live amidst the virus, understanding the immunology of the disease can assist in containing the pandemic and in developing vaccines and medicines to prevent and treat individual patients.

Coronaviruses (CoVs) are enveloped, single positive-strand RNA viruses belonging to the large subfamily Coronavirinae, which can infect mammals and several other animals. 1 Seven CoVs are known to cause human disease and can be divided into low and high pathogenic CoVs. 2 aggressively spread across the globe infecting more than 3 million confirmed cases. 5 Three central variants of the current virus that differ in their amino acid sequence have been identified, namely A, B, and C. The ancestral type A and the mutated type C are found in significant proportions outside East Asia, mainly in Europe and in the United States. The B type which has mutated and spread is the most common type in East Asia. 6 

This article is protected by copyright. All rights reserved COVID-19showsa complex profile with many different clinical presentations. Similar to many other viral infections, the characteristics of currently infected patients and their clinical outcomes may represent the tip of the iceberg (Figure 2 ). Patients may be asymptomatic, experience mild, moderateor severe symptoms, presented with or without pneumonia. 8, 9 Asymptomatic cases are common but to date there arescarceepidemiological surveys that provide a clear percentage of asymptomatic cases. 8, 10 Approximately 20% of patients are severe cases that require hospitalization. 11 As of April 2020, the mortality rate is approximately 6% of confirmed cases worldwide,but can vary significantly depending on the quality of healthcare services and hospital capacity.The case fatality ratio of COVID-19 was estimated substantially higher than recent influenza pandemics (H1N1 influenza in 2009). The mean time from onset to death was 18.8 days in China and 24.7 days out of China. Case fatality ratio was determined as 3.6% (1·9-7·2). 12 Although it is clear that asymptomatic cases exist, 8 the real percentage and how long they carry the virus is not known. This information can be obtained byscreening the population for virus-specific IgM, IgG and IgA antibodies, which is expected soon in many centers and willbe an informative and decisive factor in controlling the pandemic as it is the main indicator of the development of population immunity.

Non-SARS-CoVs account for 10-30% of upper respiratory tract infections in adults and present as a mild common cold disease in humans. 13 Patients with common allergic diseases do not develop additional distinct symptoms or severe outcomes. Allergic children show a mild course similar tonon-allergic children. 8 In a study of 1099 cases, 3 .8% presented with diarrhea and 5.0% with nausea and vomiting, and these patients were positive for SARS-CoV-2 RNA in stool samples. 14 Cases with a previously existing condition of chronic obstructive pulmonary disease or complicated with secondary bacterial pneumonia are more severe and may represent a complex immune pathogenesis. 8 Patients with hypertension, diabetes, obesity, chronic lung disease, active smoking, and old age are more prone to severe disease. 15 The cytokine storm that takes place in severe cases is a major factor for high mortality, multiorgan failure, acute respiratory distress syndrome (ARDS), and disseminated intravascular coagulation.

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As it is now a worldwide spread zoonosis, it might be practically impossible to fully eradicate the SARS-CoV-2 virus. The containment of the pandemic is challenging as it is very difficult to identify virus carriers due to the nature of this disease.There can be presumably high number of asymptomatic virus carriers. In addition, recently infected individuals before the onset of symptoms, clinically recovered individuals who still carry the virus, and many potentially susceptible domestic and wild animals in regular contact with humans ( Figure 3 ). The main question will be to learn how to live together with this virus as humans. There is a pressing need for an improved understanding of its immunopathology, much more than any previous pathogen, as COVID-19has become the number one reason of morbidity and mortality in many countries. Even though this pandemic will likely be brought under control in the coming months, unexpected outbreaks and the development of viral resistance to treatments or vaccines are highly possible due to mutations of the virus. 

Coronavirusesare namedfortheir large spikes projecting from the envelope giving the virusa crown-like shapeof approximately 100 nm. The envelope consists of a lipid bilayer derived from the cell membrane of the host and four structural proteins, spike (S), envelope (E), membrane (M), and nucleoprotein (N), as well as a variable number of nonstructural proteins. SARS-CoV-2 recognizesangiotensin-converting enzyme 2 (ACE2) to attach to cells, particularly respiratory epithelial cellsof the host ( Figure 1 ). 16, 17 . This

This article is protected by copyright. All rights reserved process is dependent on the host serine proteaseTMPRSS2, which cleaves viral spike protein at the S1/S2. S2 subunit allows for fusion of viral and cellular membranes. 18 interferons and impaired antiviral response, while increasing NF-kB activation, proinflammatory cytokine production and necroptosis. 22 All of these signaling events may lead to increased cellular death, hyperinflammation and cytokine storm.

Immunological memory in innate immune system is called "trained immunity" and may affect the spread and intensity of certain infections. During the COVID-19 pandemics, it was hypothesized that general BCG vaccination policies adopted by different countries might have impacted the transmission patterns and/or COVID-19 associated morbidity and mortality. 23 

This article is protected by copyright. All rights reserved inflammation. 27 There is limited knowledge on the innate immune response, other than elevated levels of acute phase reactants andcytokine storm. Most of the reports to date have focused on severe outcomes and adaptive immune responses.

Several innate immune signaling proteins are targeted by SARS-CoV-2 viral proteins.

The interferon (IFN) pathway is targeted by Nsp13, Nsp15 and Orf9b, and the NF-κB pathway is targeted by Nsp13, Orf9c. SARS-CoV-2 Orf6 impede NUP98-RAE1, an interferon-inducible mRNA nuclear export complex. Orf3b and Orf9c of SARS-CoV-2 are canonical for replication. As above mentioned, these data will shed light for the development of antiviral against to SARS-Cov-2. One of the antiviral drug is Remdesivir,a nucleoside analog RNA-dependent RNA polymerase (RdRP) inhibitor for treatment of COVID-19. 28, 29 

Human SARS-CoV-2 infection has a classical respiratory virus-like clinical course in more than 80% of patients with a mild to moderate and self-limiting course. It involves all of the so far known aspects of innate immune response and T and B cell immunity and anti-viral neutralizing antibody response (Table 1, Figure 4 ). Interestingly, SARS-CoV-2 infects human T cell lines via a novel route through CD147 spike protein, present on the surface of T lymphocytes. 30 CD147 (also known as Basigin or EMMPRIN) is expressed in many tissues and cells and plays a role of cell proliferation, apoptosis, and tumor cell migration, metastasis and differentiation, especially under hypoxic conditions. A second isoform of CD147, called CD147 Ig0-Ig1-Ig2, has also been characterized.

Dysregulation of CD147 has been associated with nearly every type of cancer and regulates matrix metalloproteinase (MMP) and vascular endothelial growth factor production or signals for tumor cell invasion and metastasis. 31 To block CD147 protein by meplazumab, preventing SARS-CoV-2 spike binding and subsequent infection may also have beneficial effects on COVID-19 treatment. 32

This article is protected by copyright. All rights reserved T and B cell epitopes.Upon entry into the host, a virus attaches to and invades cells expressing its specific receptor in order to replicate. Once the virus is inside the tissue cells, such as respiratory epithelial cells in the case of SARS-CoV-2, viral peptides are presented through class I major histocompatibility complex (MHC) proteins to CD8 + cytotoxic T cells. 33 

This article is protected by copyright. All rights reserved M proteins, but lacked cross-reactivity to MERS. 37 Structural proteins of SARS-CoV-2 are genetically similar to SARS-CoV, but not to MERS-CoV. Only 23% and 16% of known SARS-CoV T and B cell epitopes map identically to SARS-CoV-2, respectively. 38 Clearly recognizable T and B cell epitopes represent a potential for eliciting a robust T cell or antibody response in SARS-CoV-2 or in response to its mutual vaccine. The observation that many B and T cell epitopes are highly conserved between SARS-CoV and SARS-CoV-2 is important. Vaccination strategies designed to target the immune response toward these conserved epitope regions could generate immunity that is not only crossprotective across multiple coronaviruses, but also relatively resistant to ongoing virus evolution to protect against mutated future virus strains. 36

Lymphopenia associated with COVID-19 is an important pathological finding and severity criteria, which serves as like a biomarker and a possible target for intervention to minimize the risk of severe disease. Some infectious agents, such as human immunodeficiency virus (HIV) can cause lymphopenia in humans. Although it is not a part of the natural course and expected type of immune response, it can be observed in influenza, tuberculosis, malaria, and sepsis. 39 The changes in peripheral lymphocyte counts and the transition of lymphocyte subgroups may suggest possiblemechanisms in the pathogenesis of SARS-CoV-2 infection. Limited numbers of studies have focused on severe COVID-19 cases, which have a relatively distinct profile of decreased memory T cells and cytotoxic CD8 + T cells. Flow cytometric analyses showed that the percentage of CD4 + naïve T cells (CD3 + CD4 + CD45RA + ) increased and memory helper T cells (CD3 + CD4 + CD45RO + ) decreased in peripheral blood. 40 The percentage of CD3 + CD8 + CD28 + cytotoxic T cells also decreased in severe cases. However, there was no significant difference in activated total T cells (CD3 + HLADR + ) and activated cytotoxic T cells (CD3 + CD8 + HLA -DR + ). These severe patients also presented with lower levels of regulatory T (Treg) cells (CD3 + CD4 + CD25 + CD127 low+ ). 40 In addition, the overactivation of T cells, manifested by an increase in T-helper (Th)17 and the high cytotoxicity of CD8+ T cells, partially accounts for the severe immune injury. 41 In a similar study, the levels of peripheral lymphocyte subsets were evaluated in 60 patients with COVID-19 by flow

This article is protected by copyright. All rights reserved cytometry during the course of disease. Decrease in total lymphocytes, CD4 + T cell, CD8 + T cell, B cell, and natural killer (NK) cell counts were observed. The authors suggested that lymphopenia in CD8 + T cells could be an independent predictor for COVID-19 severity and treatment efficacy. 42 In another earlier study analysing laboratory indexes, twelve patients with COVID-19 showed a decreased percentage of lymphocytes and CD8 cell count. 43 In 286 patients with COVID-19, severe cases had higher leukocyte, neutrophil and lower lymphocytes counts,with a high neutrophil-to-lymphocyte ratio, as well as lower percentages of monocytes, eosinophils and basophils.The mean T and NK cells counts were below normal levels, whilst B cells values were at the low end of the normal range. T cells were shown to be more affected by SARS-CoV-2 as the T cell count was nearly half the lower reference limit and tend to be more reduced in severe cases. 40 Lymphocyte subset analysis revealed a decreased percentage of CD16 + CD56 + lymphocytes (4 out of 8 patients) and increased percentage of CD3 + (2 out of 8 patients),

CD4 + (4 out of 8 patients) and CD8 + (1 out of 8 patients) lymphocytes. 44 In a study analyzing critically ill patients with SARS-CoV-2 pneumonia, 85% of the patients showed lymphopenia. 45 Intensive care unit (ICU) patients suffering with this infection had a median lymphocyte count of 800 cells/microL (normal values 1000-4000 cells per 1 microL). 45, 46 It was observed that lymphocytes in patients with COVID-19 gradually decrease as the disease progresses. The older patients with lower counts of lymphocytes and platelets were at higher risk of severe disease and increased length of hospitalization. 47 A significant reduction in lymphocyte counts and theirrapid depletion may play a role in the pathogenesis and contribute to the progression to severe COVID-19. Accordingly, drugs targeting lymphocyte proliferation or preventing apoptosis, such as interleukin IL-2, IL-7 orprogrammed cell death protein 1 (PD1/PD-L1) inhibitors could help to prevent lymphopenia or restore lymphocyte counts in severe patients. 47 The mean values of the three main subsets of lymphocytes generally decreased in severe patients with COVID-19, with T and NK cells were below normal values, while B cells were at the lower end of the normal range. 40 In view of the above results, lymphocyte percentage was suggested as a predictive biomarker for severity or recovery ( 

This article is protected by copyright. All rights reserved immunity, subsequently the cytokine storm and destructive tissue inflammation ( Figure   7 ). 

Cytotoxic T lymphocytes and NK cells in patients infected with SARS-CoV-2 are essential for mounting an appropriate anti-viral response. 67 The classical convention is that the T cell receptor of the CD8 cytotoxic T cells recognizes the viral peptides 

This article is protected by copyright. All rights reserved of NK and CD8+ T cells was restored in parallel to reduced expression of NKG2A in patients convalescing after therapy. 67 These data suggest that a breakdown of antiviral immunity may play a role in the pathogenesis and severity in COVID-19. In CD8 + T cells, the frequency of the non-exhausted (PD-1 − CTLA-4 − TIGIT − ) subset in the severe group was significantly lower. 70 It was suggested that the virus promotes an initial excessive activation in the beginning of the disease and is followed by subsequent exhaustion of CD8 + T cells.

Similar to many other viral diseases, an increase in virus-specific IgM in the acute phase followed by an increase in virus-specific IgG at later phases has been observed in the course of COVID-19 ( Figure 6 ). 8 This area is fully open to future research, however it is anticipated that infusion of the convalescent serum obtained fromalready recovered patients may prevent or limit SARS-CoV-2 infection. 71 It was reported that 10 seriously ill patients receiving convalescent serum therapy demonstrated improved lung function, oxygenation, reduced inflammation, and viral load. 72 There are more than one million recovered patients as of today, whose convalescent serum can be used for passive immunization for treatment or prevention. and complement proteins (C3 and C4) in patients with COVID-19 were within normal range. 40 An increase was noted in IgG or IgM antibody levels against SARS-CoV-2 nucleoprotein (NP) or receptor-binding domain (RBD) in most of the patients 10 days or later after onset of symptoms. An early increase in IgM later followed by development of IgG is a normal expected antibody response ( Figure 6 ). However, specific IgG levels can be found at already high levels in serum at the same time or earlier than IgM against SARS-CoV-2. 34 In another study, SARS-CoV-2 virus-specific IgG and IgM reached to

This article is protected by copyright. All rights reserved peak levels 17-19 days and 20-22 days after symptom onset respectively. Another interesting observation was that IgG and IgM titers in the COVID-19 severe group is higher than the non-severe group. Different types of seroconversion was reported, such as synchronous seroconversion of IgG and IgM, IgM seroconversion earlier than that of IgG and IgM seroconversion later than that of IgG. 3474 In a study analyzing specific IgM and IgG byenzyme immunoassay, more patients were found seropositive for IgG than IgM at day 0 and day 5 of hospital admission. A higher proportion of patients in that study also had earlier IgG than IgM seroconversion. 75 specific T-cell responses, which are able to protect against SARS-CoV infection in animal models. 83 The sensitivity and specificity of current commercial specific antibody kits should be evaluated in independent laboratories and WHO-confirmed tests should be made available. The IgA-based enzyme-linked immunosorbent assay (ELISA) kit was

This article is protected by copyright. All rights reserved more sensitive but less specific than the IgG-based ELISA kit. 84 However, new kits are continuously coming to market and it is possible to develop in-house kits depending on the quality of the coated SARS-CoV-2 antigen to plates. The evaluation of IgM and IgG isotype virus-specific antibody levels together with RT-PCR are shown in Table 3 . Homemade indirect ELISA for detecting IgM, IgA and IgG antibodies against SARS-CoV-2 using purified recombinant nucleocapsid (NP) proteins as coating antigens have been studied. The development time for specific antibodies have significantly varied from method to method and in this studyit was 5 days(range 3 to 6 days) for specific IgM and IgA, whereas 14 days (range 10 to 18 days) for specific IgG after the onset of symptoms ( Figure 6 ). 85

Acute phase reactants are potential diagnostic markers and predictors of disease outcome in human and animals. 86 The overall evaluation of acute phase reactants in COVID-19 correlates high levels to increased disease severity and death (Table 4 ). In 140 hospitalized COVID-19 patients, significantly higher levels of D-dimer, CRP and procalcitonin (PCT) were associated with severe disease compared to non-severe disease. Non-survivors had higher levels of neutrophils, D-dimer, blood urea nitrogen, and creatinine compared to recovered patients. 15 Anticoagulation therapy is recommended for COVID-19 patients, when the D-

This article is protected by copyright. All rights reserved dimer value is 4 times higher than the normal upper limit, except for patients with anticoagulant contraindications. 45 (Table 4 ). Further research, consensus and standard approach is needed to identify which acute phase reactants are essential for early diagnosis, prediction and follow up of patients. 95

Although most of the COVID-19 patients recover with mild and moderate disease in one week,some develop to severe pneumonia in the second week followed by cytokine storm, ARDS, multiorgan failure and disseminated intravascular coagulation (DIC) within the 3rd week of the disease (Figure 8 ).The cytokine storm is a complex network of severe molecular events unified by a clinical phenotype of systemic inflammation, multi-organ failure, hyper-ferritinemia.It is consistently linked with severity and fatal disease outcome.

This article is protected by copyright. All rights reserved including B cells, T cells, NK cells, macrophages, dendritic cells, neutrophils, monocytes, and resident tissue cells, such as epithelial and endothelial cells, which release high amounts of pro-inflammatory cytokines. 96 Any cells that blood stream or the virus itself and degraded viral products can reach in the body can contribute to cytokine storm.

Cytokine storm can also occur in a number of infectious and non-infectious diseases, such as bacterial sepsis, Ebola and other hemorrhagic fevers, influenza, blunt trauma and as a side effect of immune stimulatory drugs. [97] [98] [99] [100] [101] [102] Although many cells are involved as mentioned above, multiple proinflammatory cytokines and inflammasome activation appear to play a major role in its pathogenesis. IL-10 appears to control tissue damage in experimental models. 103 A proinflammatory eicosanoid storm may also accompany the cytokine storm. 104 The balance of the pro-anti-inflammatory and proresolving lipid mediator response during viral infection is often decisive over the clinical outcome. 105 Among the numerous molecules that increase in serum in cytokine storm, complements, IFN-, IL-1β, IL-6, IL-12, and IL-17, and tumor necrosis factor-α (TNF-α) are of crucial importance. 106 

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It has been previously reported that the Ebola virus Tim-1 protein can induce a cytokine storm 100 . SARS-CoV activates a considerable level of pro-inflammatory cytokines in vitro, such as TNF-α, IL-6 and IL-12 release via the TLR7 and TLR8, almost 2-fold higher than a strong TLR7/8 stimulating ssRNA40. 108 Upon influenza infection, high levels of complement C3 and C5, including fragments C3a and C5a, are produced. H5N1

replicates in the lower respiratory tract leading to complement activation and C5a is responsible for the acute lung injury. 109 Similar to SARS and MERS, cytokine storm is a common feature of severe COVID-19

cases and a major reason for ARDS and multiorgan failure. Several levels of evidence suggest that mortality in COVID-19 is due to thevirus-activated "cytokine storm syndrome". 110 

ARDS is an acute inflammatory lung injury leading to severe SARS manifesting as acute hypoxemic respiratory failure with bilateral alveolar opacities on chest radiography

This article is protected by copyright. All rights reserved and decreased lung compliance (Figure 9 ). 112 Fifteen out of 75 patients (20%) have developed ARDS in 3 weeks following SARS infection 113 . In most cases, the course of COVID-19 is mild, but life-threatening ARDS develops in some critically ill patients within 8-9 days after onset of the disease. 45, 46 The reported incidence of ARDS and critical illness requiring ICU admissionsvaries widely across multiple studies. 9, 45, 46, [114] [115] [116] [117] ARDS is more common in older people, those with comorbidities, including hypertension, diabetes, coronary artery disease, bronchitis, ischemic disease of the central nervous system, and

Parkinson's disease. 118 

The most common complications frequently observed in patients who died of COVID-19 were sepsis (100%) followed by respiratory failure (98%), ARDS (93%), septic shock (70%), acute cardiac injury (59%), heart failure (52%), coagulopathy (50%), secondary infection (50%), and acute kidney injury (50%). 91 Autopsy features of COVID-19 are very similar to SARS and MERS findings. 126, 127 The macroscopic features of COVID-19 are likely to be observed in the chest and may include pleurisy, pericarditis, lung consolidation, and pulmonary oedema. A secondary bacterial infection may be superimposed on the viral infection that can lead to purulent inflammation. 128 Early histopathological features were reported in two patients who underwent surgical

This article is protected by copyright. All rights reserved resections for lung adenocarcinoma but were later found to be SARS-CoV-2 positive at the time of the operation. These patients were asymptomatic with respect to COVID-19 at the time of the operation. Non-specific findings included oedema, pneumocyte hyperplasia, focal inflammation, and multinucleated giant cell formation, while no hyaline membranes were seen. These findings may reflect early changes of acute lung injury in the infection. 129 Histopathological findings were noted in a 50-year-old man who died from severe COVID-19 infection. The microscopic findings included diffuse alveolar damage with exudates. 41 

This article is protected by copyright. All rights reserved SARS-CoV-2 and its disease COVID-19 are associated with significant morbidity and mortality globally, probably becomingone of the biggest health and economic burden of the last 100 years. COVID-19 became a major fights of humansin modern times, emphasizing the importance and need of a global strategy and solidarity among nations.

As a zoonotic disease that has already spread globally to several millions of humans and probably animals, it will be practically impossible to eradicate COVID- 19 We have to learn how to live together with the virus and disease.

The 

This article is protected by copyright. All rights reserved CD8 + T cells Severe lymphopenia (< 5%) is observed in CD8 + T cells and can be a predictor of severe disease.

Normal anti-viral immunity requires a CD4 and CD8

Th1 response. Severe disease shows a systemic severe inflammatory response with a cytokine storm.

Cytokine storm response is mainly Th1 and inflammatory. It can also have a major role in inflammasome activation.

Decreased circulating eosinophil numbers in 50 to 80% of the hospitalized patients.

In the acute phase, virus-specific IgM increases followed by virus specific IgG during convalescence.

Innate and adaptive cytokines are released in high amounts linked to severe disease.

High in severe cases. Initially high values are predictive of severe disease. 

This article is protected by copyright. All rights reserved Accepted Article Table 4 .Changes in acute phase reactants and serum biochemistry in COVID-19

This article is protected by copyright. All rights reserved 

This article is protected by copyright. All rights reserved remain SARS-CoV-2 positive, susceptible domestic and wild animals. All of these have specific immunological mechanisms that are discussed in this review. 

This article is protected by copyright. All rights reserved antibodies and rapid viral clearance, high dose exposure may cause severe disease and delayed viral clearance. This may be due to lymphopenia leading to inefficient T and B cell immunity, subsequently the cytokine storm and destructive tissue inflammation. 

Coronaviridae Study Group of the International Committee on Taxonomy of V. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2

From SARS coronavirus to novel animal and human coronaviruses

Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia

A Novel Coronavirus from Patients with Pneumonia in China

WHO) WHO. Coronavirus disease (COVID-2019) situation reports

Phylogenetic network analysis of SARS-CoV-2 genomes

Spread of SARS-CoV-2 in the Icelandic Population

Eleven Faces of Coronavirus Disease

Clinical Characteristics of Coronavirus Disease 2019 in China

Presumed Asymptomatic Carrier Transmission of

Estimates of the severity of coronavirus disease 2019: a modelbased analysis

Coronavirus Infections-More Than Just the Common Cold

COVID-19: faecal-oral transmission?

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Accepted Article This article is protected by copyright. All rights reserved 17

Infection and Rapid Transmission of SARS-CoV-2 in Ferrets

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2

Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

The intracellular sites of early replication and budding of SARS-coronavirus

Severe acute respiratory syndrome coronavirus M protein inhibits type I interferon production by impeding the formation of TRAF3

Is BCG vaccination effecting the spread and severity of COVID-19

Is global BCG vaccination-induced treained immunity relevant to the progression of the SARS.CoV-2 pandemic? Allergy

The Greek study in the effects of colchicine in COvid-19 complications prevention (GRECCO-19 study): Rationale and study design

Can melatonin reduce the severity of COVID-19 pandemic?

Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion

The biological function and clinical utilization of CD147 in human diseases: a review of the current scientific literature

Accepted Article This article is protected by copyright. All rights reserved 32

CD147 as a Target for COVID-19 Treatment: Suggested Effects of Azithromycin and Stem Cell Engagement

Influenza virus-specific CD4+ and CD8+ T cell-mediated immunity induced by infection and vaccination

Antibody responses to SARS-CoV-2 in patients with COVID-19

SARS-CoV-2 immunogenecity at the crossroads

A Sequence Homology and Bioinformatic Approach Can Predict Candidate Targets for Immune Responses to SARS-CoV-2. Cell Host Microbe

Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection

Preliminary Identification of Potential Vaccine Targets for the COVID-19 Coronavirus (SARS-CoV-2) Based on SARS-CoV Immunological Studies

Lymphocytosis and Lymphopenia Induced by Imported Infectious Diseases: A Controlled Cross-Sectional Study of 17,229 Diseased German Travelers Returning from the Tropics and Subtropics

Dysregulation of immune response in patients with COVID-19 in Wuhan, China

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan

Lung eosinophils-A novel "virus sink" that is defective in asthma?

Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan: A Retrospective Observational Study

Eosinophil Responses During COVID-19 Infections and Coronavirus Vaccination

COVID-19 Autopsies

Functional exhaustion of antiviral lymphocytes in COVID-19 patients

Contribution of Resident Memory CD8(+) T Cells to Protective Immunity Against Respiratory Syncytial Virus and Their Impact on Vaccine Design

The CD8 T Cell Response to Respiratory Virus Infections

Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients

The convalescent sera option for containing COVID-19

Treatment of COVID-19: old tricks for new challenges

Dynamics of anti-SARS-Cov-2 IgM and IgG antibodies among COVID-19 patients

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. The Lancet Infectious Diseases

Role of IgA versus IgG in the control of influenza viral infection in the murine respiratory tract

Accepted Article This article is protected by copyright. All rights reserved 77

Cross-protection in mice infected with influenza A virus by the respiratory route is correlated with local IgA antibody rather than serum antibody or cytotoxic T cell reactivity

Functional role of respiratory tract haemagglutininspecific IgA antibodies in protection against influenza

Antibody responses and protection in mice immunized orally against influenza virus

Secretory immunoglobulin A antibody response is conserved in aged mice following oral immunization with influenza virus vaccine

Superior immune responses induced by intranasal immunization with recombinant adenovirus-based vaccine expressing full-length Spike protein of Middle East respiratory syndrome coronavirus

Comparative evaluation of two severe acute respiratory syndrome (SARS) vaccine candidates in mice challenged with SARS coronavirus

Studies of SARS virus vaccines

Severe Acute Respiratory Syndrome Coronavirus 2-Specific Antibody Responses in Coronavirus Disease

Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19)

Acute phase protein response to viral infection and vaccination

Elevated Values of C-Reactive Protein Induced by Imported Infectious Diseases: A Controlled Cross-Sectional Study of 11,079 Diseased German Travelers Returning from the Tropics and Subtropics

Clinical manifestations, laboratory findings, and treatment outcomes of SARS patients

Predictive factors for pneumonia development and progression to respiratory failure in MERS-CoV infected patients

Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia

Accepted Article This article is protected by copyright. All rights reserved 91

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19

Clinical Features and Treatment of COVID-19 Patients in Northeast Chongqing

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Recommendations for Minimal Laboratory Testing Panels in Patients with COVID-19: Potential for Prognostic Monitoring

Review: Cytokine Storm Syndrome: Looking Toward the Precision Medicine Era

An interferon-gamma-related cytokine storm in SARS patients

Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology

The cytokine storm of severe influenza and development of immunomodulatory therapy

Ebola Virus Binding to Tim-1 on T Lymphocytes Induces a Cytokine Storm

Severity of the TGN1412 trial disaster cytokine storm correlated with IL-2 release

High Anti-Dengue Virus Activity of the OAS Gene Family Is Associated With Increased Severity of Dengue

Fine Tuning the Cytokine Storm by IFN and IL-10 Following Neurotropic Coronavirus Encephalomyelitis

Eicosanoid storm in infection and inflammation

Lipidomic profiling of influenza infection identifies mediators that induce and resolve inflammation

Cytokine storm and sepsis disease pathogenesis

Accepted Article This article is protected by copyright. All rights reserved

Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients

Extraordinary GU-rich single-strand RNA identified from SARS coronavirus contributes an excessive innate immune response

The role of C5a in acute lung injury induced by highly pathogenic viral infections

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med

Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic

Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment

Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study

Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Clinical characteristics of hospitalized patients with SARS-CoV-2 infection: A single arm meta-analysis

COVID-19 -what should anaethesiologists and intensivists know about it?

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

Cell-free hemoglobin: a novel mediator of acute lung injury

The Acute Respiratory Distress Syndrome: Mechanisms and Perspective Therapeutic Approaches

Management of Critically Ill Adults With COVID-19

Treatment for severe acute respiratory distress syndrome from COVID-19

Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma

An inhaled tumor necrosis factor-alpha-derived TIP peptide improves the pulmonary function in experimental lung injury

The clinical pathology of severe acute respiratory syndrome (SARS): a report from

Immunohistochemical, and Ultrastructural Findings of a Fatal Case of Middle East Respiratory Syndrome Coronavirus Infection in the United Arab Emirates

Autopsy in suspected COVID-19 cases

Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer

Histopathologic Changes and SARS-CoV-2 Immunostaining in the Lung of a Patient With COVID-19

Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center

Liver impairment in COVID-19 patients: a retrospective analysis of 115 cases from a single center in Wuhan city

Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study

Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis

Kidney disease is associated with in-hospital death of patients with COVID-19

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Clinical Features of 69 Cases with Coronavirus Disease

Characteristics of Ocular Findings of Patients With Coronavirus Disease 2019 (COVID-19

Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults

Clinical and immunologic features in severe and moderate Coronavirus Disease

Identification of Kidney Transplant Recipients with Coronavirus Disease

Clinical characteristics of 161 cases of corona virus disease 2019 (COVID-19) in Changsha

Rapid Progression to Acute Respiratory Distress Syndrome: Review of Current Understanding of Critical Illness from COVID-19 Infection

Prediction for Progression Risk in Patients with COVID-19 Pneumonia: the CALL Score

Prominent changes in blood coagulation of patients with SARS-CoV-2 infection

Elevated Plasmin(ogen) as a Common Risk Factor for