key: cord-254446-yxqbe1dj
authors: Ren, Yunzhao R.; Golding, Amit; Sorbello, Alfred; Ji, Ping; Chen, Jianmeng; Bhawana, Saluja; Witzmann, Kimberly; Arya, Vikram; Reynolds, Kellie S.; Choi, Su‐Young; Nikolov, Nikolay; Sahajwalla, Chandrahas
title: A Comprehensive Updated Review on SARS‐CoV‐2 and COVID‐19
date: 2020-05-29
journal: J Clin Pharmacol
DOI: 10.1002/jcph.1673
sha: 
doc_id: 254446
cord_uid: yxqbe1dj

This literature review aims to provide a comprehensive current summary of the pathogenesis, clinical features, disease course, host immune responses, and current investigational antiviral and immunomodulatory pharmacotherapies, in order to facilitate the development of future therapies and measures for prevention and control. This article is protected by copyright. All rights reserved

The disease name -COVID-19‖ and the associated virus name -SARS-CoV-2‖ were coined by the World Health Organization (WHO) and the Coronavirus Study Group of the International Committee on Virus Taxonomy, respectively, on February 11 1, 2 . Currently no specific drug has been approved by the FDA for treating COVID-19, and the current management of patients is mainly supportive. FDA has issued only Emergency Use Authorizations (EUA) to permit the emergency use of chloroquine phosphate, hydroxychloroquine sulfate, and remdesivir. Therapeutic development for COVID-19 includes repurposing existing medications and developing investigational candidates.

The first reported confirmed COVID-19 case was presented as atypical pneumonia on December 8, 2019 in Wuhan, China. 3 The patient was among a cluster of 41 cases reported to WHO on January 11, 2020 4 . As of May 19, 2020, SARS-CoV-2 has infected over 4.6 million people worldwide 5 . COVID-19 had resulted in a global death toll of more than 319,000.

An epidemiology study noted that of 44,672 confirmed COVID-19 cases in China through February 11, 13 .8% and 4.7% of patients were in severe and critical condition, respectively 6 .

The reported median incubation period of COVID-19 is 4 days 7 , and the median period from symptom onset to hospital admission ranges from 7 to 10 days 8, 9 . Median time from onset of the first symptom to dyspnea is 4-5 days 7, 8 ; to pneumonia, 3 days 7 ; to ICU admission, 6 days 10 ; and to acute respiratory distress syndrome (ARDS), 8 days 8 . The median duration of hospitalization is 12 days 7 to 22 days 11 ; median length of ICU stay, 18 days 10 ; median time from admission to invasive mechanical ventilation, 14.5 days 11 ; and median time from admission to death was 18.5 days 11 .

The currently estimated reproductive number (R 0 ) of SARS-CoV-2, the average number of people to which one infected individual will pass the virus, ranges from 2.2 to 5.7 [12] [13] [14] , whereas the reported R 0 for SARS-COV is approximately 3 15 .

SARS-CoV-2 is an airborne virus which can be transmitted by aerosol 16 . A hospital survey detected the maximum transmission distance of SARS-CoV-2 aerosol might be 4 meters from the COVID-19 patients 17 . In the contaminated area of the hospital, the viral nucleic acid positive rate was 75% for computer mice, 70% for floor swabs, 60% for trash cans, 43% for sickbed handrails, and 8% for doorknobs. In a virus viability test, authors used a nebulizer to generate artificial aerosols with small particle size (<5 μm) containing SARS-CoV-2 18 . The results showed that SARS-CoV-2 remained viable in the artificial aerosols for at least 3 hours. The virus is most stable on plastic and stainless steel surfaces, on which viable virus had been detected for up to 72 hours. No viable virus was detected after 4 hours on copper and after 24 hours on cardboard. The WHO, therefore, advises the public not to touch their eyes, nose, or mouth with their hands to limit self-contamination 19 . In addition, the Centers for Disease Control and Prevention (CDC) recommends wearing cloth face coverings in public settings where other social distancing measures (6 feet) are difficult to maintain 20 . A case study reported that 5 of 39 passengers on a coach bus contracted the virus from an infected patient who did not wear a protective face mask. However, the same patient bought a mask and wore it before transferring to a mini-bus, and none of the 14 passengers on the mini-bus contracted the virus 21 .

Live SARS-CoV-2 was isolated from nasal/pharyngeal swabs and sputum, but not from stool, in patients with COVID-19 22 . The live viral copies peaked during the early stage of symptom onset (≤ 4 days); and could not be detected after day 8 in samples from 9 mild cases of infection. This discovery suggests that the viral transmission occurs primarily through the airborne route rather than the fecal-oral route during early stages of the disease. Indeed, there have been sporadic case reports on the human-to-human transmission from asymptomatic or pre-symptomatic subjects [23] [24] [25] . One study estimated that the transmissibility of the asymptomatic cases is comparable to that of symptomatic cases 26 . An epidemiology report from China indicated that 1.2% (889) of 72,314 tested/suspected/diagnosed cases were asymptomatic 27 . Identification and isolation of asymptomatic subjects has helped reduce the pandemic in an Italian village 28 . These reports suggest that a panpopulation screening for viral exposure is an effective way to critically contain the spread of the disease.

Two meteorology models consistently found that higher relative humidity favored SARS-CoV-2 transmission 29, 30 . The two models differed regarding the trend of temperature effect on viral transmission, probably due to the different ranges of temperature studied in China (winter) and Brazil (autumn).

An epidemiology study from China found that although the proportion of male patients (51.4%) was comparable to that of females (48.6%), male patients (63.8%) comprised almost two-thirds of the total deaths 6 . Data from the CDC website as of May 14,  showed that among approximately 111,000 COVID-19 cases in the U.S., 3% were in children (<17 years old); 23% were in the elderly (≥65 years old), and most (74%) were in patients between 18 and 64 years old 31 . Of 580 hospitalized patients in 14 U.S. states from March 1-30, 261 (45%) were non-Hispanic white; 192 (33.1%) were non-Hispanic black; 47 (8.1%) were Hispanic; 32 (5.5%) were Asian, two (0.3%) were American Indian/Alaskan Native, and 46 (7.9%) were of other ethnic origins or unknown 32 .

Culture of bronchoalveolar lavage fluid collected from early Wuhan cases identified the etiology of the virus 33 To date, the virus phylogenetically closest to SARS-CoV-2 by genetic homogeneity is a coronavirus isolated from the horseshoe bat (Bat CoV RaTG13) with an overall genome sequence identity of 96.2%, which is higher than that of SARS-CoV (<80%) 34 . Angiotensinconverting enzyme 2 (ACE2) was identified as a shared receptor required for cell entry both for SARS-CoV and SARS-CoV-2, with higher binding affinity for SARS-CoV-2 35 .

Sequence comparison of spike (S) protein, the viral ligand of ACE2, identified three short insertions located at the N-terminus region that are conserved in SARS-CoV-2 and Bat CoV RaTG13, but not in SARS-COV 34 . Examination of the receptor-binding domain (RBD) of S protein surprisingly identified that a Malayan pangolin coronavirus had a higher degree of similarity (97.4%) than Bat CoV RaTG13 (89.2%), indicating that recombination may have occurred during the evolution of SARS-CoV-2 36 . Variation analysis based on 95 sequences of SARS-CoV-2 up to February 14 revealed very high homology (>99.9%) among different strains 37 . Another group estimated that the evolution rate of SARS-CoV-2 is approximately 1.8 × 10 -3 per base per year 38 , which indicates that SARS-CoV-2 transmission in humans is a recent event. The SARS-CoV-2 genome sequence can be found at https://www.ncbi.nlm.nih.gov/genbank/sars-cov-2-seqs/.

The direct diagnosis of COVID-19 requires detection of SARS-CoV-2-specific RNA from patients' samples. Reverse transcription-polymerase chain reaction (RT-PCR) is the most widely used technique for diagnosis. A commercial RT-PCR test kit usually uses 2 to 3 pairs of primers detecting the different regions of SARS-CoV-2 genomic RNA to increase the test specificity. The sensitivity of this method is not optimal. One paper noted that the sensitivity of RT-PCR (59%), even after 25% of patients had multiple tests, was lower than that of a CT scan (88%) 39 . A test report of 4,880 Wuhan cases with typical COVID-19 symptoms and history of close patient contact demonstrated that the positive rate was about 40% for nasal and pharyngeal swabs, 50% for sputum samples, and 80% to 100% for bronchoalveolar lavage fluid 40 . Another study screened 353 subjects in Wuhan and found that the positive rate from nasopharyngeal swabs was 2.5-fold higher than that of oropharyngeal swabs 41 .

Interestingly, pharyngeal swab viral nucleic acid screening results of 2,510 patients between January 23 and February 25 from a hospital fever clinic in Hunan Province (a neighboring province of Hubei) demonstrated that the positive rate of SARS-CoV-2 (1.3%) was lower than that of Influenza A (2.3%) and Influenza B (3.3%) 42 . It is unclear whether the lockdown status of Hubei Province or the sensitivity of the detection methods between different viruses contributed to the result.

The disease course also affects viral nucleic acid detection results. One study closely followed throat swab samples or deep nasal cavity swab samples from 56 hospitalized COVID-19 patients and found that the positive rate was the highest (100%) within Week 1 since the symptom onset 43 . However, the positive rate reduced to about one-third at Week 3.

Similar results were obtained from another study, in which the positive rate of throat swabs from 43 patients was >90% when tested within 1-3 days since symptom onset, but decreased to <80% on Day 5, and <50% after Day 14 44 .

Other than the traditional RT-PCR, other viral RNA detecting methods such as loop-mediated isothermal amplification (LAMP) were expeditiously developed and approved by the FDA 45 .

The apparent advantage of LAMP is the much shorter waiting time for the results (<15 minutes) compared to the traditional RT-PCR (3 hours). CRISPR, the powerful gene editing technique, premiered in this pandemic and was also approved by FDA, though the commercial kit requires an isothermal amplification step 46 .

Reports on the relationship between viral load in respiratory tracts and disease severity showed conflicting results. One study (N=12) reported that the high viral load from a patient's respiratory tracts is moderately associated with a high Murray score for acute lung injury and low PaO 2 /FiO 2 47 . The same study also reported that the high viral load is associated with high plasma angiotensin II concentration. However, two other studies (N=23 and N=11) did not find significant differences in viral load between mild and severe cases 48, 49 .

One study demonstrated that the speed of viral clearance differs significantly in mild and severe cases 10 . The average time of viral nucleic acid turning positive to negative was about 10 days in mild cases and 18 days in severe cases. In non-survivors, persistent viral RNA was detected until death 11 . However, another study with intensive testing was able to detect viral nucleic acid in throat/deep nasal cavity swab samples from 3 of 56 hospitalized patients with mild-to-moderate confirmed COVID-19 5 weeks after symptom onset 43 .

SARS-CoV-2 was detected in the whole blood and serum 50, 51 . More studies are needed to investigate the correlation between viremia with blood viral load and disease severity. patients on admission, and discovered that the cutoff of 2.0 µg/mL had a sensitivity of 92% and a specificity of 83% in predicting in-hospital mortality 69 .

Higher levels of hypersensitive troponin I in patients with severe COVID-19 (Table 3) indicates an association of SARS-CoV-2 infection and cardiomyopathy 8, 11 . A review summarized that cardiovascular complications associated with COVID-19 include myocardial injury, myocarditis, acute myocardial infarction, heart failure, dysrhythmias, and thromboembolic events 70 Two COVID-19-associated Kawasaki disease cases were reported in a 6-month-old girl and a 5-year-old boy, respectively 84 IL-4, IL-6, TNF-α and IFN-γ were found between the two groups. Whether the age differences between the two groups also contributed to these observed differences is unclear. Two RSV-infected children (12.5%) and one SARS-CoV-2-infected child (2.5%) developed severe pneumonia. All children survived.

Various case reports, case series, retrospective and case-controlled studies of pregnant women with COVID-19 presented clinical and laboratory data on maternal and neonatal manifestations and outcomes [89] [90] [91] [92] [93] . Reviews and analyses of published reports provided additional insights [94] [95] [96] [97] . Most of the pregnant women in these studies and reports were in their third trimester, and many of their babies were delivered by caesarean section. In general, they experienced signs and symptoms of COVID-19 much like those in non-pregnant women. No maternal deaths were reported. Fetal distress, premature births, premature rupture of membranes, respiratory difficulties, and low birth weight were observed among some babies born to mothers with COVID-19 89, 95, 98 .

No definitive cases of vertical transmission of the SARS coronavirus 2 (SARS-CoV-2) from mother to fetus have been identified, although two highly suspect cases have been reported. Wang and colleagues described a male infant delivered by emergency cesarean section to a 34-year-old woman with COVID-19 confirmed by pharyngeal swab 99 . The infant had a viral nucleic acid detected from pharyngeal swab approximately 36 hours after birth. Tests of the cord blood, placenta, and the mother's breast milk were negative for SARS-CoV-2. Both mother and infant recovered. Alzamora and colleagues reported on a 41-year-old diabetic woman with COVID-19-induced respiratory failure whose neonate was positive for SARS-CoV-2 nucleic acid from nasopharyngeal swab 16 hours after a cesarean section delivery 100 .

Serologies for SARS-CoV-2 were negative for the mother and the baby at the time of delivery. The mother converted to seropositive status on postpartum day 4; whereas the neonate, who had not been breastfed, remained seronegative at that time.

In relation to neonatal survival, Zhu and colleagues reported one neonatal death in which a male baby born to a mother with confirmed COVID-19 developed refractory shock, gastric bleeding, multi-organ failure, and disseminated intravascular coagulation approximately 8 days after birth 98 Three publications reported findings with inconsistent results from systematic reviews or meta-analyses. A systematic review by Vardavas and Nikitara found an association between smoking and COVID-19 illness progression 115 . Emami and colleagues in a meta-analysis reported a high prevalence of smoking (7.6%) in hospitalized patients with COVID-19 116 . However, a meta-analysis by Lippi and Henry found no association between smoking and COVID-19, although they acknowledged the findings reported by Liu above 117 .

The inconsistent results on smoking may be attributed to lack of data on smoking quantity and duration, small population size and/or few smokers in certain studies, and the presence of other concurrent comorbid conditions. Future research should consider including documentation of nicotine exposures through vaping and ecigarettes.

The scientific community recently has debated a possible therapeutic role for nicotine in treating COVID-19. Some epidemiologic data has shown lower numbers of smokers among patients with COVID-19, indicating that nicotine may mediate the viral transmission by lowering ACE2 levels 118, 119 . A randomized clinical study is being planned in France to more formally assess if nicotine could reduce the risk of contracting the disease 120 .

An analysis of 92 deceased patients with COVID-19 revealed that 91 deaths were due to complications directly related to the viral infection 121 . Among them, ARDS was most prevalent (76%), followed by myocardial injury (34%), liver injury (16%), and renal insufficiency (15%). Multiple organ dysfunction syndrome occurred in 15% of cases.

Autopsy and biopsy of COVID-19 cases have been sporadically reported. A report of complete autopsy in 12 consecutive COVID-19-positive deaths (8 males and 4 females with median age of 73 years) in Germany found that half of the cases had coronary heart disease and a quarter of the cases had respiratory diseases (asthma/COPD) 122 . The cause of death was found within the lungs or the pulmonary vascular system in all 12 cases. Deep venous thrombosis was identified in 7 of 12 patients (58%) in whom venous thromboembolism was not suspected before death. Pulmonary embolism was the direct cause of death in 4 patients.

The histopathology examination of lungs found diffuse alveolar damage in 8 cases. The lesions included hyaline membranes, activated pneumocytes, microvascular thromboemboli, capillary congestion, and protein-enriched interstitial edema, which were consistent with ARDS diagnosis.

However, another immunohistology investigation of lung tissues from 2 COVID-19 patients who died with respiratory failure found that the pattern of COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the inter-alveolar septa by neutrophils without hallmarks of classic ARDS 123 Three clinical studies recorded the baseline cytokine plasma concentrations in 21 124 , 43 125 , and 274 126 patients with COVID-19 on admission or from initial tests. The median time from symptom onset to admission in these three papers was 7-8 days 124 , 6 days 125 , and 9-10 days 126 , respectively. However, the cytokine examination date from a fourth study may be even later 4 , since the median time for blood sample collection in this paper was 4 days since subjects were transferred to a designated hospital.

One study reported that IFN-γ, TNF-α, IL-1β, and IL-8 plasma concentrations in COVID-19 patients were significantly higher compared to results from four healthy In addition to the consistent trend of lower lymphocyte counts observed in severe cases of COVID-19 (Table 3 ) from different studies, total T cells, CD4 + T cells, and CD8 + T cells also were significantly lower in severe/critical COVID-19 cases than in non-severe cases 124, 127, 128 . Subgroups of CD4 + T cells did not show significant proportion changes of CD45RA + naïve T cells and CD45RO + memory T cells between severe cases and moderate cases 124 . However, the proportion of CD45RA + regulatory T cells in severe cases (0.5%) was only half the value of that in moderate cases (1.1%). One study noted a slight improvement of mean T cell counts (including CD4 + or CD8 + subpopulations) in comparison to baseline values after 5-14 days of in-hospital treatment 128 . The count improvement appears baselineproportional, regardless of disease severity.

Several published studies have observed features of cellular exhaustion in T cells analogous to that described for NK cells 129 . In two related studies, the authors showed that healthy individuals could be distinguished from mild and severe COVID-

T cells; specifically, the severe group had much lower levels of non-exhausted (PD-1 -CTLA-4 -TIGIT -) CD8 + T cells 127, 131 . They also found that CD8 + T cells in COVID-19 patients exhibit many aspects of exhaustion and reduced function, such as Once in the cell, the virus is not killed or neutralized; instead, it may continue to replicate, and/or stimulate or kill the target cells, causing more inflammation and damage. Of note is that ADE is not necessarily associated with past humoral response to a related pathogen, such as dengue virus 144 , and can occur during the primary humoral response when the neutralizing antibody is at a suboptimal level. This was documented in some severe cases following SARS-COV infection 145, 146 .

In a study reporting 75 patients with SARS, the lung radiographic worsening of some severe cases was correlated with the time of IgG seroconversion 145 . The pattern is consistent with that of COVID-19, in which the disease in some severe cases suddenly worsened around one to two weeks 62, 63 , when seroconversion of anti-SARS-CoV-2 occurred (around 5 to 10 days after the onset of the first symptom) 48 . In addition, the recovered SARS patients had higher and sustainable or steadily increasing levels of both anti-N antibody and anti-S neutralizing antibody since the seroconversion 146 .

However, the titer of anti-N antibody in the SRAS non-survivors was low, and the titer of anti-S antibody decreased rapidly approximately 5 days after the peak, an observation much like that in some patients with severe cases of COVID-19 48 .

In vitro studies demonstrated that human anti-S serum enhanced SARS-COV infection in human monocyte-derived macrophages (MDM) 147 . The infection mechanism is very different from that of the ACE2-mediated, endosomal/lysosomaldependent pathway, and can be blocked by anti-FcγR II antibody 148 

On April 21, the National Institutes of Health (NIH) issued general treatment guidelines for COVID-19 150 , with the recommendations based on scientific evidence and expert opinion. We do not intend to repeat the previously well-documented work in our review, but prefer to focus on two important topics: antiviral and immunomodulatory pharmacotherapies. Because results from clinical trials currently are being generated at such a blazing pace, this review was up to date at the time it was written.

Siddiqi HK et al. 159 Many viral cellular adherence/endocytosis blocking reagents were proposed. The cellular infection mechanism of SARS-CoV-2 is believed to be the same as SARS-CoV, which is an ACE2-mediated, endosomal-dependent pathway. Chloroquine 160 and hydroxychloroquine 161 were first identified through in vitro drug screening to reduce viral titers from the supernatant of infected cell cultures. The mechanism probably is through interference with viral entry/endocytosis by increasing the pH of the endosome 162 .

Two series of open-label, non-randomized studies in France reported only one death in 80 patients with relatively mild disease treated with hydroxychloroquine sulfate (200 mg TID for 14 days) and azithromycin (500 mg on Day 1 followed by 250 mg QD) 163, 164 . The authors justified the use of azithromycin because it had been shown to be effective against Zika and Ebola viruses in vitro. Of note is that azithromycin also prolongs the QT interval.

Based on limited scientific information, it is reasonable to believe that HCQ may be an effective treatment. FDA issued an EUA on March 28 to permit the emergency use of chloroquine phosphate and hydroxychloroquine sulfate supplied from the Strategic National Stockpile to treat adults and adolescents who weigh 50 kg or more and are hospitalized with COVID-19 for whom a clinical trial is not available, or participation is not feasible 165 . It should be noted that the FDA's typical process for EUA is to review its circumstances and appropriateness periodically. The review would include regular assessments, based on additional information from the sponsor, regarding progress on the unapproved product's -or unapproved use of an approved product's-approval, licensure, or clearance.

An observational study in 1376 patients from New York City did not find a significant difference in the rate of intubation or mortality between patients who received hydroxychloroquine and those did not 166 o Intravenous immunoglobulin (IVIg) has been used to treat SARS patients [188] [189] [190] 

The COVID-19 pandemic is still ongoing, and a long time may pass before we can fully grasp the complete picture of the pathogen's characteristics; including its vulnerabilities, which can be used to inform development of effective and efficient treatments. Development of antiviral therapeutics, led by DNA/RNA polymerase and protease inhibitors, has been streamlined since their invention in combatting HIV. Given worldwide extensive efforts, we are hopeful that anti-SARS-CoV-2 replication drugs will be discovered. It is unclear whether overreactive immune response and/or CSS play important roles in patients with severe COVID-19. However, some case reports suggest the efficacy of immunomodulatory agents in treating patients with severe COVID-19, which could pave the way for large-scale randomized, blinded, and controlled clinical trials. Last, but not least, the antibody profiles and timelines in recovered COVID-19 patients are encouraging. These should inform and guide the development of the ultimate antiviral weapon, the vaccine, for preventing COVID-19 in the 21st century.

Symptom Wang D et al. 8 Deng Y et al. 9 Zhou F et al. 11 Wu J et al. 10 8 Deng Y et al. 9 Zhou F et al. 11 Wu J et al. 10 1 p≤0.001 2 counted as endocrine system disease 3 counted as heart disease 4 counted as coronary heart disease 5 patients experienced severe acute respiratory syndrome 6 the degree of severity at the time of admission using the American Thoracic Society guidelines for communityacquired pneumonia

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Analysis of 92 deceased patients with COVID-19

Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases

Clinical and immunologic features in severe and moderate Coronavirus Disease

Clinical Features of 69 Cases with Coronavirus Disease

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

Functional exhaustion of antiviral lymphocytes in COVID-19 patients

Suppressed T cell-mediated immunity in patients with COVID-19: a clinical retrospective study in Wuhan

The NKG2A immune checkpoint -a new direction in cancer immunotherapy

NKG2A is a NK cell exhaustion checkpoint for HCV persistence

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

Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19)

Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease

Interleukin-6 use in COVID-19 pneumonia related macrophage activation syndrome

On the alert for cytokine storm: Immunopathology in COVID-19. Arthritis Rheumatol

Hemophagocytic syndromes--an update

IFN-gamma and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis

Interleukin-6 in biology and medicine

Immunotherapeutic implications of IL-6 blockade for cytokine storm

IL-10: A Multifunctional Cytokine in Viral Infections

The roles of interleukin-6 and interleukin-10 in B cell hyperactivity in systemic lupus erythematosus

Interleukin-8 (IL-8) and monocyte chemotactic and activating factor (MCAF/MCP-1), chemokines essentially involved in inflammatory and immune reactions

Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19

Invited commentary: Dengue lessons from Cuba

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

Antibody responses against SARS coronavirus are correlated with disease outcome of infected individuals

Antibody-dependent infection of human macrophages by severe acute respiratory syndrome coronavirus

Anti-severe acute respiratory syndrome coronavirus spike antibodies trigger infection of human immune cells via a pH-and cysteine proteaseindependent FcgammaR pathway

Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection

COVID-19) Treatment Guidelines

Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists

Covid-19: European drugs agency to review safety of ibuprofen

Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19

Risks of ACE Inhibitor and ARB Usage in COVID-19: Evaluating the Evidence

Updated approaches against SARS-CoV-2

Controversial treatments: an updated understanding of the Coronavirus Disease

Review of Emerging Pharmacotherapy for the Treatment of Coronavirus Disease

SARS CoV-2: Recent Reports on Antiviral Therapies Based on Lopinavir/Ritonavir, Darunavir/Umifenovir, Hydroxychloroquine, Remdesivir, Favipiravir and Other Drugs for the Treatment of the New Coronavirus

COVID-19Illnessin Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal. The Journal of Heart and Lung Transplantation

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Insights from nanomedicine into chloroquine efficacy against COVID-19

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study

EUA) OF HYDROXYCHLOROQUINE SULFATE SUPPLIED FROM THE STRATEGIC NATIONAL STOCKPILE FOR TREATMENT OF COVID-19IN CERTAIN HOSPITALIZED PATIENTS

Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19

Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial

Assessment of QT Intervals in a Case Series of Patients With Coronavirus Disease 2019 (COVID-19) Infection Treated With Hydroxychloroquine Alone or in Combination With Azithromycin in an Intensive Care Unit

Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease

American Heart Association tACoCatHRS. Caution recommended on COVID-19 treatment with hydroxychloroquine and azithromycin for patients with cardiovascular disease

Detection of severe acute respiratory syndrome coronavirus in blood of infected patients

Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China

Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Coronaviruses -drug discovery and therapeutic options

Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors

Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19

Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial

Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths

Impact of corticosteroid therapy on outcomes of persons with SARS-CoV-2, SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis

COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome?

COVID-19: the new challenge for rheumatologists

COVID-19: consider cytokine storm syndromes and immunosuppression

First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab

Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report

Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome

Management of hospital-acquired severe acute respiratory syndrome with different disease spectrum

Effect of regular intravenous immunoglobulin therapy on prognosis of severe pneumonia in patients with COVID-19

Recent developments in the management of haemophagocytic lymphohistiocytosis

High-Dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients With Coronavirus Disease

Continuous Intravenous Anakinra Infusion to Calm the Cytokine Storm in Macrophage Activation Syndrome. ACR Open Rheumatol

Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study

Emapalumab for the treatment of relapsed/refractory hemophagocytic lymphohistiocytosis

Direct Antiviral Mechanisms of Interferon-Gamma

Plasma therapy against infectious pathogens, as of yesterday, today and tomorrow

The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis

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

Guidance for Industry: Investigational COVID-19 Convalescent Plasma

We would like to thank Joanne Berger, FDA Library, and Karen Valentine, FDA Center for Devices and Radiological Health, for editing the manuscript.

Procalcitonin (ng/mL) 22% vs. 75% 1, 3 N/A 1% vs 25%