Healthcare e-Compendium

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Emerging Therapies And Recommendations To Handle Covid-19 Pandemic

Author: Dr Shailaja Shankar Behera

MBBS, MD (IMS BHU); PDCC Critical Care Medicine (IMS BHU); Post-Doc Fellowship in Neurocritcal Care (NIMHANS, Bengaluru), DM (Critical Care) AIIMS New Delhi

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The World Health Organization (WHO) was informed of cases of pneumonia of unknown microbial etiology associated with Wuhan City, Hubei Province, China on 31 December 2019. The WHO later announced that a novel coronavirus had been detected in samples taken from these patients. Since then, the epidemic has escalated and rapidly spread around the world, Coronaviruses are large group of viruses that cause illness in humans and animals. Rarely, animal coronaviruses can evolve and infect people and then spread between people such as have been seen with MERS and SARS. The situation is still evolving and hence there is yet no definitive therapy but to conclude the use of repurposed medications can be a boon till a definitive therapy and vaccines are developed.


Current available evidence for COVID-19 suggests that the causative virus (SARS-CoV-2) has a zoonotic source that is related to bat-origin SARS-like coronavirus. It is an envelope RNA beta coronavirus related to the Severe Acute Respiratory Syndrome (SARS) virus; the persons infected by the novel coronavirus are the main source of infection. [1] Direct person-to-person transmission occurs through close contact, mainly through respiratory droplets that are released when the infected person coughs, sneezes. These droplets may also land on surfaces, Infection can also occur if a person touches an infected surface and then touches his or her eyes, nose, or mouth. Experts suggest the amount of infections may be much higher than India's testing rates are among the bottom within the world. The infection rate of COVID-19 in India is reported to be 1.7, significantly less than within the worst affected countries. [2]


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a previously unknown betacoronavirus that was discovered in bronchoalveolar lavage samples taken from clusters of patients who presented with pneumonia of unknown cause in Wuhan City, Hubei Province, China, in December 2019. [3] Coronaviruses are a large family of enveloped RNA viruses, some of which cause illness in people (e.g., common cold, severe acute respiratory syndrome [SARS].

Transmission Dynamics

An initial assessment of the transmission dynamics in the first 425 confirmed cases found that 55% of cases before this confirms that person-to-person spread occurred among close contacts since the middle of December 2019, including infections in healthcare workers. [4] However, these reports relate to indoor crowded spaces with poor ventilation and a detailed investigation of these clusters suggests that droplet and fomite transmission could also explain the transmission in these reports. Further research is required. [5] The virus has been found to be more stable on plastic and stainless steel (up to 72 hours) compared with copper (up to 4 hours) and cardboard (up to 24 hours). [6] In healthcare the virus is widely distributed in the air and on object surfaces in both general wards and intensive care units, with a greater risk of contamination in the intensive care unit. [7] While viral RNA has been detected on surfaces and air samples across a range of acute healthcare settings, no virus has been cultured from these samples indicating that the deposition may reflect nonviable viral RNA. [8]

Symptomatic transmission

Transmission mainly occurs from symptomatic people to others by close contact through respiratory droplets, by direct contact with infected people, or by contact with contaminated objects and surfaces.

Pre-symptomatic transmission

The incubation period is estimated to be between 1 and 14 days, with a median of 5 to 6 days. Some patients may be contagious during the incubation period, usually 1 to 3 days before symptom onset. Pre-symptomatic transmission still requires the virus to be spread by infectious droplets or by direct or indirect contact with bodily fluids from an infected person.

Asymptomatic transmission

An asymptomatic case is a laboratory-confirmed case that does not develop symptoms. There is some evidence that spread from asymptomatic carriers is possible, although it is thought that transmission is greatest when people are symptomatic.

Clinical Features

COVID-19 patients reporting to various COVID treatment facilities have reported the following signs and symptoms:

  • Fever
  • Cough
  • Shortness of breath
  • Fatigue
  • Expectoration
  • Myalgia
  • Rhinorrhea, sore throat, diarrhea

Loss of smell (anosmia) or loss of taste (ageusia) preceding the onset of respiratory symptoms have also been reported. Older people and immune-suppressed patients in particular may present with atypical symptoms such as fatigue, reduced alertness, reduced mobility, diarrhoea, loss of appetite, delirium, and absence of fever. Children might not have reported fever or cough as frequently as adults.

(As per WHO surveillance guidelines)

Severity of Symptomatic Infection

World Health Organization: COVID-19 disease severity [9]

Mild Illness

Symptomatic patients meeting the case definition for COVID-19 without evidence of hypoxia or pneumonia. Common symptoms include fever, cough, fatigue, anorexia, dyspnea, and myalgia. Other nonspecific symptoms include sore throat, nasal congestion, headache, diarrhea, nausea/vomiting, and loss of smell/taste. Older people and immunosuppressed people may present with atypical symptoms.

Moderate Disease

Adolescent or adult: clinical signs of pneumonia but no signs of severe pneumonia, including blood oxygen saturation levels (SpO₂) ≥90% on room air.

Children: Clinical signs of non-severe pneumonia (i.e., cough or difficulty breathing plus fast breathing and/or chest in drawing) and no signs of severe pneumonia. Fast breathing is defined as:

  • <2 months of age: ≥60 breaths/minute
  • 2-11 months of age: ≥50 breaths/minute
  • 1-5 years of age: ≥40 breaths/minute

Severe Disease

Children: Clinical signs of pneumonia (i.e., cough or difficulty in breathing) plus at least one of the following: 

  • Central cyanosis or SpO₂ <90%
  • Severe respiratory distress (e.g., fast breathing, grunting, very severe chest in drawing)
  • General danger sign
  • Inability to breastfeed or drink, lethargy or unconsciousness, or convulsions

While the diagnosis can be made on clinical grounds, chest imaging may assist in diagnosis and identify or exclude pulmonary complications.

Risk factors for Severe Illness

People who have any of various signs and symptoms without shortness of breath, dyspnea, or abnormal imaging. People who have respiratory frequency >30 breaths per minute, SpO₂ ≤93% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO₂/FiO₂) <300, or lung infiltrates >50%. People who have respiratory failure, septic shock, and/or multiple organ dysfunction.

Impact of Age 

Risk factors for developing severe disease are as follows: age greater than 60 years, active cigarette smoking, immune-suppressing medications or conditions, chronic pulmonary disease, and heart disease.

Pharmacological Treatments with Potential Clinical Benefit

Identify Effective Drugs for Prevention and Treatment and its Outcomes

Several clinical trials are ongoing to help establish the efficacy of various treatments, including antiviral therapies, re-purposed medications, and anti-inflammatory medications. However, a subset of patients will develop severe pulmonary disease or critical illness. For this subset of patients and patients with risk factors for developing severe disease, antiviral medications may be considered.

Virology and Drug Targets

Origin of Virus

A majority of patients in the initial stages of this outbreak reported a link to the Huanan South China Seafood Market, a live animal or "wet" market, suggesting a zoonotic origin of the virus. While the potential animal reservoir and intermediary host (s) are unknown at this point, studies suggest they may derive from a recombinant virus between the bat coronavirus and an origin-unknown coronavirus; however, this is yet to be confirmed. Pangolins have been suggested as an intermediate host as they have been found to be a natural reservoir of SARS-CoV-2-like coronaviruses. Over 5 months after the initial outbreak, the virus is yet to be identified in an animal host.


Drug targets for corona virus: A systematic review Prajapat# M ...

Figure 1: Structural details of Coronavirus

Representing the structure of novel corona virus, which is like other RNA viruses containing various glycoproteins on the envelope and the RNA genome in the core. As shown in Figure 1, the viral cycle is like other viruses consisting of attachment, integration, uncoating, use of host cell machinery for replication, assembly and finally release of virions. Steps in coronavirus replication are potential targets for antiviral drugs and vaccines. [10]

Review of Selected Repurposed Drugs

Chloroquine and Hydroxychloroquine have a long-standing history in the prevention and treatment of malaria and the treatment of chronic inflammatory diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Chloroquine and hydroxychloroquine appear to block viral entry into cells by inhibiting glycosylation of host receptors, proteolytic processing, and endosomal acidification. A recent open-label non-randomized French study of 36 patients (20 in the hydroxychloroquine group and 16 in the control group) reported improved virologic clearance with hydroxychloroquine, 200 mg, by mouth every 8 hours compared with control patients receiving standard supportive care.

Management Guidelines

Management of Mild Cases

In the containment phase, patients with suspected or confirmed mild COVID-19 are being isolated to break the chain of transmission. Patients with mild disease may present to primary care/outpatient department, or detected during community outreach activities. Patients with risk factors for severe illness should be monitored closely, given the possible risk of deterioration. Mild COVID-19 cases may be given symptomatic treatment such as antipyretic (Paracetamol) for fever and pain, adequate nutrition and appropriate rehydration. Tab Hydroxychloroquine (HCQ) may be considered for any of those having high risk features for severe disease (such as age> 60; Hypertension, diabetes, chronic lung/kidney/ liver disease, Cerebrovascular disease and obesity) that will be at high risk under strict medical supervision.

Management of Moderate Cases

The patient will undergo detailed clinical history including co-morbid conditions, measurement of vital signs, Oxygen saturation (SpO2) and radiological examination of Chest X-ray, Complete Blood Count and other investigations as indicated. Antibiotics should not be prescribed routinely unless there is clinical suspicion of a bacterial infection. Patients with suspected or confirmed moderate COVID-19 (pneumonia) is to be isolated to contain virus transmission. Patients with moderate disease may present to an emergency unit or primary care/outpatient department, or be encountered during community surveillance activities, the defining clinical assessment parameters are Respiratory Rate of more than or equal to 24 and oxygen saturation (SpO2) of less than 94% on room air (range 90-94%). Such patients will be isolated in Dedicated COVID Health Centre (DCHC) or District hospital or Medical College hospitals.

Early Supportive Therapy and Monitoring

Give supplemental oxygen therapy immediately to patients with Severe COVID and respiratory distress, hypoxaemia, or shock: Initiate oxygen therapy at 5 L/min and titrate flow rates to reach target SpO2 ≥ 90% in non-pregnant adults and SpO2 ≥ 92-96% in pregnant patients. Children with emergency signs should receive oxygen therapy during resuscitation to target SpO2≥94%. All areas where patients with Severe COVID are cared for should be equipped with pulse oximeters, functioning oxygen systems and disposable, single- use, oxygen-delivering interfaces (nasal cannula, simple face mask, and mask with reservoir bag). Use conservative fluid management in patients with Severe COVID when there is no evidence of shock.

Pathophysiology of COVID-19

SARS-CoV-2 virus is primarily known to effect respiratory tract, by entry through mouth, nose and eyes. While symptoms of the disease accounts similar to mild pneumonia of unknown origin, but are extremely heterogeneous, ranging from minimal to significant hypoxia to acute respiratory distress syndrome (ARDS). The disease progress rapidly and is known to effect other organs as well and can ultimately be fatal, if not kept under check. [11]

After inhalation of SARS-CoV-2 virus, it enters the alveoli of lungs, where it replicates and multiplies causing infection, increasing the viral load. This increased viral load when exhaled out during respiration with cough and sneezing enters outside environment from where it infects to other host organisms.

The infection of alveoli of lungs by viral or bacterial cells is termed as pneumonia. This infection causes the disruption of alveolar cells leading to release of pro-inflammatory chemicals, that is cytokines. The resulting cytokine storm thickens the walls of alveoli and increases the fluid built up in lungs, decreasing the gaseous exchange of oxygen and carbon dioxide which causes ARDS. ARDS causes the shortness of breath in infected patients and need for ventilation.

While all this process going on immune system tries to fight the infection; further, adding to thickening of alveolar wall, making it harder for gaseous exchange and building up of more fluid inside the alveoli which finally leads to collapse of alveoli. Our body then tries to repair the collapsing alveoli leading to fibrosis formation, which eventually forms the scar tissue hardening the lungs and further limiting gaseous exchange.

Moreover, the pro-inflammatory chemical goes to hypothalamus in brain causing the rise in set body temperature, that is fever. Pro-inflammatory chemicals can also spread to other body organs via blood stream, causing systemic inflammation resulting into septic syndrome. In addition to this, lack of oxygen inside body leads to multi-organ dysfunction.

If kept unchecked, all these symptoms of cough, pneumonia, fever, acute respiratory distress syndrome, systemic inflammation and organ failure, finally can be fatal to a host organism.

Pre-Clinical and Clinical Evidence of Potential Therapeutic Targets

Researches to find the cure, treatment and vaccines are going on all across the globe. For this various potential therapeutic target are being considered. Many preclinical and clinical trials are being carried out using these potential therapeutic options, showing promising evidence for treatment.

Antiviral Therapy

The treatment done using drugs which directly keeps the check on virus multiplication and decreases the viral load falls under this section of antiviral therapy.


Remdesivir is a prodrug of a nucleotide analogue that is intracellularly metabolized to an analogue of adenosine triphosphate that inhibits viral RNA polymerases. Remdesivir has broad-spectrum activity against members of several virus families, including filoviruses and coronaviruses; and has shown prophylactic and therapeutic efficacy in non-clinical models of these coronaviruses.

In order to evaluate the efficacy and safety of the drug in patients with COVID-19, a randomized, placebo-controlled, double-blind, multicenter, phase III clinical trial was done in China. Patients in the experimental group received an initial dose of 200 mg of remdesivir and a subsequent dose of 100 mg for 9 consecutive days via intravenous infusion in addition to routine treatment. [12]

One study showed 68% of clinical improvement in the category of oxygen support, 100% in improvement in patients breathing ambient air or low flow supplemental oxygen and 71% on non-invasive oxygen support. [13] Another study showed that the group of patients treated using remdesivir had shorter recovery time as compared to placebo group. [14]

In May 2020, the US FDA issued emergency use authorization (EUA) of remdesivir to allow severe COVID-19 (confirmed or suspected) in hospitalized adults and children. [15]

Lopinavir – Ritonavir

Lopinavir a peptidomimetic molecule is a protease inhibitor. Lopinavir is administered exclusively in combination with ritonavir.

Due to lopinavir’s poor oral bioavailability and extensive biotransformation, it is co-formulated with ritonavir to enhance its exposure. Ritonavir is a potent inhibitor of the enzymes that is responsible for lopinavir metabolism, and its co-administration “boosts” lopinavir exposure and improves antiviral activity. [16]

This combination was investigated in an open-label, individually randomized, controlled trial, where patients received lopinavir-ritonavir 400 mg/100 mg, orally twice daily plus standard of care. No significant effect on the primary outcome measure of time to clinical improvement and no evidence of reduction in viral RNA titres compared to control were found. However, peer-protocol analyses suggested possible reductions in time to clinical improvement, particularly in those treated within 12 days of symptom onset. Further studies of lopinavir–ritonavir are ongoing. [17]


Favipiravir is a guanine analogue with pyrazine-carboxamide structure. The antiviral activity is exhibited through selectively targeting conservative catalytic domain of RNA-dependent RNA polymerase (RdRp), interrupting the nucleotide incorporation process during viral RNA replication. [18] Favipiravir has been used in the treatment of infectious diseases caused by RNA viruses such as influenza, Ebola, norovirus and recently SARS-CoV-2.

Clinical trials testing favipiravir against COVID-19 have been carried out vigorously in various countries. A randomized control trial (ChiCTR200030254) has shown that COVID-19 patients treated with favipiravir have superior recovery rate (71.43%); and the duration of fever and cough relief time are significantly shorter than in umifenovir group. [19]

An RCT enrolling patients within 12 days of symptom onset found that favipiravir was superior to arbidol in terms of the clinical recovery rate at day 7 in patients with mild illness, but not in those with critical illness. [20]

Anti-inflammatory Medications

The novel coronavirus SARS-CoV-2 that causes COVID-19 invokes a hyper-inflammatory state driven by multiple cells and mediators. This condition can be managed using various anti-inflammatory medications.

Glucocorticoids (Corticosteroid)

During the SARS-CoV epidemic of 2003, therapeutic systemic corticosteroids were administered in patients who were infected and developed severe respiratory disease. [21]

Dexamethasone is a corticosteroid used in a wide range of conditions for its anti-inflammatory and immunosuppressant effects. It was tested in hospitalized patients with COVID-19 in the U.K. national clinical trial RECOVERY and was found to have benefits for critically ill patients.

According to preliminary findings shared with WHO, for patients on ventilators, the treatment was shown to reduce mortality by about one third, and for patients requiring only oxygen, mortality was cut by about one fifth. Dexamethasone was administered as an oral (liquid or tablets) or intravenous preparation, at a dose of 6 mg once daily for ten days.

Tocilizumab and Siltuximab

Considering the proven role of cytokine dysregulation in causing this hyperinflammation in the lungs with IL-6 being a key driver, particularly in seriously ill COVID-19 patients, it is crucial to further explore selective cytokine blockade with drugs like the IL-6 inhibitors. Several randomized controlled trials (RCT) of tocilizumab and siltuximab, alone or in combination, are now proposed in patients with severe COVID-19. [22]

Tocilizumab is a recombinant humanized anti-IL-6R monoclonal antibody and is antagonists of the IL-6 receptors. In Italian Phase II open-label trial (NCT04315480) with tocilizumab 8 mg/kg single dose is being conducted in patients with severe multifocal interstitial pneumonia due to COVID-19 to evaluate its role in the virus-induced cytokine storm. [23]

Siltuximab prevents the binding of IL-6 to both soluble and membrane-bound IL-6R, inhibiting IL-6 signaling. A Phase II, randomized, open-label study to compare the efficacy and safety of siltuximab versus methylprednisolone in hospitalized patients with COVID 19 pneumonia has begun recruiting patients in Spain (NCT04329650). An another retrospective observational case–control study evaluating the use of siltuximab in patients diagnosed with COVID-19 infection who have developed serious respiratory complications is also registered in Italy (NCT04322188). [24]

Convalescent Plasma

Convalescent plasma is obtained from the individual who was suffering from SARS-CoV-2 infection and now is been recovered from the disease. During infection, the patient’s immune system tries to fight infection, in response to which particular antibodies are generated. By the time infection ceases these antibodies are present in the circulating blood, which can be separated from blood as plasma. These extracted plasma containing particular antibodies can be administered to the other infected person as a treatment therapy. [25]

The use of convalescent plasma was earlier used for treatment during outbreaks of Ebola virus (2014), and MERS (2015). This approach with other viral infections such as SARS-CoV, also suggested that transfusion of convalescent plasma was effective. In severe illness, one uncontrolled study of five patients given convalescent plasma suggested a possible benefit. [26]

However, Casadevall and Pirofski highlighted few risks related to passive administration of convalescent sera, which falls into two categories, serum disease and antibody-dependent enhancement of infection. Serum disease is associated with the transmission of other blood infections, whereas the antibody-dependent enhancement is the concern that antibodies to one form of coronavirus could enhance infection to another viral strain. [27]

Complications and Prognosis of COVID 19

SARS-CoV-2 initially effect respiratory system causing COVID19. These accounts for the mild-to-moderate symptoms causing distress; but if accompanied by other ailments or not kept under check, its course of progression becomes serious, causing severe symptoms. This may account for may complication requiring a need for ventilation, IV therapies and a longer hospital stay.

Complications arising are associated with infection due to invasive mechanical ventilation, increased chances of ventilated related pneumonia and catheter-related bloodstream infection. Apart from these taking lots of drug medication required for treatment cause ulcer formation and may lead to GI tract bleeding. During longer hospital stay patient is bedridden and develops bedsores and ICU-related weakness. All these complications accounts for additional measures to be taken to prognoses the correct course of recovery.


SARS-CoV-2 has infected a large number of population all across the globe. While researches are going on to find cure and treatment still not available calls for symptomatic management. This has recommended to testing and trials using various proposed medication showing promising results to treat COVID19. Based on preclinical and clinical trials of potential therapeutic targets such as antivirals remdesivir and favipiravir, a high dose of anti-inflammatory medications and convalescent plasma therapy can be safe for the treatment of the disease. Additionally, various other measures should be accompanied to reduce the incidences of associated complications as well.


  1. E. Keyaerts, S. Li, L. Vijgen, E. Rysman, J. Verbeeck, M. Van Ranst, P. Maes, Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice, Antimicrob. Agents Chemother. 53 (2009) 3416–3421, https://doi. org/10.1128/AAC.01509-08
  2. J. Gao, Z. Tian, X. Yang, Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies, Biosci. Trends 14 (2020) 72–73,
  3. Ren LL, Wang YM, Wu ZQ, et al. Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study. Chin Med J (Engl). 2020 May 5;133(9):1015-24
  4. Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020 Mar 26;382(13):1199-207
  5. World Health Organization. Transmission of SARS-CoV-2: implications for infection prevention precautions. 2020 [internet publication]
  6. van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med. 2020 Apr 16;382(16):1564-7
  7. Guo ZD, Wang ZY, Zhang SF, et al. Aerosol and surface distribution of severe acute respiratory syndrome coronavirus 2 in hospital wards, Wuhan, China, 2020. Emerg Infect Dis. 2020 Apr 10;26(7)
  8. Zhou J, Otter JA, Price JR, et al. Investigating SARS-CoV-2 surface and air contamination in an acute healthcare setting during the peak of the COVID-19 pandemic in London. Clin Infect Dis. 2020 Jul 8 [Epub ahead of print]
  9. World Health Organization. Clinical management of COVID-19: interim guidance. 2020 [internet publication]
  10. K.V. Holmes, SARS coronavirus: a new challenge for prevention and therapy, J. Clin. Invest. 111 (2003) 1605–1609,
  11. K. Yuki, et al. COVID-19 pathophysiology: A review. Clinical Immunology 215 (2020) 108427.
  12. Renyi Wu, et. al. An Update on Current Therapeutic Drugs Treating COVID-19. Current Pharmacology Reports. 2020.
  13. J. Grein, et. al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020. 382:2327-36. DOI: 10.1056/NEJMoa2007016
  14. J.H. Beigel, et. al. Remdesivir for the Treatment of Covid-19 — Preliminary Report. N Engl J Med. 2020. DOI: 10.1056/NEJMoa2007764
  16. slp. KALETRA (lopinavir and ritonavir) tablet. 12/2019
  17. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020.
  18. Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(7):449–63.
  19. Chen C, ZhangY, Huang J, Yin P, Cheng Z, Wu J et al. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. medRxiv. 2020:2020.03.17.20037432.
  20. Chen C, Huang J, Cheng Z, et al. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. medRxiv. 2020. DOI: 10.1101/2020.03.17.20037432
  21. Veronese N, et. al. Use of Corticosteroids in Coronavirus Disease 2019 Pneumonia: A Systematic Review of the Literature. 2020. Front. Med. 7:170. doi:10.3389/fmed.2020.00170
  22. S. Atal, Z. Fatima. IL‑6 Inhibitors in the Treatment of Serious COVID‑19: A Promising Therapy? Pharmaceutical Medicine. June 2020;
  23. Tocilizumab for SARS-CoV2 (COVID-19) Severe Pneumonitis. 2020.
  24.; May 2020.]
  25. G V Kumar et. al. A short review on antibody therapy for COVID-19. New Microbes and New Infections. May 2020; Vol. 35, number C
  26. Shen C, Wang Z, Zhao F, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA. 2020; DOI:10.1001/jama.2020.4783
  27. Casadevall Arturo, Pirofski Liise-anne. The convalescent sera option for containing COVID19. J Clin Invest 2020. JCI138003