Introduction
What do humans do when faced with a collective threat? Since the advent of man and civilization, war, disasters, natural calamities, and diseases have ravaged and brought humankind to its knees. Yet, people have huddled together and pulled each other by their collective bootstraps. Overcame every obstacle and found a way to survive. That is the human answer to a problem-face it head-on, together because there is strength in numbers. But what to do when the nature of an unseen enemy requires the core tenets of human society to be disrupted and turns all the methods of dealing with threats on its head, that is, the reality facing the world today – the harsh aggression of coronavirus disease 2019 (COVID-19). It is an enemy that knows no distinction between geopolitics, economic stature, or religious morality; an enemy that requires us to face it in tandem but alone.
In December 2019, a previously unknown coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was discovered in Wuhan, Hubei province of China. It was sequenced and isolated by January 2020. SARS-CoV-2 is associated with an ongoing outbreak of atypical pneumonia (COVID-2019) that has affected over 2,118,700 people and killed more than 141,900 of those affected in >210 countries as of April 16, 2020.[1]
On January 30, 2020, the World Health Organization (WHO) declared the SARS-CoV-2 epidemic a public health emergency of international concern. In India, the first COVID-19 case was confirmed in's Thrissur district, Kerala, on January 30.[2] On February 4, the state of Kerala declared coronavirus a state calamity after a third case tested positive. On March 11, the WHO declared the COVID-19 outbreak as a pandemic. By March 24, India took the decision to lockdown the country to break the chain of transmission, curb the disease, flatten the curve of spread, and prepare our country for a post- COVID world with 571 confirmed cases. As of May 4, India has 42,546 cases and has suffered 1391 deaths, the way out of this pandemic would test this country's preparedness to counter this virus and for people and the economy to survive long enough to have a fruitful life for as many people as possible.
Coronavirus-Virology
SARS-CoV-2 is a member of the family Coronaviridae and the subfamily Coronavirinae. It belongs to the genera Betacoronavirus.[3] It is a medium-sized (80–150 nm) enveloped nonsegmented positive sense single-stranded RNA viruses. SARS-CoV-2 genome encodes four structural proteins, S, M, N, and E [Figure 1]. The spike (S) protein projects through the viral envelope and forms the characteristic spikes in the coronavirus “crown.” This is critical for binding host cell receptors to facilitate entry into the host cell. In SARS-CoV-2, S protein has two parts, S1 and S2. S1 portion contains the receptor-binding domain (RBD).[4]
;)
Figure 1:
The structure of the severe acute respiratory syndrome coronavirus-2 virus
Theories of Severe Acute Respiratory Syndrome Coronavirus 2 Origins
It is improbable that SARS-CoV-2 emerged through laboratory manipulation of a related SARS-CoV-like coronavirus.[4] Even though it is possible that SARS-CoV-2 acquired RBD, mutations during adaptation to a passage in cell culture, coronaviruses from pangolins with nearly identical RBD, however, provide a much stronger explanation of how SARS-CoV-2 acquired these via recombination or mutation.[4] The acquisition of both the polybasic cleavage site and predicted O-linked glycans also argues against culture-based scenarios.[4]
Pathogenesis
In the case of SARS-CoV, the spike glycoprotein (S protein) on the virion surface mediates receptor recognition and membrane fusion. S1 contains the RBD, which directly binds to the peptidase domain of angiotensin-converting enzyme 2 (ACE2), whereas S2 is responsible for membrane fusion.[5]
Once the virus enters the cells, antigenic peptides are presented by major histocompatibility complex and then recognized by virus-specific cytotoxic T-lymphocytes. It subsequently stimulates the body's humoral and cellular immunity, which are mediated by virus-specific B- and T-cells.
Pulmonary Thrombosis
The key pathogenic molecular step of SARS-Cov2 is to attack the 1-beta chain of hemoglobin (Hb) and hunting the porphyrins dissociating the iron form it and releasing iron into the circulation.[6] Thus, Hb loses its capacity to bind with oxygen, so oxygen is not supplied to major organs.[6] The free iron released into the circulation is causing oxidative inflammation of alveolar macrophages.[6] The body tries to compensate this by elevating the rate of Hb synthesis which explains why Hb is high in those patients.[6] Other compensatory mechanisms to deal with such iron load are increasing ferritin production (iron store) which explains the very high ferritin levels observed in those patients.
Transmission Cycle
Coronaviruses are widespread among birds and mammals, with bats being host to the largest variety of genotypes. Although its origins are not entirely understood, these genomic analyses suggest that SARS-CoV-2 probably evolved from a strain found in bats. The potential amplifying mammalian host, intermediate between bats and humans, is, however, not known [Figure 2].
Figure 2:
Transmission of coronavirus
Epidemiology
COVID-19 is predominantly seen in the older population with chronic medical conditions. There is a male preponderance. The median age was 55–59 years.[7] More than 75% admitted in one case series were older than 50 years of age.
SARS-CoV-2 is also more likely to manifest with complications in high-risk groups of people, such as, elderly ≥60 years of age, and in those with certain underlying conditions, such as cardiovascular, cerebrovascular diseases, diabetes, hypertension, chronic kidney/lung/liver diseases, and immunocompromised states. Severe manifestations may also be associated with coinfections of bacteria and fungi.
Coronavirus has an R0 of 3.28. The case fatality rate for coronavirus has been reported between 0.5% and 4%.[8]
Unlike European countries and the USA, the majority of the cases in India are affecting people of age group between 31 and 40 years.
Fewer COVID-19 cases have been reported in children <15 years. In summary, children might be less likely to be infected or, if infected, present milder manifestations than adults.
Incubation Period
The average incubation period is 5–6 days. However, symptoms may appear in as few as 2 days or as long as 14 days after exposure.
Routes of Transmission
The latest guidelines described three main transmission routes for the COVID-19: (1) droplets transmission, (2) contact transmission, and (3) aerosol transmission.[7]
The virus can be transmitted through all disease stages. The shedding of the COVID-19 virus is highest in the upper respiratory tract (nose and throat) early in the course of the disease, that is, within the first 3 days from the onset of symptoms. People may be more contagious around the time of symptom onset as compared to later in the disease.
Clinical Manifestations
The most common symptoms of SARS-CoV-2 include fever, dry cough, dyspnea, chest pain, fatigue, and myalgia. Less common symptoms include headache, dizziness, abdominal pain, diarrhea, nausea, and vomiting. Except sore throat, very few COVID-19 patients show prominent upper respiratory tract signs and symptoms such as rhinorrhea and sneezing, suggesting that the virus might have a greater preference for infecting the lower respiratory tract. Pregnant and nonpregnant women have similar characteristics.
Pulmonary Manifestations
COVID-19 presents with a myriad of pulmonary symptoms from mild upper respiratory tract infection, bilateral pneumonia, and acute respiratory distress. As such, the WHO recommends screening all patients with severe acute respiratory infections (SARIs), influenza-like Illness, and acute respiratory illness for COVID-19 in affected areas.[791011]
However, there are certain findings that set COVID-19 apart from other viral causes of pneumonia or acute respiratory distress syndrome (ARDS). The patients can turn bad to worse in hours. “Happy hypoxia” is a new term coined that means that the patient is still very much conscious and happily answering questions, even with SpO2 of 70 or lower. Most of the postmortem revealed that pulmonary thrrombosis and not typical ARDS features is the cause for the pulmonary involvement.[6]
Hematological Manifestations
Lymphopenia is the cardinal laboratory finding, with prognostic potential.[12] Neutrophil-to-lymphocyte ratio and peak platelet-to-lymphocyte ratio may also have prognostic value in determining severe cases. Longitudinal evaluation of lymphocyte count dynamics and inflammatory indices, including lactate dehydrogenase, C-reactive protein, and interleukin 6 (IL-6) may help to identify cases with dismal prognosis.[12]
Blood hypercoagulability is common among hospitalized COVID-19 patients. Elevated D-Dimer levels are consistently reported.[12] Other coagulation abnormalities such as prothrombin time and activated partial thromboplastin time prolongation, and fibrin degradation product increase with severe thrombocytopenia lead to life-threatening disseminated intravascular coagulation (DIC) which necessitates continuous vigilance and prompt intervention.[12]
Neurological Manifestations
Neurologic manifestations ranged from specific symptoms (e.g., loss of sense of smell or taste, myopathy, and stroke) to more nonspecific symptoms (e.g., headache, depressed level of consciousness, dizziness, or seizure). Neurologic symptoms were more common in patients with more severe disease.[13]
Gastrointestinal Manifestations
The incidence of less common features such as diarrhea, nausea, vomiting, and abdominal discomfort varies significantly among different study populations.[14] Mild-to-moderate liver injury, including elevated aminotransferases, hypoproteinemia, and prothrombin time prolongation, has been reported in the existing clinical investigations of COVID-19.[14]
Cutaneous Manifestations
Approximately 20% of cases of COVID have so far presented with cutaneous manifestations as heralding signs, these are urticaria, morbilliform rash, acral ischemia, livedo reticularis, chicken-pox like vesicles, and petechiae.[15]
Renal Manifestations
Renal disturbances consist of acute kidney injury (AKI) due to acute tubular necrosis induced by sepsis, hydration, cytokine storm syndrome, rhabdomyolysis, and hypoxia.[16] The direct cytopathic effect of virus on various renal cells has been detected in previous studies; direct virus invasion to the renal tubular cells and interstitium or glomeruli is possible.[16] Coronavirus enters into the cells by ACE2 receptors that are extensively presented in the renal cells. Further, AKI in COVID-19 is strongly associated with higher mortality and morbidity and is an indicator for survival with coronavirus infection.[17] There is a possibility of cardiorenal crosstalk from COVID-related cardiomyopathy contributing to renal injury.[18]
Cardiac Manifestations
Myocarditis defined as an inflammatory disease of the cardiac myocytes and pathologically defined by mononuclear cells infiltration of the myocytes has been noticed.[19] Newly diagnosed cardiomyopathy versus acute on chronic heart failure exacerbation has been experienced in patients with COVID-19.[20] The relationship of COVID-19 to induction of arrhythmia can be due to acute cardiac injury from different etiologies such as hypoxia mediated, worsening of coronary perfusion, direct tissue damage, a product of hyperacute systemic inflammatory response syndrome, or it could be due to the effects of medications used in the management of COVID-19.[20]
Complications
Pneumonia is often bilateral, ARDS, AKI, secondary bacterial and fungal infections, septic shock, DIC, cardiac arrest, and death.[11]
Laboratory Diagnosis
The methods and modalities of testing are a constantly changing landscape. This is done on the basis of the WHO case definitions of cases and contacts.[7] Confirmatory testing is now done with reverse transcription-polymerase chain reaction on samples from the nasopharynx, oropharynx, sputum, and bronchoalveolar lavage in India. In addition, rapid antibody testing is also being used in various countries to quickly ascertain the burden of the disease. [Figure 3] elucidates the testing options, strategies, and sensitivities of the available tests.[78] India is testing an average of 24 asymptomatic people to find one case of COVID-19. As such, the Indian Council of Medical Research has suggested adopting a pool testing strategy to ramp up the number of testing.[21]
Figure 3:
Coronavirus disease 2019 testing type, timeline, and sensitivity
Certain countries have also adopted radiological findings like interstitial pneumonia-like pattern on chest X-ray and ground-glass opacity, consolidation, reticular pattern, and crazy-paving pattern on high-resolution computed tomography of the thorax[1022] in the setting of appropriate clinical findings for rapid diagnosis of cases[102324] [Figure 4].
Figure 4:
Computed tomography findings such as ground-glass opacities in the right and crazy paving (yellow arrows) in the left are common findings. The appearance of such common features also tends to follow a fixed timeline[24]
Differential Diagnosis
During outbreak settings, other prevalent infections are often overlooked. Coinfections are also possible. Seasonal influenza can present with similar clinical picture with bilateral pneumonia and ARDS. Tropical infections such as dengue, malaria, leptospirosis, and rickettsia are still common causes of ARDS in tropical country like India. Bacterial pneumonia by both typical and atypical organisms should be ruled out.
Management
COVID-19 has no definite cure. In the absence of the same, the management guidelines for this virus are constantly evolving. This article will thus present a condensed summary of the approaches being tried.
For mild cases,[125] antipyretics and antitussives form the baseline. If antibiotics is indicated azithromycin or amoxicillin–clavulanate are given. Tablet oseltamivir 75 mg bd should be administrated for 5 days for high-risk influenza if suspects.
for Moderate-To-Severe Cases
Supplemental oxygen therapy needs to be initiated immediately to patients with SARI and respiratory distress, hypoxemia, or shock. Antipyretics and antitussives are given. When indicated antibiotics are given. Metered dose inhaler is preferred for nebulization. Hydroxychloroquine 400 mg BD should be administrated for 1 day followed by 200 mg BD for 5 days. It should be instituted early In combination with azithromycin 500 mg OD for 5 days.[26] Drugs such as lopinavir/ritonavir may be considered on case-to-case basis, same as Zinc and Vitamin C supplements. There is no routine use of steroids. Nonsteroidal anti-inflammatory drugs are avoided.
Indications for Mechanical Ventilation and Anticoagulation
Indications for mechanical ventilation and anticoagulation include persistent hypoxia (SpO2 <90%) on 60% venturi mask, persistent tachypnea (Respiratory rate (RR) >30cpm) or respiratory distress, systolic blood pressure <90 mmHg despite fluid resuscitation[26] and vasopressors, and Glasgow Coma Scale <8.[27] The patient should be in prone ventilation for 12 h a day.[27]
COVID-19-infected patients whether hospitalized or ambulatory are at high risk for venous thromboembolism,[25] and an early and prolonged pharmacological thromboprophylaxis with low-molecular weight heparin is highly recommended.[28] Heparin binds tightly to COVID19 spike proteins and they also downregulate IL-6 and directly dampen immune activation.[5]
Recommendation for Empiric Use of Hydroxychloroquine for Prophylaxis of Severe Acute Respiratory Syndrome-Coronavirus-2 Infection
The National Task Force for COVID-19 recommends the use of hydroxychloroquine for prophylaxis of SARS-CoV-2 infection for asymptomatic health-care workers involved in the care of suspected or confirmed cases of COVID-19. Asymptomatic household contacts of laboratory-confirmed cases. The chemical components in chloroquine phosphate compete with the porphyrin and bind to the viral protein, thereby inhibiting the viral protein's attack on heme or binding to the porphyrin.[6]
Discharge Criteria
The clinical criteria for discharge require that a person be asymptomatic and clinically stable for 72 hours. The radiological criteria require clearances of chest X-ray. Two swab tests (24 h apart) should be repeated if the above criteria have been fulfilled, and both the tests should be negative. Once the patient is discharged, he/she shall be shifted to designated quarantine facilities for a minimum of 14 days for monitoring.
Potential Treatments for Coronavirus Disease 2019
Remdisivir, an adenosine analog, can target the RNA-dependent RNA polymerase (RdRp) and block viral RNA synthesis.[25] Favipiravir is the latest drug to receive emergency approval from the Food and Drug Administration. It is an antiviral agent that selectively inhibits the RdRp of RNA viruses.[29]
Other putative and probable therapy modalities and prevention strategies are under study, such as the role of tocilizumab to block cytokine storm;[30] convalescent plasma therapy for reducing disease severity;[31] whether universal Bacille Calmette–Guérin vaccination contributes to protection from increased disease burden;[32] and if Vitamin D supplementation can reduce the risk of infections.[33]
Until further data are available, renin–angiotensin–aldosterone system inhibitors should be continued in patients in otherwise stable conditions who are at risk for, being evaluated for, or with Covid-19.[30]
Novel Vaccine and Drug Research Methods
As per the landscape document by the WHO, there are two candidate vaccines in clinical trials. Along with that 42 candidate vaccines are in preclinical studies.[34] Interestingly, this pandemic has prompted more examples of innovative ways that coronavirus researchers are avoiding cruel and archaic tests on animals in favor of cutting-edge, human-relevant methods.[35]
Prevention
Apart from isolation of confirmed cases till they meet recovery criteria or quarantining a probable/suspect case for 14 days, there are certain measures that need to be adopted by populations. These are handwashing with soap and water for 40 s or using alcohol-based hand sanitizer with 70% alcohol, maintaining cough etiquette, and social distancing.[36]
Medical-grade N95 masks should be used by individuals with respiratory symptoms, care providers to individuals with respiratory symptoms, or by a health worker. People in affected areas should be wearing homemade masks while venturing outside.[37]
The specific of the role of herd immunity in COVID-19 is still an unknown and as such is not a recommended strategy in the absence of an effective vaccine. The role of community based efforts towards prevention of disease and its impact on nations is represented in [Figure 5].[37]
Figure 5:
Modeling and disease prediction of coronavirus disease 2019 in India using (a) no intervention, (b) early intervention, and (c) late intervention. Predicted using coronavirus outbreak in India using Epidemic Calculator (
http://gabgoh.github.io/COVID/index.html)
Conclusions
The current COVID-19 pandemic is clearly an international public health problem. There have been rapid advances in what we know about the pathogen, how it infects cells and causes disease, and clinical characteristics of disease. Due to rapid transmission, countries around the world should increase attention to disease surveillance systems and scale up country readiness and response operations including establishing rapid response teams and improving the capacity of the national laboratory system.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Addendum to Treatment of Severe COVID Cases
As per the recent statements released from the chief investigators of the RECOVERY trial, on June 16 2020, low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19.
Dexamethasone was given at a dose of 6mg once per day (PO or IV) for ten days. Dexamethasone reduced deaths by one-third in ventilated patients and by one fifth in other patients receiving oxygen only. There was no benefit among those patients who did not require respiratory support.
As such, dexamethasone is recommended for patients presenting with respiratory complications of COVID19 either requiring oxygen support or ventilatory therapy.[38]
REFERENCES
1. Zayet S, Kadiane-Oussou NJ, Royer PY, Toko L, Gendrin V, Klopfenstein T. Coronavirus disease 2019: New things to know! J Med Virol. 2020:e1–2 doi:10.1002/jmv.25874
2. Gupta N, Agarwal S, Ish P, Mishra S, Gaind R, Usha G, et al Clinical and epidemiologic profile of the initial COVID-19 patients at a tertiary care centre in India Monaldi Archives for Chest Disease, 90.
https://doi.org/10.4081/monaldi.2020.1294
3. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure function, and antigenicity of the SARS-CoV-2 spike glycoprotein Cell. 2020;181:281–920
4. Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS-CoV-2 Nat Med. 2020;26:450–2
5. Belouzard S, Chu VC, Whittaker GR. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites Proc Natl Acad Sci U S A. 2009;106:5871–6
6. Liu W, Li H. COVID-19: Attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme Metabolism ChemRxiv. 2020 Preprint.
https://doi.org/10.26434/chemrxiv.11938173.v8
7. Adhikari SP, Meng S, Wu YJ, Mao YP, Ye RX, Wang QZ, et al Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: A scoping review Infect Dis Poverty BioMed Central Ltd. 2020;9:1–12
8. Singh A, Shaikh A, Singh R, Singh AK. COVID-19: From bench to bed side Diabetes Metab Syndr. 2020;14:277–81
9. Khoo EJ, Lantos JD. Lessons learned from the COVID-19 pandemic [published online ahead of print, 2020 Apr 14] Acta Paediatr. 2020 10.1111/apa.15307. doi:10.1111/apa.15307
10. Hosseiny M, Kooraki S, Gholamrezanezhad A, Reddy S, Myers L. Radiology perspective of coronavirus disease 2019 (COVID-19): Lessons from severe acute respiratory syndrome and middle east respiratory syndrome AJR Am J Roentgenol. 2020;214:1078–82
11. Jin H, Lu L, Liu J, Cui M. Complex emergencies of COVID-19: management and experience in Zhuhai, China Int J Antimicrob Agents. 2020;55:105961 doi: 10.1016/j.ijantimicag.2020.105961
12. Terpos E, Ntanasis-Stathopoulos I, Elalamy I, Kastritis E, Sergentanis TN, Politou M, et al Hematological findings and complications of COVID-19 [published online ahead of print, 2020 Apr 13] Am J Hematol. 2020 10.1002/ajh.25829. doi:10.1002/ajh.25829
13. Pleasure SJ, Green AJ, Josephson SA. The Spectrum of Neurologic Disease in the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic Infection: Neurologists Move to the Frontlines JAMA Neurol. 2020;77:679–80 doi:10.1001/jamaneurol.2020.1065
14. Gu J, Han B, Wang J. COVID-19: Gastrointestinal manifestations and potential fecal-oral transmission Gastroenterology. 2020;158:1518–9
15. Recalcati S. Cutaneous manifestations in COVID-19: A first perspective J Eur Acad Dermatol Venereol. 2020 [published online ahead of print, 2020 Apr 21] 10.1111/jdv.16519. doi:10.1111/jdv.16519
16. Rohollah V, Azar B, Azin M, Bhaskar Lakkakula VK. Coronavirus-nephropathy; renal involvement in COVID-19 J Ren Inj. 2020;9:e18
17. Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L, et al Kidney impairment is associated with in-hospital death of COVID-19 patients medRxiv. 2020 preprint. Doi:
https://doi.org/10.1101/2020.02.18.20023242
18. Ronco C, Reis T. Kidney involvement in COVID-19 and rationale for extracorporeal therapies Nat Rev Nephrol. 2020;16:308–10
19. Fung G, Luo H, Qiu Y, Yang D, McManus B. Myocarditis Circ Res. 2016;118:496–514
20. Basu-Ray I, Soos MP. Cardiac manifestations of coronavirus (COVID-19) StatPearls. Treasure Island (Finland): StatPearls Publishing;. 2020 Available from:
https://www.ncbi.nlm.nih.gov/books/NBK556152. [Last accessed on 2020 May 04]
21. ICMR. Advisory on Feasibility of Using Pooled Samples for Molecular Testing of COVID-19. 2020 Available from:
https://www.mohfw.gov.in/pdf/letterregguidanceonpoolingsamplesfortesting001.pdf. [Last accessed on 2020 May 04]
22. Ye Z, Zhang Y, Wang Y, Huang Z, Song B. Chest CT manifestations of new coronavirus disease 2019 (COVID-19): A pictorial review [Online ahead of print] Eur Radiol. 2020:1–9 doi: 10.1007/s00330-020-06801-0
23. Ng MY, Lee EY, Yang J, Yang F, Li X, Wang H, et al Imaging profile of the COVID-19 infection: Radiologic findings and literature review Radiol Cardiothorac Imaging. 2020;2:e200034
24. Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coronavirus disease 2019 (COVID-19): A systematic review of imaging findings in 919 patients [published online ahead of print] AJR Am J Roentgenol. 2020:1–7 10.2214/AJR.20.23034
25. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review JAMA. 2020;323:1824–36 doi:10.1001/jama.2020.6019
26. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Int J Antimicrob Agents. 2020 doi: 10.1016/j.ijantimicag.2020.105949. Online ahead of print
27. Meng L, Qiu H, Wan L, Ai Y, Xue Z, Guo Q, et al Intubation and ventilation amid the COVID-19 outbreak Anesthesiology. 2020;132:1317–32 doi: 10.1097/ALN.0000000000003296
28. Mount Sinai Mount Sinai COVID 19 Anticoagulation Algorithm; Ver 1.1. 2020. Available from:
https://emergencymedicinecases.com/wp-content/uploads/2020/04/COVID-19-Anticoagulation-Algorithm-version-final-1.1.pdf. [Last accessed on 2020 May 04]
29. Chen C, Huang J, Cheng Z, Wu J, Chen S, Zhang Y, et al Favipiravir versus arbidol for COVID-19: A randomized clinical trial medRxiv. 2020 Preprint. doi:
https://doi.org/10.1101/2020.03.17.20037432
30. Ye Q, Wang B, Mao J. Cytokine storm in COVID-19 and treatment J Infect. 2020;80:607–13 doi: 10.1016/j.jinf.2020.03.037. Epub 2020 Apr 10
31. Chen L, Xiong J, Bao L, Shi Y. Convalescent plasma as a potential therapy for COVID-19 Lancet Infect Dis. 2020;20:398–400
32. Ayoub BM. COVID-19 vaccination clinical trials should consider multiple doses of BCG Pharmazie. 2020;75:159
33. Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, et al Evidence that Vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths Nutrients. 2020;12:988
34. WHO. DRAFT Landscape of COVID-19 Candidate Vaccines; 20 April. 2020:e1–7 Available from:
https://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus-landscape-ncov.pdf. [Last accessed on 2020 May 04]
35. Cimolai N. Defining protective epitopes for COVID-19 vaccination models J Med Virol. 2020 10.1002/jmv.25876. doi: 10.1002/jmv.25876. Online ahead of print
36. Paakkari L, Okan O. COVID-19: Health literacy is an underestimated problem Lancet Public Health. 2020;5:e249–50
37. Mandal S, Bhatnagar T, Arinaminpathy N, Agarwal A, Chowdhury A, Murhekar M, et al Prudent public health intervention strategies to control the coronavirus disease 2019 transmission in India: A mathematical model-based approach Indian J Med Res. 2020;151:190–9 doi: 10.4103/ijmr.IJMR-504-20
38. . Press Release of 16 June 2020, “Statement from the Chief Investigators: low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19” Available from,
https://www.recoverytrial.net/files/recovery-dexamethasone-statement-160620-v2final.pdf. [Last accessed on 2020 Jun 17]
