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Table of Contents
GUEST EDITORIAL
Year : 2020  |  Volume : 8  |  Issue : 3  |  Page : 104-106

Uncertainty in the time of Covid-19


1 Department of Internal Medicine and Pulmonology, Narayana Hrudayalaya – Mazumdar Shaw Medical Center, Bengaluru, Karnataka, India
2 Department of Internal Medicine and Infectious Diseases, Narayana Hrudayalaya – Mazumdar Shaw Medical Center, Bengaluru, Karnataka, India

Date of Submission12-Jun-2020
Date of Decision13-Jun-2020
Date of Acceptance13-Jun-2020
Date of Web Publication15-Jul-2020

Correspondence Address:
Dr. B V Murali Mohan
Department of Internal Medicine and Pulmonology, Narayana Hrudayalaya - Mazumdar Shaw Medical Center, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJIM.AJIM_42_20

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How to cite this article:
Murali Mohan B V, Varghese GK. Uncertainty in the time of Covid-19. APIK J Int Med 2020;8:104-6

How to cite this URL:
Murali Mohan B V, Varghese GK. Uncertainty in the time of Covid-19. APIK J Int Med [serial online] 2020 [cited 2020 Aug 14];8:104-6. Available from: http://www.ajim.in/text.asp?2020/8/3/104/289793



The world has been brought to its knees by the effects of “a single strand of RNA,” the Novel Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Being highly, infectious, “novel” and a respiratory virus, in this era of rapid travel, the virus has rapidly spread across the global village. The pandemic has turned “life” as people knew it upside down and threatens to reorder the world. Without discrimination of color, creed, or economic status, it has swept globally and been an irresistible leveller. Invisible, and aided by social media, it has generated fear and made people hunker down in a “panic room” under the cover of masks and gloves and hand sanitizer.

Donald Rumsfeld, former US Secretary of State for Defence, once said: “There are known knowns. There are things we know that we know. There are known unknowns. That is to say, there are things that we now know we do not know. However, there are also unknown unknowns. There are things we do not know we don't know.”[1] This is probably more relevant to the COVID-19 pandemic, than at any other time.

What are the things we know that we know for certain about the COVID-19 pandemic? It is caused by a novel variant of the corona virus, a single-stranded RNA virus, the genome of which has been completely sequenced. Over time different isolates have been identified. The origins of the virus have fairly clearly been shown to be from Wuhan in China and are of zoonotic origin.[2] Transmission is by respiratory droplet infection, probably contact transmission and aerosol transmission. Of these the first is by far the most common, while surface transmission and aerosol spread may be relatively less important. The virus enters cells through ACE-2 in the airway. Most infected persons are asymptomatic or mildly symptomatic. Some develop an influenza-like illness and a few develop a severe acute respiratory illness, both defined by the WHO.[3] Males are affected more than women, while children seem to be less affected. Severe infections occur in only a small minority and case fatality rates are in the region of 0.55% in Iceland to 14.4% in Italy. India has overall a case fatality rate of 2.81%. (Data as on June 7, 2020). Mortality rates are the highest among those older than 65 years of age and those who are affected by other morbidities. Diabetes and cardiorespiratory diseases like heart failure and COPD seem to carry a high risk.[4],[5],[6]

SARS-CoV2 does not restrict itself to the organ of entry but spreads throughout the body. Atypical presentations involve the gastrointestinal tract, the central nervous system, and the cardiovascular system. A remarkable autopsy study has demonstrated that the SARS-CoV2 produces an endothelialitis, microvascular thrombosis, and an intussusceptive vascular angiogenesis that is distinctly different from the pulmonary pathobiology of equally severe influenza virus infection.[7] This has led to the recommendation of early and perhaps universal use of anticoagulation in hospitalised patients with COVID-19. Again very distinct to COVID-19 is the rapidity with which deterioration can set in and the phenomenon of “happy hypoxia” which again is multifactorial, involving not only severe inflammation, micro thrombosis, and endothelialitis but also the stripping of the iron ion from heme thus rendering the hemoglobin molecule incapable of transporting oxygen.[8]

In short, we know much about the virus, its genome, its mode of entry into tissues, the pathobiology, the high-risk groups, and risk factors for severe disease. All these have been comprehensively reviewed by Prof V Kamath and colleagues in this issue of the journal.

What are the things we know that we do not know for certain about the COVID-19 pandemic? The origin of the virus is disputed. It probably is of natural origin, though this is by no means certain. Unfortunately, politics and great power rivalry have muddied the waters and the truth may never emerge.

Despite the explosion of knowledge about the disease, the ideal treatment remains elusive. While the putative mechanism of action of hydroxychloroquine (HCQ) and chloroquine in the treatment of COVID-19 seems convincing, actual and robust scientific evidence has been hard to come by. Again, politics and the need to provide hope have influenced politicians to push for the use of HCQ without proof of efficacy in either the treatment or prophylaxis of COVID-19. Recently, a paper in one of the most prestigious journals reporting increased mortality risk from HCQ was heavily criticised and withdrawn hastily by the lead authors. Soon followed the the RECOVERY trial report from the UK, about the lack of efficacy of HCQ. Less well designed studies from India have reported its benefit in prophylaxis among healthcare workers. There has been great fear of the potential adverse effects including increased mortality from HCQ especially when combined with the macrolides. This was partially debunked in the HYPE study from our own colleagues in Bangalore, who conducted a survey of HCQ users and reported a greater incidence of nonserious adverse events, but no serious adverse cardiovascular effects or mortality.[9] Other anti-viral drugs too have been proposed for repurposed use in COVID-19 but with little encouraging evidence. There is some evidence that remedesivir may shorten the clinical course. Results from the SOLIDARITY multinational multicentric trial, including centers in India, may provide a clearer picture.

Even less is known about the progression of the illness and its transformation in some from a respiratory infection to a hyperinflammatory state characterised by a cytokine storm, and possibly a secondary hemophagocytic lymphohistiocytosis syndrome. We do not know if, when and in whom the transformation occurs from predominant infection to predominant inflammation and how to predict the change. This may underlie the contradictory results from the antiviral drugs efficacy studies as they probably will have no role to play in the later inflammatory phase, when an anti-inflammatory drug may be more useful. Suggested anti-inflammatory drugs have included steroids, the interleukin-6 inhibitor monoclonal antibody tocilizumab. Another MAb itolizumab that selectively targets CD6, a pan T-cell marker involved in co-stimulation, adhesion, and maturation of T-cells has also been approved in India for a multicentric trial in COVID-19. Key to the outcomes of all these trials may be the recognition of the inflexion point between predominant infection and inflammation phases and this may depend on a combination of clinical parameters, biomarkers and scores such as the H score. Ivermectin and colchicine have joined this list of repurposed drugs.[10],[11] Another promising area of treatment has been the use of convalescent plasma and limited evidence suggests that it may be useful. Thus far, all we have are anecdotal reports of benefit.

In the long run, we will need to rely on the production of an effective vaccine and perhaps the development of herd immunity. Despite regular press items about their imminent discovery, the reality is that it may be anywhere from a few months to a year away for an effective vaccine against a highly mutable virus. We then must prove its safety against a disease which may produce its worst effects through excessive immunity and a cytokine storm and finally mass produce and administer it to vast populations.

In parallel with the cytokine storm, there has been a perfect storm of literature on the subject– sometimes changing so rapidly that it is difficult to be sure of the scientific validity and applicability of the available material! Most of the literature understandably has been of a preliminary nature and therefore has had limited peer review. Many of the references below are preprint articles. Letters to the editor are circulated as avidly as original papers, and given as much importance. Aided by the lockdown, there has been an explosion of “webinars” on COVID. Social media is in overdrive and case numbers and fatalities are monitored almost like an India-centric T20 cricket match.

Perhaps even more than the medical impact has been the socio-economic impact-loss of jobs, reverse migration, hunger and the near collapse of many sectors of the economy. Unfortunately, many of these issues seem to have been “forgotten” in the urgency of implementing an almost overnight rigorous lockdown. Memories of the Spanish Flu mortality numbers were mirrored in many of the modelling exercises.

One lives in hope. A related virus SARS which began in November 2002 and spread to a lesser extent than the current virus ended abruptly and without obvious cause by July 2003. Though this time round, the scenario has been clearly worse all over, let us hope this corona virus will follow suit. The medical and nursing professions have always been more callings than mere jobs, and currently we are in the frontlines. Let us pray that we will be able to get a much needed rest sooner rather than later and be able to get on with our work, as doctors rather than warriors-neither heroes nor villains.



 
  References Top

1.
Logan DC. Known knowns, known unknowns, unknown unknowns and the propagation of scientific enquiry. J Exp Botany 2009;60:712-4.  Back to cited text no. 1
    
2.
Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 2020;382:1199-207.  Back to cited text no. 2
    
3.
4.
Yan Y, Shin W, Pang Y, Meng Y, Lai J, You C, et al. TheFirst 75 Days of Novel Coronavirus (SARS-CoV-2) Outbreak: Recent Advances, Prevention, and Treatment. Int J Environ Res Public Health 2020;17:2323. doi: 10.3390/ijerph17072323.  Back to cited text no. 4
    
5.
Available from: https://ourworldindata.org/mortality-risk-covid#the-case-fatality-rate. [Last accessed on 2020 Jun 07].  Back to cited text no. 5
    
6.
Jordan RE, Peymane A, Cheng KK. Covid-19: Risk factors for severe disease and death. BMJ 2020;368:m1198.  Back to cited text no. 6
    
7.
Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020. DOI: 10.1056/NEJMoa2015432.  Back to cited text no. 7
    
8.
Wenzhong l, Hualan L. 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.  Back to cited text no. 8
    
9.
Nagaraja BS, Ramesh KN, Dhar D, Mondal MS, Dey T, Saha S, et al. HyPE study: Hydroxychloroquine prophylaxis-related adverse events' analysis among healthcare workers during COVID-19 pandemic: A rising public health concern. J Public Health Preprint. https://doi.org/10.1093/pubmed/fdaa074.  Back to cited text no. 9
    
10.
Sharun K, Dhama K, Patel SK, Pathak M, Tiwari R, Singh BR, et al. Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19. Ann Clin Microbiol Antimicrob 2020;19:23. https://doi.org/10.1186/s12941-020-00368-w.  Back to cited text no. 10
    
11.
Deftereos SG, Siasos G, Giannopoulos G, Siasos GD, Giotaki S, Gargalianos P, et al. The Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention (GRECCO-19 study): Rationale and study design. Hellenic J Cardiol 2020. doi:10.1016/j.hjc.2020.03.002.  Back to cited text no. 11
    




 

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