EXECUTIVE SUMMARY: 

Over a year and a half into the global outbreak of the COVID-19 pandemic, the repeatedly rising and falling infections rates across countries mean that an end to this worldwide public catastrophe is nowhere in sight. 

Just like in the case of its predecessors SARS and MERS, no treatment regimen is currently accepted as gold standard against the novel coronavirus even as several clinical trials are ongoing. The treatment for COVID-19 currently involves a combination of antiviral and anti-inflammatory drugs. Laboratory studies have shown the promising role of antibody mediated therapeutic strategies in coronavirus infections. Based on the experience with Ebola, SARS, and MERS on the use of convalescent plasma therapy, interest around its use as a therapeutic adjunct in the treatment of COVID 19 grew and quickly fell. Clinical trials have not been able to establish its significant benefit. Presently, anti-virals such as Remdesivir and Favipiravir have received restricted use approval in India based on preliminary clinical data, along with a recommendation to use Dexamethasone in individuals who have lower levels of oxygen. Adjunctive treatment with agents like antihistamines, cholesterol lowering agents, and other anticoagulants are advocated in selected individuals after clinical evaluation.

In the absence of proven effective therapy, the strategy to address an epidemic like COVID 19 fundamentally rests on reducing the prevalence and incidence of infection rates to below acceptable threshold levels. Failing this, the goal of eradication of infection from the population will continue to be an uphill task. Since SARS- CoV-2 is highly contagious, preventive measures such as vaccines and non-pharmacological interventions with historical precedents (largely patterned after the 1918 pandemic of influenza), are being implemented. 

Epidemics of infectious diseases in the past have shown how human behavior and the social determinants of health can influence the natural course of a disease outbreak. The most successful campaigns to address contagious diseases have exploited the synergy between appropriate technology (such as vaccines) and behavioral factors. Given the unique attributes of COVID-19, this paper recommends the adoption of a comprehensive multi-pronged strategy designed to “identify, treat, and trace.” 

In the absence of clear answers on the longevity of immunity conferred by vaccines and natural infection and the emergence of immune-evading variants, the prevention of acquisition of infection continues to be the best way to contain the spread of the virus. Given the intensity and magnitude of the COVID pandemic, it is desirable for the populace at large to accept and implement all of the components of non-pharmacological interventions: use of masks, physical distancing; personal and environmental hygiene with at least greater than 75 percent adherence to ensure success. However, any coercive strategy for implementation of public policy is prone to systemic distortion as well as pervasive evasion. The successful implementation of NPIs depends on careful articulation of non-coercive measures that are nuanced to local contexts and are not blanket decisions with potential socio economic side-effects and only a marginal impact on containing the virus. 

An integrated public health approach is one with a high degree of collaboration and communication among policy makers, implementers, and healthcare providers and professionals. The success of this strategy requires the integration of prevention (vaccination, NPI), detection (surveillance, testing, and contact tracing) and treatment into a continuum of responsive and compassionate care. The foundation of this strategy is “credible treatment” in the absence of which any resource put into prevention activities is an exercise in futility. 

Given the high prevalence of asymptomatic infections and low levels of mortality among symptomatic cases, a more nuanced approach to addressing the epidemic is desirable. The expectation that an extended period of lockdown will help us see the end of the pandemic is increasingly proving to be  naïve. It is slowly becoming clear that lockdowns can at best flatten the epidemic curve and buy necessary time for augmenting health infrastructure and resources.

The ideal response to a pandemic like COVID-19 is one that integrates a foundation of high quality clinical care with appropriate testing, along with broadly accepted epidemic control measures in the form of voluntary, non-pharmacological interventions, and effective vaccination of a critical majority of the population. In India, the COVID response has been characterized largely by inadequate adherence to non-pharmacological interventions and slow vaccination campaigns. Even as science continues to unravel the many facets of the novel coronavirus, the responsibility of taming the COVID-19 pandemic also rests with governments and the general populace alike. 

INTRODUCTION:

Since January of 2020, COVID-19 has caused a global pandemic with millions of infections and deaths. SARS-CoV-2 is a newly described Beta coronavirus that was first noted to cause severe illness in Wuhan, the capital of the Hubei province in the People’s Republic of China. It rapidly evolved into a global pandemic with a large number of infected people.

To date there is no regimen of therapy accepted as “Gold Standard” even as clinical trials on the use of antivirals are currently ongoing. For individuals who develop severe illness and need mechanical ventilation, the current treatment strategy has a poor outcome in terms of the mortality rate. In individuals presenting clinical signs and symptoms due to COVID 19 infection, early administration of a combination of antivirals and anti-inflammatories will lead to better clinical outcomes and perhaps a reduction in viral shedding, thus helping mitigate the epidemic with reduced horizontal spread. It is reported that individuals who have recovered from COVID 19 illness very often have a prolonged recovery path with considerable long-term disability. This needs adequate evaluation. 

Anecdotal experience with treatment regimens for coronavirus infection causing SARS and MERS have not yielded great promise and could not therefore establish any kind of precedent for the current COVID infection induced illness. During the previously described coronavirus outbreaks of serious illness due to SARS and MERS, effective antiviral therapy had not been established. This prompted multiple efforts to understand the mechanisms of infection caused by coronaviruses, elucidating the role of the spike protein of coronaviruses in cellular entry and the role of various antibodies in blocking the pathogenesis of coronavirus infections. There have also been efforts to develop potential therapies (including small molecules) based on the understanding of the structure and pathogenesis of coronavirus infections. Laboratory studies have elucidated the promising role of antibody mediated therapeutic strategies in coronavirus infections. 

Early experience with Influenza outbreaks and Ebola Virus Disease rekindled the interest in the experience with convalescent plasma for the treatment of illness during the “Spanish Flu” outbreak. There have been several trials on the use of convalescent plasma therapy either alone or in conjunction with other therapies for managing illness due to Ebola, SARS, and MERS. Since the first description of COVID 19 infection and increasing anecdotal experience of severe illness exacting a high toll, interest has centered on convalescent plasma as a therapeutic adjunct in the treatment of serious illness due to COVID 19. Clinical trials, however, have not yet established any significant benefit. Moreover, the Government of India dropped the use of plasma for the list of accepted treatments for COVID 19 earlier this year. 

It is important to obtain, as far as possible, comparative data with other regimens of treatment that are either ongoing or complete. Therefore, obtaining high quality data with a controlled trial design is imperative. Currently anti-virals such as Remdesivir and Favipiravir have received restricted use approval in India based on preliminary clinical data, along with a recommendation to use Dexamethasone in individuals who have hypoxemia (lower levels of oxygen). Adjunctive treatment with agents like antihistamines (Famotidine); Cholesterol lowering agents (Statins) and N acetylcysteine and other anticoagulants (Low molecular weight heparin or rivaroxaban) are advocated in selected individuals after clinical evaluation.

As a specialist with decades of experience managing clinical illnesses in immunocompromised patients as well as experience with epidemiology and public health, I believe that it is important to address the unique attributes of this unprecedented public health catastrophe the world is now experiencing. The following are my personal views about a strategy to address COVID in India under the current epidemic conditions.  

IDENTIFY;  TREAT AND TRACE 

SARS-CoV-2 a beta coronavirus has now caused a global pandemic with millions of infections and substantial morbidity and mortality worldwide. The strategy to address an epidemic like COVID 19 fundamentally rests on the goal of eradication of infection from the population, failing which reducing the prevalence and incidence to below acceptable threshold levels is desirable. Since SARS- CoV-2 is highly contagious with no proven effective therapy, preventive measures such as vaccines and non-pharmacological interventions with historical precedents (largely patterned after the 1918 pandemic of influenza), are being implemented. 

NON-PHARMACOLOGICAL INTERVENTIONS (NPI):

SARS-CoV-2 is spread through airborne droplets that can spread the infection from an infected individual to a susceptible individual by inhalation of contaminated air or by transfer through touching a contaminated surface (less common). Prevention of acquisition of infection requires adequate ventilation and an adjunct appropriate form of air filter (properly fitted and used masks) used by the infected and uninfected person as well as meticulous personal hygiene, especially hand cleansing. Using gloves without adequate hand cleansing is ineffective. It is important to understand that the protection afforded by gloves does not last beyond 30 minutes. A sanitary environment by appropriate disinfection of contaminated surfaces is equally important. Ensuring clean air (adequate ventilation); clean hands (personal hygiene) and a clean environment to reduce the risk of infection and spread is both an individual and a collective societal responsibility.

It is quite clear from the history of epidemics of infectious diseases that human behavior and the social determinants of health have a strong influence over the natural course of epidemics. The most successful campaigns to address contagious diseases have exploited the synergy between appropriate technology (e.g.: vaccine) and insightful determination of human factors, engineered as a comprehensive multi-pronged strategy. Given the intensity and magnitude of the COVID pandemic, it is desirable for the populace at large to accept and implement all of the components of non-pharmacological interventions: physical distancing; personal and environmental hygiene with at least greater than 75 percent adherence to ensure success.

Humans, by nature, are social beings. They are fiercely independent and resent external control. The demands of NPI run counter to this nature and are probably unrealistic for any reasonable length of time. The present conditions of the COVID pandemic are such that “state” agencies consider it necessary to resort to extraordinary measures such as a “lockdown”. It is difficult for state authorities to refute the logic of this strategy, given the historical precedent of the 1918 global pandemic of Influenza.

Implementation of NPI

What started out as a limited time “broadly accepted” intervention has evolved into a more coercive “grudgingly accepted” intervention with a debate about the endpoint and the risk benefit analysis. The intensity and magnitude of the “lockdown” is unprecedented in its social impact and the staggering economic cost, borne disproportionately by the most vulnerable. The socio-economic cost escalation threatens to overwhelm and negate societal acceptance of the sacrifice needed to save lives. By any analysis, the principal benefit of the lockdown is in flattening the epidemic curve and mitigating the risk of overwhelming health care resources due to an acute unmanageable crisis than actually “eliminating” the contagion. The timing of the lockdown was unable to pre-empt the introduction of the contagion into our communities. The debate about whether or not we are in the “third wave” of the epidemic is largely academic at this point. The key question is what would make NPI a viable strategy?

The Coercive Strategy: 

Any coercive strategy for implementation of public policy is prone to systemic distortion as well as pervasive evasion.

1. Evasion: There is an incentive for people to escape adverse impacts of policy. With reference to COVID, individuals try to avoid testing and labelling due to adverse consequences such as stigmatization and quarantine at home or institution. This disincentive has an inherent compounding influence due to the lack of effective therapy and the very real risk of suboptimal healthcare under the present circumstances.
2. Systemic Distortion: The implementers of the policies prescribed by the state have shown a predilection towards a blunt sledgehammer approach rather than an appreciative and sensitive minimalist  (surgical precision) intervention approach. This has resulted in complaints of “excesses” as well as allegations of corruption in allowing exemptions from the lockdown etc. There are allegations of both undertesting as well as selective targeting of groups for testing. Whether these distortions are a consequence of actual policy, overtly stated or unspoken, or merely overzealous implementation by officialdom at multiple levels based on interpretations of perceived preferences of the elite, is difficult to establish. To add to all of these is the inherent inadequacy of an overburdened and chronically under resourced public health infrastructure trying to cope with an unprecedented challenge. 

The Non-Coercive Strategy: 

The nihilist will dismiss this strategy as utopian. Nevertheless, faith in the inherent wisdom of self-interest of the majority in open societies has historically triumphed over authoritarian regimes. Only an open society can overcome the weight of accumulated systemic contradictions in societal hierarchy and control structures through necessary and continuous reform [1]. . The key attributes of a policy that makes NPI more palatable are the following:

1. Tangible rather than abstract benefits:

1. Assurance that any inconvenience caused to the most vulnerable is addressed in real time.
2. Prompt access to reliable testing and follow up.
3. Assurance of access to credible treatment with minimal inconvenience and cost.

2. NPI that is modulated and nuanced with relevance to local conditions.
3. A clearly articulated and implemented strategy of public health measures that integrate early detection with testing and treatment (see next section).
4. Vaccination 

INTEGRATED PUBLIC HEALTH APPROACH

“Not by Bread alone” Humans have an indomitable spirit that allows them to overcome any challenge and willingly engage in battle. The need of the hour is to tap into this enormous resource of hope that COVID can be and must be conquered. Success of this strategy requires integration of Prevention (Vaccination, NPI); Detection (surveillance, testing, and contact tracing) and Treatment into a continuum of responsive and compassionate care. The foundation of this strategy is “Credible Treatment” in the absence of which any resource put into prevention activities is an exercise in futility. Quite predictably, testing efforts encounter fierce resistance.

Treatment

The absolute prerequisite for any treatment is compassion and equity in access. It took us (healthcare professionals in particular) many decades to understand and appreciate the superior therapeutic efficacy of “palliative” care compared to “aggressive” medical care of many cancers. In the context of COVID, it is imperative to guard against the perception of assured benefit from regimens “recommended” by health agencies as being “proven” in efficacy. As an advocate of salutogenesis (promotive health) and participatory action strategy in health, I feel it is our responsibility to communicate to our partners in health the current scientific evidence to facilitate an informed choice. Where evidence of proven therapy is lacking, it is necessary to offer alternatives, the most desirable being ethically and scientifically sound clinical trials. The added advantage of such clinical trials is reinforcing the treating clinician with the experience of other capable professionals who can assist and supervise the provision of high quality health care and also generate evidence for greater public benefit. High quality treatment requires adequate infrastructure (hospitals that have adequate space, running water and clean toilets; PPE; medications; medical instrumentation: diagnostic laboratories and test reagents) as well as trained personnel who are provided with all necessary implements in real time. The information age has facilitated rapid dissemination of knowledge of best practices. However, translating such knowledge into actual practice requires a substantially greater investment in resources, urgently! That we have fallen short of providing our frontline personnel adequate PPE with unacceptable outcomes is tragic. Needless to say, such a state is not reassuring to anybody contemplating treatment at such facilities.

Treatment sites:

Institutional: The advantage of specialized center institutionalization, whether special quarantine units or acute care in a dedicated hospital, is the efficiency of concentration of resources in specialized approaches. The secondary advantage would be avoiding cross infections of non-COVID patients in general hospitals due to nosocomial transmission. The possible concern of concentrating large numbers of COVID patients in geographically restricted areas is the risk of cross infections/superinfections of individuals. In some infections a previously infected person can be reinfected/superinfected by a heterologous strain of the pathogen acquired from another infected individual. The two distinct populations can then mix and reassort to allow the emergence of a population with attributes acquired from both of the parent populations. This has been seen multiple times in infections such as HIV or CMV and also occurs quite frequently in nature with multiple different strains of influenza viruses mixing and reassorting in birds and pigs.

The significance of such reassortment in viral populations is the possible emergence of either enhanced virulence, enhanced replication, or resistance to antiviral agents or any combination thereof. Many decades ago, Paul Ewald suggested that all populations of living organisms always evolve strategies for perpetuation of the species regardless of consequences to the host. [2] Stuart Kauffman’s theories of life forms being autocatalytic and auto-poetic [3]. suggest a mathematical inevitability of population expansion through replication as the primary phenomenon. Any pathogen population is agnostic towards outcomes in the host, its primary imperative is perpetuation of the species. For many respiratory pathogens, the strategy best suited for perpetuation of the species is replication and transmission without immediately killing the host, that a minority of infected hosts develop fatal disease appears to be more a consequence of the host immune response as we see in Mycobacterium tuberculosis and COVID. 

Paul Ewald further suggests that “virulence” of a pathogen as manifested in host outcomes may in part be influenced by behaviors in the human population. Inferentially, if large numbers of infected individuals allow very efficient transmission of the pathogen by close proximity etc, one would anticipate the emerging populations of the COVID virus to use reassortment as a means to preferentially increase the rate of replication and transmission with immediate elimination of the host being a constraint on transmission to a new host. The consequences of such a phenomenon make increased transmission efficiency and higher replication mathematically inevitable. 

For COVID 19 the concern is that enhanced replication with greater viral loads probably contributes to higher mortality in infected individuals. A further concern is that SARS- CoV-2 may actually represent a population with a very high replication rate and therefore this viral quasispecies [4] may not be amenable to treatment with a single antiviral agent alone, thus requiring combination antivirals for effective viral control and prevention of emergence of resistance. 

Domiciliary: The obvious disadvantage of domiciliary quarantine and care is that decentralized resource application is inherently less efficient and in the event of need for critical care, impractical. The clear advantage would be greater convenience and comfort for individuals in their own homes/communities as opposed to institutionalization. Since all household contacts have already been exposed to the index case there probably isn’t any significantly greater concern for household transmission. In circumstances where critical care is not needed and especially if effective medication can be used domiciliary care obviates all the concerns about cross infections from other institutionalized infected persons as discussed in the previous section.  

Testing

Clinical testing for SARS- CoV-2 currently relies on detection of the virus in clinical specimens utilizing nucleotide amplification by PCR, or detection of antigen (POC). The acceptance of testing is tied to perceptions of reliability as well as possible benefit accruing from access to early curative treatment. Conversely the barriers to acceptance are the absence of proven therapies and the very real possibility of stigmatization and involuntary restriction of personal freedom. In a coercive testing environment, there is an incentive for either complete avoidance of testing or using unconventional avenues of testing where it is possible for individuals to conceal both the act of testing as well as the results. For improving the acceptability of testing, it needs to be voluntary and clearly tied to tangible benefits with mitigation of risks described. 

The extant and access to testing are also influenced by policy regarding who and how much to test, as well as policy implementation with a systemic incentive or lack thereof to promote testing. Policies surrounding testing influence precision in quantification of the size and character of the epidemic. A policy of very restrictive testing may underestimate the true number of infected individuals and also reduce the probability of early detection of a problematic index case or localized clusters with consequent loss of opportunity for effective epidemic control intervention in a timely manner. A completely uncontrolled access to a liberal regime of testing is wasteful of resources and sometimes creates avoidable distress due to inappropriate testing, particularly a positive test in asymptomatic individuals imposing undue restrictions of personal freedom quite apart from the rare albeit very real possibility of a false positive test. It is important to acknowledge that at the current level of understanding it is unclear if a positive test in an individual who has clinically recovered translates into an actual risk of transmission of infection to others.

Contact Tracing

In a highly transmissible infection like SARS- CoV-2, contact tracing and testing are invaluable tools of epidemic control. Contact tracing does, however, raise concerns about privacy of the index case as well as contacts. To be effective, privacy concerns need to be addressed with sensitivity, particularly when newer tools such as cellular phone contacts and or social media activity are included as strategies to enhance contact tracing. Done inappropriately, contact tracing can lead to stereotyping of distorted perceptions of  communal behavior. Contact tracing when done well with appropriate safeguards, augmented with powerful data processing and analytic tools such as geospatial mapping integrated with other epidemiologic data, allow triangulation of all sources of relevant information with powerful insights into epidemic characteristics and possible innovations in epidemic control. Protection of civil liberties and privacy cannot be overemphasized if the hazard of active and systematic concealment of COVID is to be prevented.

Early Detection

Early detection facilitates timely epidemic control interventions. The key tools for early detection are surveillance integrated with testing. Whether surveillance is laboratory based (passive surveillance) or population based is predicated on the type of problem being evaluated. In the context of a large pandemic like COVID 19, multiple methods such as syndromic surveillance integrated with testing and tracing would be most cost effective. 

A high level of health literacy in the population through effective educational campaigns is potentially helpful in early reporting of conditions that need immediate investigation (active surveillance). Currently sero-epidemiologic studies based on antibody testing for SARS- CoV-2 are providing useful prevalence data. Targeted surveillance and testing of high risk individuals based on epidemiologic factors such as travel to high prevalence areas or contact with infected individuals provides necessary information for intervention as well as measuring the effectiveness of epidemic control measures. Random population testing is a tool used to determine community level prevalence and transmission.

The Identify; Treat and Trace strategy is predicated on growing scientific evidence that SARS-CoV-2 maybe susceptible to the currently in-development antiviral agents with an acceptable safety profile and that early treatment apart from reducing mortality and morbidity will also reduce horizontal spread and help to contain the epidemic. For best results in individual patients, prompt recognition and therapeutic intervention in the early stages of illness are critical. 

COVID-19 clinical course of illness 

The first phase of the COVID-19 infection involves an incubation period of variable duration, with a median of 5.1 days. The second is an acute or mild phase that most commonly includes flu-like symptoms like cough, fevers, and myalgias, but can also include gastrointestinal symptoms. Some patients progress to an ARDS hyperinflammatory phase that is often marked by dyspnea, tachypnea, and hypoxemia. The respiratory viral load rises before the onset of symptoms and peaks around the onset of symptoms. It declines over the first week. Severe cases have higher viral loads compared with mild cases. Prolonged viral shedding in severe and mild cases is reported. [5].

Identify 

Early Identification is key to optimum benefit from treatment. It is necessary to identify as quickly as possible those individuals who are candidates for treatment. Until rapid testing using point of care technology becomes widely available it may be necessary to institute treatment based on syndromic identification of presumed COVID 19 illness.

Individuals presumed to have COVID 19 illness may be additionally risk stratified for urgent transport to inpatient treatment by screening for high risk attributes such as raised CRP, LDH, Ferritin and low lymphocyte counts. Advanced age and concurrent hypertension, diabetes, renal failure, lung disease, heart disease or other chronic illness also increases the risk profile of individuals. 

There is an urgent need to implement a strategy of ensuring that all individuals confirmed to have COVID 19 illness are provided appropriate early antiviral treatment and in appropriate clinical conditions other interventions such as anti-inflammatory treatment, prophylactic anticoagulation, adjunctive treatment approaches such as statins and where necessary critical care support with high flow oxygen and/or support with ventilator/pressor etc.

It is clear from current data that a large majority of the individuals with SARS-CoV2 infection are asymptomatic and at least some of the milder illness may be managed with appropriate home care, thus optimizing resource utilization. The imperatives of reducing viral transmission dictate a very liberal policy of antiviral treatment of even minimally symptomatic individuals to ensure that “Treatment is Prevention” is successful. 

Treat

Treatment is Prevention! This paradigm is well proven by evidence from the HIV epidemic. For reducing the risk of transmission, it would be critical to intervene early enough and use antiviral agents that rapidly reduce the viral load and quantity of virus shedding. It is clear from studies of transmission dynamics that the pre-symptomatic rise in viral population is most significant in the 2 days prior the onset of illness.

At the current time there is scientific evidence of possible benefit from multiple regimens for treatment particularly if it is instituted in the early stages of infection. Clinical trials with more effective regimens are desirable.  

Trace

An intensive tracing strategy will assist in rapid identification of COVID illness at an early stage as well guide appropriate epidemic control interventions such as targeted testing with isolation of infected individuals to limit the spread. In view of the rapidity of spread of SARS-CoV-2 in the vulnerable population, innovations in tracing such as digital methods along with strong data analytics is desirable. Expeditious investigations of clusters along with contact tracing are invaluable.

CONCLUSION

The ideal approach to COVID epidemic response is integrating a foundation of high quality clinical care with appropriate testing and epidemic control measures that provide broad acceptance of voluntary, non pharmacological interventions and effective vaccination of a critical majority of the population. In India, the COVID epidemic response has been characterized largely non pharmacological interventions and very slow vaccination campaigns. 

Given that 80 percent of all infected persons are asymptomatic and of those testing positive, less than 4 percent have a fatal outcome, a more nuanced approach to addressing the epidemic is desirable. There is an almost unreal and naïve expectation that the lockdown extended for a long enough period of time will provide the principal solution. There is insufficient recognition or acknowledgement that the lockdown can at best flatten the epidemic curve, buying necessary time for building crucial, credible health care systems by augmenting infrastructure and human resources. 

The scientific and technical response (largely non state entities) to the epidemic in areas of diagnostic technology, vaccine and therapeutic options have far outpaced the cumbersome state regulatory apparatus in place, using legacy processes to evaluate newer modalities. The pandemic has exposed the stark and tragic inadequacy of the health care infrastructure and human resource capacity to respond to this unprecedented public health emergency. The socio-economic consequences of the lockdown threaten to cause greater damage than the current state of the epidemic. The chronic systemic neglect of public health, environmental degradation and complete disregard for the role of animals in human health needs a transformational paradigm shift towards the goal of “One Health”. COVID 19 is a warning wakeup call from nature. We ignore it at our own peril.

Dr. Vijay V. Yeldandi, M.D., FACP, FCCP, FIDSA
Head Infectious Diseases and Public Health SHARE INDIA
Clinical Professor of Medicine and Surgery University of Illinois at Chicago

  [1] (The end of History and the Last Man by Francis Fukuyama, Freepress 1992)

  [2] (The evolution of virulence by Paul W. Ewald. Scientific American; April 1993; 86-93.)

  [3] (A world beyond Physics. The emergence and evolution of life, by Stuart A. Kauffman. Oxford University press 2019)

  [4] https://data.worldbank.org/indicator/SH.XPD.OOPC.CH.ZS?locations=IN (Viral Quasispecies by Manfred Eigen Scientific American Vol 269 # 1, July 1993 pp 42-49)

  [5] Meyerowitz EA, Vannier AGL, Friesen MGN, et al. Rethinking the role of hydroxychloroquine in the treatment of COVID-19. The FASEB Journal. 2020;34(5):6027-6037. doi:10.1096/fj.202000919.

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