Horace Greeley said once, “Common Sense is very uncommon!” This is all about the recently published interim report of the extended solidarity trial published in NEJM on 2 December 2020.
The article “Repurposed Antiviral Drugs for Covid-19” reported that antiviral drugs (hydroxychloroquine, remdesivir, lopinavir, interferon) failed to win the race when compared to the placebo, in an assigned group of patients. WHO does not trust drugs like ivermectin, Doxy etc. Many senior microbiologists, intensivists would laugh it out arguing that these drugs would only help in controlling parasitic infestations. Harrington et al., therefore, appropriately chose a title (“A Large, Simple Trial Leading to Complex Questions”) for their argumentative editorial. They wrote- “No intervention acts on two persons in an identical fashion: patients present with different risk factors, are treated in different health care settings, and begin treatment at different stages of illness. In particular, the effectiveness of an antiviral agent can depend on whether a patient presents early (during viral pathogenesis) or later (when immunopathologic conditions or other complications may be more important).” They also pointed out the usefulness of the result of the ‘solidarity trial’ in denying the role of antiviral agents in patients who have entered the second phase of illness described as the cytokine storm. Rightly, they asked “what is a more effective timing for the use of remdesivir, and should it be used in combination with other agents? How is the course of hospitalisation affected by the type and level of care delivered in particular settings?”
This is the question of common sense: why not to use an antiviral agent when the virus is replicating? What role can they play once the war for life has entered a phase where the virus itself has been cornered?
This is the argument extended in the recovery trial against an early use of steroids, so that, not to time it with the viral replication phase. The results of the Recovery trial, however, support the use of the steroids in the late 1st and 2nd week when evidence of lung involvement is evident by rising oxygen requirement and falling SPO2 <95%. In various articles, it has been shown that viral replication in the upper respiratory tract, to a larger extent, is immunologically inert. Once the virus climbs down to the pneumocyte type II cells, its pathological journey starts and gets reciprocated by the dysregulated immunological response sequentially leading to diffuse alveolar damage, inflammatory infiltrates, microvascular thrombosis resulting in a simulating picture of adult acute respiratory syndrome. No wonder, classical findings of rising levels of interleukins 10/6, TNF α, evidence of lymphocyte exhaustion and lymphopenia, come almost hand in hand.
Drugs like Doxycycline and Ivermectin have been used rampantly in every nook and corners of northern-western India. Interestingly, ICMR is playing once bitten and twice shy. Because India was the first country that boldly adopted HCQ prophylaxis and was thoroughly criticised by Americans. The criticism came in the wake of deaths reported in Covid patients receiving HCQ. The analysis says, HCQ and also azithromycin are the potential drugs that may adversely affect the conduction system; at least 60-70% of patients with late-phase Covid, may have myocardial edema, making them a substrate for arrhythmia. Cautious use is needed. It is the CDC that allows almost no medicines in the first week of illness. India has improved in its recovery rate, remarkably from 60% to 95%. How? I keep on talking to many of my friends who were partying hard, and one after another, the whole group became Covid positive. They consulted a local physician and got a prescription of Ivermectin 24 mg, Doxy 100 mg twice a day, Zn, vit D, vit C and even favipiravir, as soon as the report was received, and recovered completely. Many patients presented with anosmia. Those who were treated with the Ivermectin, recovered within 7-10 days. I came to know about this in March but experienced it now when I became Covid-19 positive. Globally, people are experiencing good results of ivermectin use.
Therefore, there is evidence that many repurposed antivirals, antiprotozoal, anti-bacterial drugs have hidden talents to combat Covid-19 at least partially. These drugs are less harmful when one compares them to the 5-10% chance of having serious lung, heart, kidney and brain complications. Probably they need cardiac care, LMWH or antiplatelets, statins for a longer period. In nutshell, patients who recover the second or third phase, obviously are not the fittest to survive.
Jeon et al wrote, “Among the 48 drugs that were evaluated in our study, 24 drugs showed potential antiviral activities against SARS-CoV-2, with IC50 values in between 0.1 and 10 μM, few of them are as follows- tilorone, cyclosporine, chloroquine, mefloquine, amodiaquine, proscillaridin, salinomycin, ouabain, cepharanthine, ciclesonide, oxyclozanide, anidulafungin, gilteritinib, berbamine, ivacaftor, bazedoxifene, niclosamide, and eltrombopag.”
It is common sense that the first 5 days are of viral replication and subsequently a 10% chance of having an immunological vicious storm. Conversely, it is logical to use repurposed antiviral drugs when the virus is replicating and steroid only when the body is brewing cytokines, to bring a storm and lymphocytes in the backfoot.
Vaccines are illusionary, in view of the fact, the duration of trials has been accelerated too fast. Tinkering with the immune system is always a double-edged sword. Oral Polio was introduced in the 70s and fear was expressed about its association with autism. It took >20 years to convince the government in the US. Till now, the flu vaccine is not considered the safest and efficient vaccine for various reasons. We must remember that natural infection has failed to ensure long-lasting immunity. There are articles suggesting that the virus may co-exist with IgG in patients asymptomatic or mildly symptomatic patients.
The writer is a Pediatric cardiologist, Manipal Hospital, Delhi.
