Fighting Corona: Look at local data, not a national curve

An RT-PCR test takes several hours for the result to be available. We cannot make a patient who comes with a non-Covid-19 problem wait till that result is available.

K. Srinath Reddy (Portrait by Shyam Kumar Prasad)
K. Srinath Reddy (Portrait by Shyam Kumar Prasad)

There has been a surge in report of asymptomatic SARS-CoV-2 infected cases from across the world. Dr Srinath Reddy, president of the Public Health Foundation of India and a member of the WHO committee steering the SOLIDARITY trial sheds light on the implications of this and other Covid-19-related hot topics in an interview with Sarthak Ray. Edited excerpts:

A senior ICMR researcher said that 80% cases could be asymptomatic. Is ‘flattening the curve’ even possible in such a scenario?
The ICMR protocols for determining who should be tested have changed over time, becoming less restrictive, but not including the general population at any time. From the cumulative numbers of all persons tested, a large proportion of the persons who were found to be positive for viral presence by the RT-PCR were classed as asymptomatic. Some of them could have developed symptoms later on, if they were tested in the pre-symptomatic phase. Since all antigen-positive persons are isolated and followed up, it should be possible to ascertain what proportion of these remained asymptomatic for at least two weeks after the test. Some could have been ‘pauci-symptomatic’, that is, with minor symptoms that were not reported or recorded. Some others could have had symptoms like loss of smell or loss of taste, which have only been recently added to the recognised symptom list by the US Centers for Disease Control. However, it is also likely that a large number were truly asymptomatic and remained so, as is also being reported from other countries.

We cannot do a population wide ‘search and sieve’ testing to detect all asymptomatic persons who neither have travel exposure nor report contact history but might still be infected. We can do a random sample testing of the population to determine the extent to which such persons are present in the whole population, at the time of survey. These numbers will change over time. There may also be a high proportion of false positive reports if asymptomatic persons are tested in the general population. Nevertheless, the protective personal behavioural triad of physical distancing, hand washing and face masks offer the best protection against the spread of infection from asymptomatic virus positive persons.

The shape of the curve related to the number of infected persons should be assessed by comparing case numbers obtained while using the same eligibility criteria for testing, and after adjusting for day-to-day variations in the numbers of tests performed. If the eligibility criteria have remained the same over the past 10 days, and the testing number adjusted curve is steadily shifting to a lower slope, that trend may be taken as evidence of a slowdown in transmission. During lockdown, even asymptomatic cases (tested and untested) would have been in enforced isolation. The real challenge will come after the lockdown ends, when undiagnosed infected persons may become mobile in the community. We must continue the triad of general protection measures till the tested positive cases are nil, and no symptomatic cases emerge for a month. The assessment must be on a district-by-district basis, with situation-specific decisions based on local data, and not on a single national curve.

With such a high level of asymptomatics, would testing alone give us the true picture? The Santa Clara and Los Angeles studies relied on antibody testing.
Clearly, it is not feasible to conduct widespread RT-PCR testing in a large population sample. Even pooled testing will not be feasible in large surveys which involve throat swab collection, due to logistical challenges. Antibody testing, as done in Santa Clara and Los Angeles, is far more feasible, but may yield a large number of false positives in a population survey. Still, a random sample population survey can be conducted in each district, with antibody testing, to get an estimate of the comparative prevalence of asymptomatic positives.

In such a scenario, what needs to be done?
We have to use a combination of strategies. Symptom-based and contact-based antigen testing must be supplemented by symptom-based syndromic surveillance for influenza like illness through house-to-house visits by frontline health workers supported by community volunteers. Random sample surveys with antibodies will give us additional information on persons without symptoms. It is unrealistic to think we can catch every single infected person—capturing both symptomatic and asymptomatic virus visited persons—in our large population. We must try to identify and isolate as many as we can, during the infective period, and rely on the protective triad of personal safety measures to prevent spread in the general population. Mass testing was not adopted as the prime strategy in Vietnam, which has Asia’s best record of containment. We too must be adept in using multiple methods of detection and several measures of containment.

WHO is warning against ignoring the possibility that the virus could become endemic. China is reportedly seeing a second wave … What does this mean for us?
This virus came from our forests and will stay on this planet, perhaps as a seasonal visitor to different countries at different times of the year. We, in India, too must assume that it will be a recurrent threat. A vaccine is needed for protection, especially for the elderly and others with pre-existing health disorders. Will the virus remain stable or will it mutate to more or even less dangerous forms? Long-term prospects of mass immunity, acquired through exposure to the virus or a vaccine, will also depend on whether and for how long the virus will remain stable. We have many uncertainties about the behaviour of this new virus. However, with science and social solidarity, we can overcome its challenge even if it stays with us.

Does plasma therapy represent a cure? Or is it, at the very best, a disease management tool in severe cases?
Passive antibody therapy has been used in seriously ill patients with other viral diseases, with some success. Even in Covid-19, there are a few anecdotal reports of success. They were mostly based on use for compassionate indications. Large-scale trials have started in some countries.

However, there are uncertainties about the nature and duration of acquired immunity. Do the antibodies provide full or partial protection? Or is immunity against this virus based on cell-mediated immunity, the Gemini twin of the immune response? Even if humoral immunity mediated by antibodies is the key protective response, what levels must be attained by the infected donor to be protective for the recipient? Also, how long will this protection last? Despite these uncertainties, passive antibody therapy has sufficient scientific rationale to be tried in clinical trials and, even as they are being completed, to be tried for compassionate use in very sick patients.

Dr Robert Gallo has talked of harnessing OPV’s innate immunity activating capacity… Is there any trial planned for India?
The polio vaccine is a non-specific booster of innate immunity, like the BCG vaccine. It may have a protective effect, through this mechanism, as suggested by Russian research of half a century ago. Does it also block the Covid-19 virus through gut immunity? Some patients of Covid-19 present with diarrhoea, and the virus has been isolated from stool samples. Does the polio vaccine prevent the gut entry of the Covid-19 virus through the intestinal immunity that it is known to promote? That is speculative. A non-specific potentiation (increase in strength) of innate immunity is, however, both plausible and possible.

I am, however, not aware of such a trial starting in India. Perhaps the health minister, Dr Harsh Vardhan, who played a prominent role in the eradication of polio in the country through the polio immunisation programme, can lead such a trial.

HCQ, remdesivir, etc, have seen contradictory research reports emerge around them… What are the underlying factors? How do we get more clarity on these?
Clinical trials, for evaluating drugs, require randomisation of patients to active and control groups, comparing the investigational drug with current standard therapy. They also need a large enough sample size to detect a clinically meaningful protective effect. It is necessary to show impact on major clinical outcomes such as recovery time from serious illness or improved survival with lower mortality in the active group. The trials so far have been inconclusive because of small sample sizes, non-event based intermediate outcomes like viral load, variable drug combinations and non-comparable dosage schedules. Larger, more standardised and clinical event based trials are now underway, including the WHO led multi-country trial SOLIDARITY, which evaluates several treatment options. As Louis Pasteur advised his young research fellows, “Keep your enthusiasm, but let strict verification be its constant companion”.

New guidelines talk about home isolation of very mild cases… Can symptoms progressively worsen? In such a case, what does this mean for mortality?
There is at present no evidence-based specific treatment for Covid-19. The care is supportive, and is based on the clinical severity of the disease. Many of the infected persons have no symptoms or mild symptoms. They can be managed well at home. Primary healthcare teams should regularly visit the homes to provide advice. Now that tele-consultations are permitted, medical advice can be obtained even by phone. If the condition worsens, the person can be transferred to a nearby designated hospital. Home-care for mildly symptomatic cases will also create space for the more serious patients and reduce the pressure on the healthcare providers. That may, in fact, save more lives by enabling better and more focused care for serious patients. Please also note that hospitals are also places where patients can catch other infections, called nosocomial infections. Serious patients have to be in hospitals for care and protection, but why should mildly symptomatic persons subject themselves to that risk?

The govt has directed hospitals not to ask every patient to get tested for Covid 19 before offering treatment. Given the spectrum of symptoms now associated with SARS-CoV-2 infection, and the shortage of proper PPE for healthcare workers, what, in your opinion, could be the best recourse?
Under ideal circumstances, we should know the viral status of every patient. However, that is not possible for reasons that go beyond the availability of testing kits. An RT-PCR test takes several hours for the result to be available. We cannot make a patient who comes with a non-Covid-19 problem wait till that result is available. Also, the fact that a patient who tests negative today can get infected two days later does not provide a non-Covid warranty for the revisit a few days later. We have to screen for Covid-19 symptoms, fever and history of close contact when a person first registers at the outpatient service, like was done at airports. Those who do not pass that screening may be tested. Even sample collection for antigen testing requires PPE for the tester. So, the shortage of PPEs is not an argument for mass screening of all non-Covid-19 patients seeking healthcare.

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