Science

Will India’s devastating COVID-19 surge provide data that clear up its death ‘paradox’?

A team of researchers in rural Maharashtra state in India visits houses to track the spread of COVID-19 over time.

Raja Sengupta

Science’s COVID-19 reporting is supported by the Pulitzer Center.

VADU, INDIA—At a tiny rural hospital about 1 hour’s drive northeast of Pune, India, in early April, a team of workers loaded an SUV with coolers, syringes, vials, thermometers, and electronic tablets. They drove 20 minutes to the village of Karandi, slowing to pass caravans of migrant sugarcane cutters in ox carts. They spent more than 1 hour taking blood samples at a cluster of houses shared by three generations of one family. Later, the team would scour the blood for antibodies that indicate past run-ins with COVID-19.

Girish Dayma, who helps oversee this research program run by a satellite of King Edward Memorial (KEM) Hospital in Pune, says the team’s surveys to date show that up to 40% of these villagers have antibodies for SARS-CoV-2, the virus that causes COVID-19. “When we started this serosurveillance, it was thought that the rural area was not much affected,” Dayma says. “The data are very much important to convince the policymakers that we need interventions in rural areas.”

Studies like KEM’s are also crucial to tracking India’s pandemic and determining whether, as some researchers believe, the horrific death toll is actually lower than expected from the rate of infections. Good data are scarce. Yesterday, hundreds of Indian researchers signed an appeal for the government to release what it has and collect more. “While new pandemics can have unpredictable features, our inability to adequately manage the spread of infections has, to a large extent, resulted from epidemiological data not being systematically collected and released in a timely manner,” they wrote.

The current COVID-19 surge, which first overwhelmed Maharashtra state and now is rolling through the rest of India, has humbled those who thought the country had bested the disease. In early February, with cases dropping below 10,000 per day, restrictions were dropped, political leaders staged massive rallies, and masks became a rare sight in many crowded locales. Some researchers even suggested that, because nearly half of people in several places had antibodies indicating previous infection, India might be approaching herd immunity.

But the devastating surge starting in late March gave the lie to that idea, with 10,000 cases alone in hard-hit Pune the day the KEM team visited Karandi. A few weeks later, India topped 350,000 cases in 1 day, setting a new world record. By then, many hospitals had become overwhelmed.

Debate has swirled over whether new variants or a waning of immunity are at work in the current explosion of cases, just how many people have become infected, and—most contentious—how many have died. Official figures suggest that, compared with other countries, India has recorded relatively few deaths given its count of COVID-19 cases. “We have been trying to find explanations for the low number of deaths in India since last year,” says a signatory of the appeal, microbiologist Gagandeep Kang from the Christian Medical College. “When we do not even have access to reporting of death by age, gender, and location, how do we construct a hypothesis or design a study?”

“The ‘Indian paradox’ really is quite puzzling,” says Prabhat Jha, an epidemiologist at the University of Toronto. Explanations range from gross underestimates of deaths to demographic effects, environmental factors like abundant vitamin D from the Indian climate, and the country’s high percentage of vegetarians. But now, with hospitals struggling to find enough oxygen for their COVID-19 patients, crematoria running out of wood to burn the deceased, and media reports of intentional undercounting of deaths to make the current deluge look less dire, the seeming paradox may be disappearing.

In India’s first wave, which ran from June through November 2020, cases never went above 100,000 per day. Hospitals struggled to provide personal protective equipment for staff—the KEM intensive care unit in Pune for a time relied on raincoats instead of proper gowns—but few were overwhelmed with severely ill patients.

A seeming paradox

Even as millions have fallen ill in India, researchers have struggled to explain why mortality rates there are lower than in other countries.

SouthAfricaItalyIranUnitedKingdomBrazilUnitedStatesIndia1.11.82.72.93.03.42.90123Deaths per 100 cases050150250350,000March2020August2020January2021April2021Daily new cases7-day rolling average

(Graphic) K. Franklin/Science; (Data) Our World in Data COVID-19 Data Repository via Johns Hopkins Center for Systems Science and Engineering; Johns Hopkins Coronavirus Resource Center

Even then, it was hard to nail down the magnitude of infections and death. “We rely on reporting of positive cases, which obviously leaves big gaps because a large percentage of people are asymptomatic, and a lot of people don’t have access to testing,” says Soumya Swaminathan, chief scientist at the World Health Organization and a native of India. For mortality, she notes that only 20% of death certificates list a cause.

The notion of an Indian paradox surfaced as early as April 2020, and the health minister has repeatedly noted the low death rate, but it largely remained speculation. One of the convincing studies looked at 12 of the most populous Indian cities—including New Delhi, Mumbai, Pune, Kolkata, and Chennai—and found something was different about India’s first wave. Led by Jha, the study looked at data from nearly 450,000 people who sought COVID-19 tests between June and the end of 2020. It found that seropositivity over time jumped from about 17.8% to 41.4%. Factoring in 30% underreporting of COVID-19 deaths in these cities—the worldwide average—the team calculated about 41 deaths from COVID-19 per 100,000 population, they reported on 24 March in a preprint on medRxiv. That rate is less than half the corresponding U.S. figure of 91 per 100,000 in 2020, according to the U.S. Centers for Disease Control and Prevention.

Other studies, however, suggested the demographics of the outbreak could explain the anomaly. One thorough study looked at reported COVID-19 cases and deaths last spring and summer in two southern Indian states, Andhra Pradesh and Tamil Nadu, that are home to about 10% of the country’s population. The researchers reported in the 6 November 2020 issue of Science that older adults—the group at greatest risk of dying—accounted for relatively few of India’s infections.

One reason is that India’s population skews young. In 2011, the most recent census year, 45% of the population was 19 years or younger, and only 4% were 65 or older. (In the 2010 U.S. census, 24% were 18 or under and 13% 65 or older.) And infection rates in the old were unusually low, perhaps because those who survive to old age in India are often wealthier and were better able to socially distance, the researchers argue. As a result of both factors, only 17.9% of the deaths in the study were in people 75 years of age or older, compared with 58.1% in that age bracket in the United States.

That doesn’t mean COVID-19 is any less deadly in India, notes the paper’s first author, Ramanan Laxminarayan, an economist and epidemiologist who founded the Center for Disease Dynamics, Economics & Policy in Washington, D.C., and New Delhi. His study reported that, unsurprisingly, increasing age was accompanied by a steady climb in the COVID-19 death rate, peaking at 16.6% in those 85 and older. “If you have 65% of your population in an age group where mortality rates are extremely low, then obviously, you’re going to see an overall case fatality rate that’s extremely low,” he says. He calls claims of an India paradox “nonsense.”

Other factors also help explain India’s seemingly low death rates, Laxminarayan says. In the first wave, infections spread disproportionately in the urban poor, many of whom do manual labor and had to show up for work even during lockdowns, he says. Compared with wealthier city dwellers and those who live in rural villages, the urban poor are younger and have less obesity—characteristics linked with lower likelihood of severe COVID-19. “The urban rich actually were by and large spared the disease,” he says.

The states where the team worked have reliable death numbers, the researchers write, because they started “rigorous disease surveillance and contact tracing early in response to the pandemic.” But elsewhere in the country, Laxminarayan suspects far more people have died than reported. He points to a study from the Indian Council of Medical of Research, published on 27 January in The Lancet Global Health, that looked for antibodies in the blood of nearly 29,000 people over age 10 from more than 15,000 households in 21 of India’s 36 states and union territories. The study found antibodies in 7.1% of people, implying that India had nearly 75 million cases by mid-August 2020, when the study finished collecting data. At the time, the official case count was about one-thirtieth as high, at 2.7 million. “By that token, is it really unreasonable to think that deaths are underreported by a factor of four or five?” he asks.

Will India’s devastating COVID-19 surge provide data that clear up its death ‘paradox’?

In early April, the surge in cases had just begun to fill COVID-19–dedicated intensive care units like this one at King Edward Memorial Hospital in Pune, India.

Raja Sengupta

Several factors could lead to lower death rates in India. One, Jha says, is household structure. As with the family in Karandi, three generations sharing a home is a norm in much of the country. India’s relatively small older population means young people, who are more mobile, are the most likely to bring virus into a household, and because COVID-19 is generally less severe in the young, they have lower levels of virus and more asymptomatic infections. Jha notes that reports suggest between 70% to 90% of infected people in India don’t develop symptoms. As a result, older people tend to be exposed to lower doses of virus, which their immune systems may be more likely to control. “Some studies now do say that if you’ve got a reasonably low viral load hit, then your chances of getting sick and dying are also lower.”

Some scientists have suggested genetics might also play a role. Anurag Agrawal, who heads the Council of Scientific & Industrial Research’s Institute of Genomics and Integrative Biology, the leading contributor of a consortium that sequences SARS-CoV-2 in India, says there might be genetic explanations, but they’re tightly tied to the Indian environment. Indians who live in the United States or the United Kingdom, he says, suffer just as much from severe COVID-19 as people there from different genetic backgrounds. His team has its own “very controversial” theory, which it has yet to publish because the lead author fell ill with COVID-19. Although dismissed by some, studies have found lower rates of COVID-19 hospitalization in smokers. Agrawal points out that high death rates from the disease tend to occur in countries with the best air quality. His team contends that smokers and the many Indians who live with bad air pollution might overexpress a variation of an enzyme, CY1P1A1, that “detoxifies” the lungs and destroys the virus through a previously described phenomenon, “xenobiotic metabolism.”

Jha and others are skeptical. “There’s very little association with particulate matter and COVID infection cases or deaths in our analysis,” Jha says.

The mortality pattern may shift during the current surge. This time the virus appears to be causing serious illness in younger people more frequently and walloping wealthier populations. “It was the slums that got hit the first time, and this time, it seems to be more of the affluent areas of Bombay, for example,” Laxminarayan says. And Swaminathan notes that unlike in India’s first wave, when hospitals never filled to capacity, “People are dying unnecessarily because health systems can’t cope.”

But Jha says those trends are not dispelling the paradox. Recent data from Maharashtra suggest mortality rates of confirmed cases haven’t changed much—deaths have surged catastrophically, but so have cases overall. “The Indian paradox of lots of infection but relatively few deaths I think likely continues in this wave.”

Only more and better data will resolve whether India is benefiting from a “paradox” and, if so, whether it will hold. Agrawal, who is in New Delhi, says India is now in a wait-and-see mode. “It’s just crazy here these days,” he says. If patterns from other countries play out in India, he predicts the wave will begin to die down in mid-May. “Until then, we need to hold on.”

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