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It isn’t clear yet why so many Indian covid patients developed mucormycosis during the pandemic years.

The real prevalence of mucormycosis prior to 2020 was unknown, because it was such a rare, and often undiagnosed, disease. Arunaloke Chakrabarti, a mycologist at the Chandigarh’s Post Graduate Institute of Medical Education and Research (PGIMER) and his colleagues did attempt to arrive at an estimate using individual hospital data. They calculated that India was likely seeing 14 mucormycosis cases per 100,000 people, or an average of 171,504 cases per year.

If correct, this estimate makes India the mucormycosis capital of the world, with a prevalence that is 70 times the global average. Scientists speculate that the large number of patients with uncontrolled diabetes in India, along with climatic conditions that favour high numbers of Mucorales spores in the air, contribute to these numbers. But Chakrabarti cautions that modelled prevalence estimates can be very different from reality, because they involve too many assumptions.

Whatever the pre-covid numbers, everyone agrees that there was a large and distinct mucormycosis spike in 2020 and 2021: PGIMER, for instance, which was used to seeing roughly 50 mucormycosis cases a year until 2019, saw 100 in 2020. The next year, this number jumped to around 350 by mid-June alone. And these extra infections occurred overwhelmingly among active or recovering covid patients, a condition now termed Covid Associated Mucormycosis (CAM). Other major Indian hospitals, such as Vellore’s Christian Medical College, reported similar trends.

A bouquet of possibilities

What was behind the CAM phenomenon?

Infectious disease specialists who first spotted the increasing trend in 2020 considered several hypotheses then. Some wondered if the oxygen administered to covid patients, or the water in the humidifiers the oxygen passed through, was contaminated with Mucorales. Others wondered if the pandemic lockdowns led to diabetic patients not taking their drugs or exercising regularly, causing their blood sugars to spike. Diabetes was a well-known risk factor for mucormycosis, even before the pandemic.

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Yet another suspect was treatment with corticosteroids (steroids), again a known risk factor for mucormycosis in pre-pandemic times. Finally, some hypothesized that covid itself was making people vulnerable to mucormycosis, steroids or not.

Out of this bouquet of possibilities, the strongest, so far, is the steroid hypothesis: i.e that steroids were the biggest novel factor in 2020 and 2021 which sent mucormycosis cases soaring to historic highs. Two published studies support this idea. The first, conducted in a network of 16 hospitals called MucoCovi between 1 September and 31 December 2020, compared 187 CAM patients with 100 mucormycosis patients who didn’t have covid. The second, conducted by a network of ophthalmologists called COSMIC between 1 January 2021 and 26 May 2021, studied 2826 CAM patients, but no control group.

Both studies found that the vast majority of CAM patients either had diabetes, or received steroids, often in high doses. To be sure, steroids are a lifesaving covid treatment; however, they can be dangerous when used too soon, or for too long. The World Health Organisation recommends administering only 6 mg a day of the steroid dexamethasone to covid patients, and that too, only after they begin to need oxygen. Treatment with steroids beyond 10 days is not advised.

The MucoCovi study found these guidelines violated in 64% of CAM patients. Chakrabarti, an investigator on this study, says that panicked doctors who weren’t able to arrange oxygen or beds for patients during the covid pandemic likely prescribed irrationally high steroid doses to make up for it. “Some patients were given 30 mg of dexamethasone per day, which is five times the permissible limit. Others got dexamethasone over 20-30 days continuously." The COSMIC study confirmed this pattern of excessive steroid use in 2021.

Simultaneously, support for the contaminated-oxygen hypothesis is weakening. Chakrabarti has argued that Mucorales spores cannot grow in pure oxygen. And humidifier water is agitated when oxygen passes through it, making it hard for fungal spores to grow there either. “Mucorales need a static environment to produce spores," he says. Nevertheless, PGIMER and two other hospitals did try to isolate Mucorales from the oxygen pipelines and cylinders supplying to patients. They didn’t succeed. Joy Michael, a microbiologist at the Christian Medical College, said her hospital, too, conducted a similar exercise, but wasn’t able to isolate the fungi.

So, were steroids the only driver that turned mucormycosis from a rare disease into a headline grabbing epidemic? The story may not be that simple either. For one thing, both the MucoCovi and COSMIC studies found that a small proportion of CAM patients neither had diabetes, nor were treated with steroids. To be sure, these numbers were tiny: around 7% in the Mucovi study and 2% in COSMIC.

Yet, doctors find these examples striking enough to warrant further investigation. Raghuraj Hegde, an ophthalmic surgeon at Bengaluru’s Manipal Hospitals, says he has come across asymptomatic covid patients, who received no treatment at all, yet developed the deadly fungal infection. These patients learnt they had previously had covid only when they took antibody tests after developing mucormycosis. “How do you explain this?" he asks.

Others point out that while steroid overuse did intensify during the pandemic, high doses are not an uncommon phenomenon in respiratory illnesses. If so, there is something about covid alone, they say, and not just its treatment, that’s triggering mucormycosis.

The link between covid and diabetes

Theoretically, if covid triggered a diabetes-like condition in patients, it could explain CAM too. And some scientists have postulated mechanisms for this. A recent study of covid patients in Italy found that some patients had raised blood sugars, even though they were not diabetic, and that their sugars stayed elevated for months after recovery. These patients also tended to have higher insulin levels and inflammatory proteins, called cytokines, in their blood. The authors hypothesized that the cytokines were triggering insulin resistance, a condition seen in Type 2 diabetes.

Meanwhile, in another 2021 study, scientists infected human pancreatic islets, a region of the pancreas that produces insulin, with the SARS-COV-2 virus, in a petri-dish. They found that the islets were damaged by the virus and produced less insulin, similar to what happens in Type 1 diabetes.

That’s not all, says Surabhi Madan, an Ahmedabad-based infectious disease specialist. Covid is probably doing more than just raising blood sugars to make the body more hospitable for Mucorales: it could also be raising blood iron levels or depressing immune cells called neutrophils and macrophages, she suggests.

Some clarity on if these mechanisms were behind the CAM epidemic may come soon. In an ongoing study in 27 hospitals, the MucoCovi network will compare levels of inflammatory markers, as well as immune cells, such as neutrophils, in covid patients who develop mucormycosis with those who don’t. This will help understand if covid affects patients who developed mucormycosis in a different way than it does the rest. The results are expected in a few months.

At the end of the day, it is likely that no single factor led to the unprecedented CAM epidemic, but a mix of them, says Madan. High steroid use, India’s high diabetes prevalence, covid’s impact on the immune system, and on blood sugar levels, could have all come together.

And the result was a perfect storm of fungal disease that no one predicted.

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