PremiumIn August 2020, as covid-19 cases were rising in north India, Arunaloke Chakrabarti noticed a troubling pattern. At the large teaching hospital where he works—Chandigarh’s Post Graduate Institute of Medical Education and Research (PGIMER)—the professor noticed that the number of patients suffering from a rare but mutilating fungal infection, called mucormycosis, had doubled compared to the years before. And the excess cases were almost exclusively among covid-19 patients. “I knew something was wrong," recalls Chakrabarti, a microbiologist who specializes in the study of fungal pathogens, or mycology.
The uptick worried him. Until 2020, mucormycosis was a rare disease in India. PGIMER’s 2,000-bed hospital, which attracts patients from neighbouring states, only saw about fifty cases a year. The rarity was something to be thankful for, because the fungus killed over 50% of those it afflicted, often by ravaging facial tissues before it reached the brain. If this invasive fungus was now spreading, it wasn’t good news. To ascertain this, Chakrabarti began calling fellow microbiologists in other states. They confirmed his worst fears— the uptick was happening everywhere.
What Chakrabarti spotted were the early stirrings of what was to become India’s worst recorded human fungal pathogen outbreak. Thereafter, the spike in mucormycosis cases died down briefly, following the trend of covid-19 cases, only to make a staggering resurgence in April 2021. The second mucormycosis outbreak left thousands dead or disabled after facial surgeries to remove portions of infected eyes, noses or jaws. According to government numbers, India clocked over 40,845 cases, and 3,129 deaths until 28 June this year. The government hasn’t clarified the starting date for the period during which these cases occurred, but it is likely to be 19 May, 2021, when it made mucormycosis a notifiable disease.
Despite the early signal in 2020, which Chakrabarti says he flagged to the Indian Council of Medical Research (ICMR)—the country’s apex medical research agency—India remained deeply unprepared for the devastating second outbreak. Mucormycosis has historically had a high fatality rate for a number of reasons: doctors do not identify the disease early enough; a delay in treatment increases chances of death; and the best drug available—an antifungal called amphotericin B—is both prohibitively expensive and highly toxic.
With the mucormycosis cases hitting the roof in 2021, this situation worsened. Amphotericin B stocks ran out across India, likely pushing up fatality rates compared to pre-pandemic times. The government’s estimate of this fatality rate, at 7.7% between 19 May and 28 June, is almost certainly incorrect. Many deaths due to mucormycosis occur weeks after the infection, and it is likely that the government systems are not tracking patients this long, experts say.
Could India have handled the outbreak differently? Chakrabarti and other mycologists argue that the outbreak’s impact could have been blunted if research into fungal diseases was not so chronically neglected both globally and in India. While public health has always been underfunded in the country, fungal diseases are particularly orphaned. There are historical reasons for this neglect: throughout human history, bacteria, viruses and parasites were much bigger killers among microbes. Think of the tuberculosis or the plague bacterium, the Sars CoV-2 or the influenza virus, and the malaria or leishmaniasis parasites, respectively. Fungi, in comparison, were minor league players. They were known, more often, to cause skin-deep ailments, such as ringworm, rather than an invasive disease—a term for life-threatening infections, like mucormycosis, that affect multiple organs. “Historically, fungal diseases were definitely a nuisance, but they didn’t cost the life of a patient," says Jagdish Chander, a mycologist at Chandigarh’s Government Medical College and Hospital (GMCH).
Also Read: Decoding the link between covid and mucormycosis
But this situation is changing fast. For many reasons, invasive disease caused by fungal genera like Candida, Aspergillus, and the order Mucorales are growing more common. Candida and Aspergillus cause deadly blood infections in hospitalized patients, while Mucorales cause mucormycosis. Yet, neither medical training, nor surveillance programs, have kept up with this epidemiological sea change, mycologists say. Diagnosing and treating fungal diseases needs special training, which clinicians and microbiologists often don’t receive. “There is no uniformity in training. Except some of India’s top medical colleges, few expose their students to the diagnosis and treatment of fungal diseases," says Rungmei Marak, a mycologist at Lucknow’s Sanjay Gandhi Postgraduate Institute of Medical Sciences. As for surveillance, the Indian government has never made a fungal disease reportable, until the unprecedented mucormycosis epidemic occurred. Making matters worse, the global neglect of research into fungal pathogens has left doctors with too few diagnostic tests and drugs for these deadly diseases.
If India had a fungal pathogen surveillance program, the government may have picked up on the early warnings of a mucormycosis spike in 2020 itself. This would have given them lead time to prepare, perhaps by boosting amphotericin B production, or issuing treatment guidelines quickly, thus muting the damage from the epidemic, Chakrabarti says. For now, the mucormycosis outbreak should warn us that fungi can wreak public-health havoc just like viruses and bacteria can, he cautions. “We have to change our goalposts. Fungi are going to become much bigger public-health problems in the future."
Unexpected ways
Although the sudden explosion of mucormycosis during the pandemic surprised mycologists, this isn’t the first time a fungal pathogen has behaved unexpectedly. Fungi are often free-living organisms, subsisting on decaying matter in the environment, until humans come in contact with them and become infected. Their life cycle in the environment is not always well understood, making their behaviour hard to decode, says Chakrabarti. As a result, several aspects of historical outbreaks, where fungi showed up in new geographies and in new hosts, remain riddles.
In the late nineties, for instance, Canada saw an outbreak of lung disease by the fungal species Cryptococcus gattii, which had never been seen in those parts before. C. gattii was hitherto restricted to the warmer climes of Australia and South America, raising questions about when, how and why it made a move to the temperate Canadian climate. Scientists have since speculated that the fungi might have travelled via ship from South America to the Canadian island of Vancouver. Here, helped by the warming local climate, it may have colonized trees, before jumping to humans. From here, it spread to the US, causing an outbreak of lung infections and meningitis.
Another example of an unexpected jump is the species Sporothrix brasiliensis. Fungi in the Sporothrix genus (to which brasiliensis belongs) have previously been mainly soil-dwellers. Until the nineties, they primarily caused skin infections among agricultural workers who got cuts or were pricked by plants. Sometimes, cats infected with Sporothrix transmitted the fungus to humans, but these cases were rare.
All this changed in the late nineties, when doctors in Rio de Janeiro, Brazil, started seeing a more severe form of skin infections by Sporothrix. Eventually, epidemiological investigations showed that a new Sporothrix species, christened brasiliensis, was spreading among stray cats. It could transmit more easily to humans through bites and scratches, and spread to most of Brazil within a couple of decades. How did the fungus adapt from being mainly a soil dweller to infecting cats? Scientists don’t have the answers yet.
Closer home, a species called Candida auris is wreaking havoc by causing invasive infections in the intensive are units (ICUs) of hospitals today. It, too, has a puzzling history. C. auris was first isolated from the ear canal of a Japanese patient in 2009, but within a few years, it popped up, independently, in several countries, including India. And everywhere, it was resistant to multiple anti-fungal drugs.
The emergence of Candida auris is shrouded in mystery. For one thing, other human fungal pathogens are typically slower to become drug resistant. In the normal course, they cause disease in humans for several years, are treated with anti-fungals, which turns them into the so-called superbugs. But many isolates of C auris were already superbugs when they made their first appearance in humans.
It is also unclear how C auris became a human pathogen near simultaneously in so many countries on three continents. The genomes of the fungi in these continents are not closely related, suggesting that it didn’t hop from one continent to another. Did something change simultaneously in these geographies that facilitated this transition—perhaps the increased use of anti-fungals in agriculture, which made the fungus more resistant to human anti-fungals too? It isn’t clear yet. Whatever the reasons, C auris’ arrival hasn’t been good news. Candidemia, a deadly blood infection caused by the Candida genus, has always been a killer in Indian hospitals. Until a few years ago, other species, such as Candida tropicalis and Candida albicans were its dominant causes in India. But ever since 2009, C. auris is nudging them aside. Few estimates of countrywide prevalence exist, given the lack of surveillance. But one study from Delhi’s Jai Prakash Narayan Apex Trauma Hospital found that between 2012 and 2017, the proportion of C auris grew steadily as a cause of candidemia at the hospital, averaging 17% over all five years. This is worrying, because C. auris resists common anti-fungals and kills patients more often. Even worse, microbiologists struggle to differentiate this species from other Candida species, which means doctors use the wrong drugs to treat it, further pushing up mortality.
When the covid pandemic hit India last year, mycologists feared that Candida and Aspergillus would ravage Indian hospitals. Sick patients often acquire these two bugs in hospitals; in other words, they are ‘hospital-acquired’ infections, rather than ‘community-acquired’ ones. The key to preventing the disease in such cases is to practice strict infection-control measures: isolate infected patients quickly, disinfect surfaces aggressively, wash hands often, and conduct invasive procedures like mechanical ventilation hygienically. The worry was that with ovid patients overwhelming hospitals, infection-control would break down. Doctors and nurses would become careless, and these fungi would run riot. These fears did come true. Several hospitals have reported an increase in Candida and Aspergillus outbreaks since last year. This wasn’t really a surprise.
What blindsided everyone was mucormycosis—a disease mainly acquired outside hospitals—which no one thought would reach such high numbers. “We never knew that such a such a jump would occur with mucormycosis," says Chakrabarti. What about covid had made patients more susceptible to mucormycosis? Mycologists are still trying to answer this question.
The puzzle
In pre-covid times, mucormycosis was a rare disease that affected mostly people with uncontrolled diabetes. While humans breathe Mucorales all the time, healthy people fight off an infection. But those with diabetes may not have a strong immune system, explaining why over 70% of Indian mucormycosis patients in the years before 2020 were diabetics. Less commonly, cancer patients, organ-transplant recipients, and people treated with high doses of immunity-damping drugs called corticosteroids (steroids), developed this disease too. The links between diabetes and the fungal infection are manifold. Diabetes raises glucose and iron in the blood, both of which Mucorales feed on. Also, when a diabetic patient suffers a complication called ketoacidosis, their blood becomes acidic, while their immune system takes a hit, again creating favourable conditions for infection (See accompanying article). Steroids acts along similar lines to trigger mucormycosis, by spiking blood sugar, and depressing the immune system.
Two studies conducted during the pandemic suggest that steroids were the main reason behind the massive jump in mucormycosis during 2020 and 2021. Both found that a large proportion of mucormycosis patients were diabetic. This was expected, because it was true even before the pandemic. But they also found that an equally large proportion of patients were treated with steroids for covid.
Steroid prescriptions, in fact, had jumped through the roof in the last two years. Even though they are a recommended treatment for moderate covid, doctors were often prescribing them for mild covid, and in unnecessarily high doses—a reflection of the panic the pandemic engendered all around.
But the steroids explanation doesn’t fully solve the puzzle. Several experts point out that while covid did push up steroid use, this isn’t the first time it has happened in India. And yet, India never saw such a large epidemic of the fungal pathogen before. For instance, Indian doctors treat several other respiratory diseases, including influenza, with steroids, says Ashwin Rajenesh, an internal medicine specialist at Kollam’s NS Memorial Institute of Medical Sciences. Yet, influenza season, which occurs every year, doesn’t coincide with mucormycosis outbreaks. “What we see is uncommon and unusual, to say the least," Rajenesh says. He and several doctors believe that it’s not just the treatment for covid, but covid itself that is making patients biologically vulnerable to Mucorales.
And there is some emerging evidence for this idea—preliminary studies show that covid can raise blood sugar in some patients, triggering a diabetes-like condition. Chakrabarti and his team are pursuing this hypothesis in two new studies, and some results may be out later this year. But if this hypothesis pans out, this won’t be the first time a new viral disease also created a susceptible host for a fungus.
A deadly turn
Through most of human history, the diseases that caused most deaths were bacterial, viral or parasitic. Fungal infections have always been less widespread.
A major point of inflection occurred in the eighties, when the human immunodeficiency virus (HIV) first started spreading in humans. The virus ravaged patients’ immune systems, leaving them vulnerable to infections from several fungal genera, including Candida, Cryptococcus, and Pneumocystis. So much so, that in the early years of AIDS, when doctors lacked diagnostic tests, they relied on fungal infections as a marker of the disease. “If a patient presented with candidiasis or cryptococcosis or pneumocystis, doctors suspected that the patient had HIV," says GMCH, Chandigarh’s Jagdish Chander. From then on, fungal-disease burden has grown steadily. “AIDS opened the floodgates of fungal infections," Chander says.
The emergence of AIDS wasn’t the only seminal event that altered the landscape of fungal infections. The modern human lifestyle and longer lifespans have brought with them more cancer and diabetes, both of which depress the immune system too. Also, paradoxically, modern treatments that have prolonged lives—such as the use of invasive catheters and potent antibiotics—are making people easy pickings for fungi. A urinary catheter can trigger a fungal infection, for instance, by moving a pathogen from the skin to the bladder.
If humans are growing more vulnerable to fungi, the environment is also changing in ways that help these organisms infect humans better. Activities like construction, deforestation, and excavation let environmental fungi loose on humans, increasing chances of infection. Hospital mucormycosis outbreaks, for instance, sometimes occur when construction activity disperses microbes growing on walls and floors.
To boot, the use of anti-fungals in plants and in humans is helping these pathogens resist the drugs better. Perhaps the most overarching human influence on fungal pathogenicity, though, is global warming. Several scientists have hypothesized that fungi are gaining an edge over humans with this phenomenon. The idea makes sense. Historically, humans have resisted fungal infection, because fungi thrive better in the cooler temperatures. The 37-degree celsius of the human body, that rises further in a fever, keeps fungi away better than plants and insects can.
But global warming could change this, because it will select for heat-tolerant fungi in the environment, which can then breach the temperature-gap between them and humans. American infectious disease researcher Arturo Casadevall has argued that Candida auris, the superbug spreading quickly in Indian hospitals today, could be the first fungal disease that arose due to the warming weather.
Delayed diagnosis
Sometime in the last week of April 2021, the right side of Manish’s (name changed on request) face began to hurt. The 45-year old car mechanic, who lives in Haryana’s Kurukshetra district, first went to a local doctor, who prescribed some medicines. When they didn’t help, and the pain kept worsening, he went to a government hospital in the Ambala district. Here, records show, the doctors conducted tests that showed Manish’s blood sugar to be extremely high, suggesting possible diabetes. They also did a CT-scan of his head, which showed inflamed sinuses. He was admitted to the hospital for two weeks, and received pain-killers and other drugs for his symptoms. But nothing worked. So, the doctors referred him to a larger hospital, Chandigarh’s GMCH. It was only when he arrived there, in mid-June, one and a half months after his symptoms began, that doctors finally pinpointed his ailment correctly.
A series of tests conducted at the hospital’s lab, headed by mycologist Jagdish Chander, showed that Manish’s sinuses were infected by two deadly fungi—an Aspergillus and a Mucorales species, which cause aspergillosis and mucormycosis, respectively. The hospital began treating him with amphotericin B, which fights both fungi. But supply of the drug has been extremely erratic during the nationwide mucormycosis epidemic, says Chander. He points out that Manish’s very delayed diagnosis is not unusual. In an ideal scenario, the Ambala hospital doctors would have suspected a Mucorales infection based on the CT-scan results and the fact that Manish had high blood sugar. They would have prescribed amphotericin immediately, improving his chances of a full recovery without debilitating after-effects.
Today, Manish remains hospitalized, and portions of his sinuses have been removed. Chander thinks Manish is lucky to have escaped without major disability, possibly because he first caught a slow-moving fungal infection, Aspergillus, followed by the more deadly mucormycosis. Many other mucormycosis patients who received treatment too late lost their lives, their eyesight, or portions of their faces, requiring extensive reconstructive surgery. “This is the tragedy of mucormycosis," Chander says, “If you suspect it early and begin treatment, half the battle is won. If you don’t, you can’t do much to compensate for the delay."
Catch me if you can
A key reason why mucormycosis takes so long to diagnose is that it doesn’t have characteristic symptoms. For instance, the symptoms for the most common form of the disease—called rhino-orbital-cerebral mucormycosis, because it affects the nose, eyes and brain—are facial pain, swelling and nasal discharge. A CT-scan can show inflammation in the sinuses, as it did for Manish. But all these signs can easily be explained by other bacterial infections, or other fungal infections. And treatment for each of these pathogens is different. So, confirming the diagnosis needs both an alert clinician and a trained microbiologist. An alert clinician would suspect mucormycosis as a possible cause of the symptoms when the patient also has risk factors like diabetes. They would then send a sample of infected tissue from the patient to the microbiologist to confirm their suspicion.
This is where the trained microbiologist comes in: they would follow several steps to positively identify the Mucorales. Typically, they would first do a so-called potassium hydroxide mount, a quick screening test for the fungus. Here, they would bathe infected tissue with potassium hydroxide and observe it under a microscope. Mucorales have cottony filaments that form distinctive patterns, which trained microbiologists can identify.
Once this test is positive, the patient is classified as having suspected mucormycosis, and started on treatment, although the lab must do further tests for confirmation. The microbiologist will now stain the infected tissue with special dyes that make the fungal filaments and tissue even easier to see. This allows them to spot the filaments invading the human blood vessels—an important step, because it proves that Mucorales is causing the disease, instead of merely being present in a patient’s body as a bystander, while something else is the real cause of the symptoms.
In the third and final step, the microbiologist multiplies the fungus in a nutrient-rich gel. Once the fungus grows, the microbiologist looks at its shape and structure under a microscope again, thus identifying the species. This entire complicated process requires microbiologists to be both trained and to stock the right dyes and gels, which are different from the dyes and gels for bacteria. “It is important to be familiar with the potassium hydroxide mount. If you haven’t done it anytime in your life, a cotton fibre will look like a fungus to you," says Chander. Similar diagnostic challenges exist for other fungi too, including Candida, Aspergillus and hundreds others that cause human disease.
For several fungal infections, such advanced methods don’t even exist, because research into them is so neglected, says Neil Stone, a mycologist at London’s University College Hospital for Tropical Diseases. For instance, most mucormycosis diagnostic tests today require a tissue sample to be taken from the infected area, like the sinuses, which often require a surgeon’s help. A simple blood test would make life much easier for clinicians, but no one has developed it yet, he says.
Marak points out that testing fungi for their susceptibility to antifungal drugs is a key part of finding the right treatment. But many microbiologists are not trained in conducting the gold-standard test for susceptibility, called broth-microdilution. “It is labour intensive and you need a specially trained person to do this," she says. All this means that the patient may not get the right anti-fungal at the right time, increasing chances of mortality.
Slow progress
Eight years ago, Chakrabarti decided it was time to do something to strengthen fungal diagnostic capacity across the country. The prevalence of several fungal infections had been rising steadily since the eighties. But neither clinician training, nor diagnostic capacity in India was up to the mark. So, Chakrabarti mooted to ICMR the idea of a government-controlled network of reference laboratories for fungal diseases. The idea was for each state to have at least one such lab, with people trained to conduct sophisticated tests like broth-microdilution.
Smaller hospitals could send their samples to them. Further, these labs could carry out surveillance to capture early signals of fungal outbreaks. And they could also train personnel from smaller labs and hospitals, all the way down to primary healthcare centres. ICMR did begin work on eight such labs, but only in 2019. And since then, only two labs have begun functioning in the right earnest: at Bhopal’s All India Institute of Medical Sciences and New Delhi’s Lady Hardinge Medical College, says Chakrabarti.
For a country India’s size, it’s hardly enough. In contrast, ICMR today runs a network of 105 labs to detect viral pathogens, called the Viral Research & Diagnostics Laboratories (VRDL).
Questions from Mint to Samiran Panda, an epidemiologist at ICMR, who is coordinating the establishment of the India’s fungal reference laboratories, about the slow progress on the project, went unanswered.
Chakrabarti and fellow mycologists, who run a network called the Fungal Infections Study Forum, are doing all they can to meet the shortfall. They have been conducting two-day training programs across the country for a couple of years now. "Ever since the mucormycosis outbreak began, they have stepped it up," says Atul Patel an Ahmedabad-based infectious disease specialist and a member of the forum. Some other major Indian medical institutions, such as Vellore’s Christian Medical College, also run such training programs.
But it’s all too little, too slow, rues Chakrabarti. Just the other day, he recalls, a doctor called him from the Uttar Pradesh district of Bareilly, asking for help in confirming diagnosis for a case of mucormycosis. Chakrabarti couldn’t agree to take the sample, because his lab is already overwhelmed.
“India is too vast a country. Unless there is a government effort, whatever changes we make won’t be significant". However, not making these changes could lead to unacceptable risks— another deadly fungal outbreak, like mucormycosis, that will leave India floundering again like it did in 2021.
Priyanka Pulla is a Bengaluru-based reporter covering health. Her reporting on covid-19 is supported by a grant from the Thakur Family Foundation. The Foundation exerts no editorial influence on her work.
