The alarming rise in India recently in the incidence of mucormycosis — a rare fungal infection — in patients who have been diagnosed and treated for COVID-19 has come as no surprise to those of us in the medical oncology community. This outcome was our greatest fear as the administration of dexamethasone and other steroids began to become common. As oncologists who rely on steroids in many of our protocols, and having managed several cases of mucormycosis, we are acutely aware that treatment protocols need to differ from patient to patient due to the complexities in clinical presentation and an individual’s tolerance to treatment.
However, we find ourselves in a different position today because of the magnitude of cases being reported, and the inability of treating physicians to create individualised treatment protocols under this burden. Some States, including Tamil Nadu, have declared mucormycosis as a notifiable disease under the Epidemic Diseases Act. Guidelines and protocols need to be adapted and modified rapidly to arrest this growing epidemic.
Why did the risk of mucormycosis overwhelming us come as no surprise? The estimated burden of mucormycosis in India is 14 per 100,000 in a study published in Current Fungal Infection Reports . This is almost 70 times higher than what is reported in other countries. In a multi-centre study across several tertiary-care hospitals in India, published in Clinical Microbiology and Infection , the rough estimate of proven mucormycosis was around 40 cases on an average over a 21-month period observed at each centre.
Focus on diabetes
It must be made absolutely clear that mucormycosis is not transmitted from one individual to the other, the way COVID-19 is. The most common cause is uncontrolled diabetes mellitus (raised blood sugars). Other causes include the treatment of some cancers; steroids, chemotherapy or immunotherapy, and solid organ or stem-cell transplantations. The common sites of presentation include rhino-cerebral involvement (i.e., the fungus can damage the nose, paranasal sinuses, the eyes and the brain), and pulmonary involvement (i.e., the fungus can cause pneumonia).
Raised blood sugars being a cause is of particular concern for multiple reasons. According to a study in The Lancet , the number of people with diabetes increased to 65 million in 2016 in India. The highest prevalence of diabetes was observed in Tamil Nadu, Kerala and Delhi. The crude prevalence of diabetes above 20 years of age has increased to 7.7% in 2016, from 5.5% in 1990. Further, there is an underlying higher genetic susceptibility to diabetes in Indians; some of these cases could get unearthed only after exposure to steroids.
Editorial | Another challenge: On the rise in mucormycosis cases
The treatment of COVID-19 is, unfortunately, only worsening this situation. In a lab study published in Nature Metabolism , SARS-CoV-2 can potentially multiply in pancreatic cells and contribute to increased blood sugar levels in COVID-19 patients. Steroids form a very important aspect of treatment for COVID-19 because they lower death rates by reducing the cytokine storm phase which can develop in some patients. However, steroids when used excessively or prematurely, and without medical supervision can be harmful. Besides causing reduced immunity levels, steroids can also increase blood sugar levels which can cause additional harm if left unchecked. Dexamethasone, methylprednisolone or prednisone are among the steroids used in the treatment of COVID-19.
Treatment approach
Mucormycosis is associated with very high morbidity and mortality. Its treatment requires a multi-disciplinary team approach that includes microbiology, pathology, radiology, infectious diseases, surgery, pediatrics, hematology, intensive care, dermatology, and pharmacology. A multi-disciplinary approach is simply not feasible on a large scale, especially in areas with limited medical access.
Surgery for mucormycosis can be debilitating requiring major resections. Additionally, there are limited antifungal drugs available for mucormycosis. The gold standard drug is liposomal amphotericin B, which is priced out of reach for many. Amphotericin B deoxycholate (conventional) is cheaper, but is associated with an unfavourable toxicity profile including kidney problems, abnormalities in electrolyte levels; reduced sodium, potassium, calcium and magnesium levels can lead to other toxicities. Some other expensive treatment options include posaconazole and isavuconazole. All these medicines often have to be administered for prolonged durations, making treatment protocols difficult to sustain on a large scale, given the cost implications and difficulty in drug administration due to its side-effects.
When a patient is recovering from COVID-19 infection, it is certainly going to be a challenge to perform debilitating surgeries and administer these antifungal drugs for a prolonged duration. In the case of rhino-cerebral mucormycosis especially, surgery is usually required in addition to antifungal drugs. If these surgeries cannot be performed, the outcome is dismal. It is also important to keep in mind that treatment for mucormycosis will require prolonged hospital admissions. Given the health-care constraints we are faced with, this infection should be avoided at all costs.
Monitoring is essential
What can be done to reduce the number of cases and the intensity of mucormycosis? Steroid use at home for COVID-19 should be only under the supervision of a health-care worker. The control of blood sugars during steroid intake is crucial to avoiding mucormycosis. When patients are medicating themselves at home, monitoring of capillary blood glucose is essential. If high blood sugars are encountered, a tele-consult with a doctor is advisable. Going a step further, health authorities may consider arranging for blood glucose monitoring for patients at home on steroids, and also promoting awareness campaigns on the importance of controlled blood sugar levels.
Patients on steroids for COVID-19 should report symptoms of mucormycosis at the earliest. Among other symptoms, they should look out for facial swelling on one side, protrusion of the eyeball, new-onset visual disturbances, headache and vomiting, new onset swelling or ulcers with blackish discolouration, and prolonged fever. COVID-19 treatment experts and policy-makers may consider widespread training of health-care personnel including Accredited Social Health Activists (ASHAs) and nursing professionals to raise awareness on mucormycosis while educating people locally.
The prolonged requirement for hospital admission linked to COVID-19 will also lead to a rise in other hospital-acquired infections necessitating the use of multiple antibiotics. We are staring at the grim reality of managing large numbers of patients with other long-standing side-effects of steroids. Additionally, the concern is the alarming increase in multi-drug resistant bacterial infections for which we are grossly unprepared.
Dr. Nikita Mehra is Associate Professor of Medical Oncology, Adyar Cancer Institute (WIA), Chennai
