A tale of two infections
The life-threatening infection, mucormycosis, informally referred to as the black fungus, is currently raging as a part of the aggressive second wave of Covid-19. Epidemiological data suggests an estimated global prevalence of 140 cases per million population, of which over 40% is contributed by India. The fungal order responsible for causing it is Mucorales, the third most common pathogenic fungal infection following Candidiasis and Aspergillosis. The mucorales like others (yeasts, moulds, mushrooms) are ubiquitously distributed fungi that exist in decaying organic matter, damp places, soil, plants, water, air and animals.
At greatest risk are people with uncontrolled diabetes mellitus, blood cancer, and those with organ transplantation or receiving regular immunosuppressive drugs and/or steroids. Hyperglycemia (high sugars), especially in the presence of elevated available serum iron and diabetic ketoacidosis (DKA), is the most common factor. The inability of a compromised host immune system to suppress Mucorales germination precipitates infection, which, upon widespread dissemination, is virtually impossible to resolve.
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The hallmark of mucormycosis is the invasion of blood vessels by Mucorales spores that germinate and invade host cells causing tissue necrosis (death), which becomes visible only at very late stages of infection. More often than not, diagnosis is delayed. The high mortality rates (45-60%) associated with mucormycosis are reflective not only of the aggressive nature of the infection, but also of the dysregulated innate immune response seen in Covid-19 as well as the cytokine storm observed in the more severe disease with eventual immune exhaustion.
A recent publication by Soliman and others from the University of California Los Angeles in Nature Microbiology (March 2021) has demonstrated that high mortality of the condition is attributed to the release of a preformed toxin (new venom), named Mucoricin, which could also be the promising therapeutic target.
The widespread reports of mucormycosis point to multiple factors, of which high prevalence of diabetes mellitus — over 80 million known cases in India and several that remain unreported or undetected — is of utmost importance. Of the over 8,500 reported cases of mucormycosis in India, over 90% are in people who are either known diabetics or have new onset (Covid or steroid related) diabetes mellitus.
The injudicious use of steroids with improper dosage, duration, timing as well as self-medication contributes directly or indirectly to this. Generalised lymphopenia induced by Coronavirus, characterised by the specific depletion of killer T-cells, provides further impetus to the deadly fungus.
In addition to hyperglycemia, DKA is known to predispose subjects with diabetes to mucormycosisowing to the high cellular iron and low serum pH (acidosis). Iron is an essential micronutrient for most organisms and fungi are no exception. A report published in the April 2021 issue of Journal of Fungi suggests that iron metabolism holds the key for the development of mucormycosis, and that serum iron and glucose together enhance the expression of glucose-regulated protein 78 (GRP78), the novel host receptor that mediates invasion and damage of human endothelial cells by Rhizopus oryzae.
Published literature, supported by the European Food Safety Authority (EFSA), recommend six vitamins (D, A, C, Folate, B6, B12) and four minerals (zinc, iron, copper and selenium) as essential constituents for resistance to viral infections because of their ability to enhance immune function and reduce inflammation.
But addition of zinc may worsen the course of mucormycosis. This is supported by the fact that Zinc chelators (compounds that bind it in blood) like Clioquinol with posaconazole are the most active combination in ameliorating mucor in animals. This may be relevant in the Indian setting as during the pandemic, there has been an unprecedented, over the counter use of drugs of unproven benefit such as vitamin C, D and zinc. The latter may be doing more harm than good and may explain the high incidence of mucormycosis.
The key to prevention of mucormycosis is prompt control of hyperglycemia, maintenance of hygiene, and judicious use of steroids; the key to treating it is early diagnosis for ameliorating morbidity and mortality. It is critical to have high index of suspicion even on observing subtle symptoms. For suspected cases, prompt imaging (contrast enhanced MRI of paranasal sinuses/ brain or plain CT chest), with or without fungal scrapping/culture from the accessible tissues, is of utmost importance. Successful treatment of mucormycosis requires multidisciplinary approach involving multiple specialists.
General experience of treating patients with various brain tumours, endocrine disorders such as the Cushing’s syndrome as well as a multitude of other medical indications where steroids are generally prescribed in high doses shows opportunistic fungal infections especially mucormycosis do occur, but in modest proportions. Why then is there a sudden spurt in cases in Covid-19 where comparatively moderate steroid doses of short duration are used? Could there be a specific affliction between Sars-CoV-2 derived viral proteins and the steroid compounds? Are there specific host determined factors that might predispose a certain group of individuals? Clearly, further research is needed to understand the pharmacokinetics of drug-protein interaction, besides devising easier diagnostic and prophylactic strategies.
Even though mucormycosis is a serious opportunistic infection among patients with Covid-19 treated with steroids and those having uncontrolled hyperglycemia, it is important to remove undue fear and anxiety by creating guarded awareness among health care workers and the public.
Mohd Ashraf Ganie is the Professor of Endocrinology and Metabolism at Sher-I-Kashmir Institute of Medical Sciences, Srinagar
NK Mehra is Indian Council of Medical Research Emeritus Scientist (Hon) and former Dean of the AIIMS, New Delhi
The views expressed are personal