Emergence of Mucormycosis during COVID-19 Pandemic in India

a Institute of Veterinary Science and Animal Husbandry, SoA University, Odisha, India and ICARDFMD, Mukteswar, Nainital, India and FAO Ref Centre for FMD in South Asia, Bhubaneswar, Odisha, India. b ICAR-National Institute of Veterinary Epidemiology and Disease Informatics (NIVEDI), Yelahanka, Bengaluru, India. c Department of Studies in Food Technology, Davangere University, Davangere, Karnataka577007, India. d SVP University of Agriculture & Technology, Meerut, India. e Department of Biotechnology and Bioinformatics, School of Life Sciences, JSS Academy of Higher Education and Research, Mysuru, Karnataka570015, India. f Department of Studies in Biotechnology, Davangere University, Shivagangotri, Davangere, Karnataka-577 007, India. g Department of Sciences, Amrita School of Arts and Sciences, Amrita Vishwa Vidyapeetham, Mysuru Campus, Mysuru, Karnataka570026, India. h Department of Microbiology, School of Life Sciences, JSS Academy of Higher Education and Research, Mysuru, Karnataka570015, India.


INTRODUCTION
Most fungi are saprophytic and not pathogenic to humans, animals and plants. Fungi members of the genera Aspergillus, Fusarium, Alternaria, and Mucor are emerging pathogen in humans mostly in immunocompromised people. Mucormycosis is an emerging opportunistic fungal infection/ disease, caused by Mucoromycetes of the order Mucorales, in people with risk factors, such as immunosuppression, diabetes, trauma and malignancies [1], and of late associated with second wave of COVID-19 in India. In a prospective multicenter study, Mucormycosis is reported at large numbers in uncontrolled diabetics across India [2]. Trauma [3].
Mucor circinelloides is one of the most frequent species causing fatal mucormycosis.
Mucorales infections are difficult to treat due to fast dissemination within the host tissues and low susceptibility to antifungal agents, and may lead to aspergillosis . They observed that phenotypical characteristics related to virulence include higher germination rate, spore size and protein secretion. Mucormycosis remains a major fungal infection in people with diabetes (Prasad et al., 2018). Therefore, an insight in to overall picture of Mucormycosis and its causative agents are discussed in this review.

NATURE OF FUNGI
Fungi are eukaryotes that include microorganisms such as yeasts, moulds, and mushrooms, and are classified as a kingdom separate from the other eukaryotic kingdoms of Plantae, Animalia, Protozoa, and Chromista [4]. The fungi are unique in having chitin in the cell wall, and have different morphologies and varied replication strategy. The Kingdom Fungi, has been estimated to have more than 2 million species; >8,000 species known to be pathogenic to plants and about 300 that can be pathogenic to humans. As in other eukaryotes, fungal cells contain nuclei with chromosomes that contain DNA with introns and exons, mitochondria, and ribosomes. Fungi typically have haploid nuclei. As in plants, fungi have cell wall but lack chloroplast (no photosynthesis). Fungi, like animals, are heterotrophs; and secrete digestive enzymes into their environment.

MUCORMYCOSIS
Mucormycosis/ zygomycosis remains a devastating invasive fungal infection with high mortality rates and is being reported over the past decades from India [5]. Mucormycosis in India has unique features as rhino-orbito-cerebral disease in people with uncontrolled diabetes. Also, renal mucormycosis has been diagnosed.
1. Rhinocerebral mucormycosis -It is also known as the rhino-orbital or rhinoorbito-cerebral mucormycosis that involve sinuses and brain in people with diabetes and/or renal complications [8,9,10]. 2. Pulmonary mucormycosis-It is detected in people suffering from hematologic malignancy or following organ/ stem cell transplant [11]. 3. Gastrointestinal mucormycosis-It commonly occurs in children, with premature birth or low birth weight, and also due to antibiotics/immunosuppressant, and surgery [12]. 4. Cutaneous mucormycosis-It commonly occurs due to entry of the fungi through breaks/ abrasions in the cutaneous/skin tissues [13]. 5. Disseminated mucormycosis-It commonly affects the vital organs, such as brain, heart, spleen, kidney and skin, upon spread of the fungus through the bloodstream [14].

The Agent
Mucormycosis is caused by fungi belonging to the phylum Mucormycota and order Mucorales, which grow in all kinds of moist, decaying organic matter in the environment. As many as 261 species diversified into 55 genera comprise the order Mucorales, of which nearly 38 species have been reported to be infectious to humans. The thermo tolerant nature of these organisms empower them to grow at the human body temperature (Roden et al., 2005).

Mode of Transmission
Common route of transmission is inhalation or inoculation through trauma or surgery, with subsequent haematogenous or contiguous spread . Mucormycosis exhibits in a variety of human organs including rhino-orbital-cerebral, pulmonary, gastrointestinal, cutaneous, as well as disseminated disease. Pulmonary mucormycosis is the second most common presentation (after Rhinocerebral), representing up to 58% of infections [16], and is known for its aggressive clinical course with a mortality rate of up to 80% [17,18].

The Disease and Symptoms
Based on the site of infection, the cases of mucor mycosis were categorized as Rhino-orbitocerebral (63.9%), pulmonary (12.9%), cutaneous (9.5%), gastro intestinal (6.4%), renal (5.4%), and others [18]. The clinical symptoms and signs first appear usually in the infected body area, accompanied with fever, headache, reddish and swollen skin over nose and sinuses, dark scabs in nose, swelling of eye and problem in vision, facial pain, coughing with dark exudate, shortness of breath, abdominal pain etc.

Diagnosis
Sometimes diagnosis becomes very difficult due to non-specific symptoms. Early diagnosis of fungal infection along with the identification of the causative fungi, is needed for effective therapy. Early diagnosis of mucormycosis in humans remains elusive due to difficulty in sample collection from deep tissues and absence of a biomarker [19]. The isolation of Mucorales fails in considerable number of cases due to the delicate nature of the hyphae. The cases of mucormycosis can be diagnosed by histopathological and mycological techniques. Ribosomal DNA is targeted for precise diagnosis [20].

Treatment
Pharmaceutical formulations of amphotericin B (AmB), usually liposomal AmB (lAmB) has been used to treat mucormycosis, cryptococcal meningoencephalitis, and Candidiasis of CNS. Flucytosine, and triazoles like Voriconazole, Posaconazole, Itraconazole, Isavuconazole have been used in therapy of different fungal infections of CNS and other vital organs.
Patients managed with a combination of surgical debridement and AmB therapy had significantly lower mortality [21]. AmB, posaconazole, and deferasirox are used to treat mucormycosis patients in India.

CONCLUSION
Co-morbidity and also immunosuppression can make commensals/ saprophytes opportunistic pathogens. Mucormycosis is one such condition. Mucorales are pathogenic to both plants and humans. The India saw increasing instances of COVID-19-associated mucormycosis (CAM), a systemic fungal infection caused by the Mucorales species. The epidemiology of mucormycosis in India is different from European countries and the United States. Diabetes mellitus is the predominant risk factor in India but during the second wave of COVID-19, emergence and spread of mucormycosis since April-May 2021 has become a threat to the Covid-19 control program in India. This has been a threat to the critical care Covid-19 patients, and also convalescent ones. Due to aerosol transmission of fungal spores/ hyphae, necessity of additional safety requirements has further stressed the national COVID task force and the health system. To learn a lesson from Covid-19-Mucormycosis complex, it would be apt to plan for establishment of mechanically ventilated (100% exhaust/ fresh air) hospital wards as a routine across the country. In order to take preventive measures, COVID-19 protocols like wearing of mask, maintaining physical distance, washing of hands with soap and use of sanitizers would be of more handy.

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by personal efforts of the authors.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.