Role of Zinc and Clinicopathological Factors for COVID-19-Associated Mucormycosis (CAM) in a Rural Hospital of Central India: A Case-Control Study
Sunil Kumar, Sourya Acharya, Shraddha Jain, Samarth Shukla, Dhruv Talwar, Divit Shah, Vidyashree Hulkoti, Sana Parveen, Mansi Patel, Sujal Patel
Cureus, doi:10.7759/cureus.22528
Introduction Coronavirus disease 2019 (COVID-19)has been a difficult enemy to beat for healthcare professionals around the world. However, even before the end of the COVID-19 pandemic, there has been an emergence of a new combatant in the form of opportunistic fungal infections with a high rate of morbidity and mortality, creating havoc throughout the globe. 
 Methods A case-control single-center study was conducted in Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra. All the subjects who were included in the study were tested positive for COVID-19 through the reverse transcriptase-polymerase chain reaction (RT-PCR) method and the cases were defined as patients with biopsy-proven mucormycosis, whereas control were subjects who did not develop mucormycosis. The duration of the study was three months, from June 2021 to August 2021. 
 Result A total of 55 cases and 50 controls were enrolled in the study. The use of zinc was found to be significantly associated with COVID-19-associated mucormycosis, with 89.1% of the cases having a history of zinc intake and only 52% of controls having a history of zinc intake( p-value <0.001). Diabetes mellitus was found to be significantly associated with COVID-19-associated mucormycosis with 83.6% of the cases and 16% of the controls having diabetes mellitus (p-value <0.001). Although the use of steroids in cases was more with 98.2% of the cases and 54% of the control receiving steroids; this difference was not significant statistically (p-value of 1.00). 
 Conclusion We conclude that apart from diabetes mellitus and other immunosuppressive states, zinc might be the hidden culprit behind the sudden surge of COVID-19-associated mucormycosis worldwide owing to the selfadministration of zinc by the patients to acquire innate immunity and over-prescription of multivitamins by the treating clinicians. However, this association required further studies in order to be proved.
Additional Information Disclosures
References
Ahmadikia, Hashemi, Khodavaisy, The double-edged sword of systemic corticosteroid therapy in viral pneumonia: A case report and comparative review of influenza-associated mucormycosis versus COVID-19 associated mucormycosis, Mycoses, 
doi:10.1111/myc.13256Alanio, Dellière, Fodil, Bretagne, Mégarbane, Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19, Lancet Respir Med, 
doi:10.1016/S2213-2600(20)30237-XAlexander, Tinkov, Strand, Alehagen, Skalny et al., Early nutritional interventions with zinc, selenium and vitamin d for raising anti-viral resistance against progressive COVID-19, Nutrients, 
doi:10.3390/nu12082358Bawiskar, Talwar, Acharya, Kumar, Hematological manifestations of COVID-19 and their prognostic significance in an intensive care unit: a cross-sectional study, Cureus, 
doi:10.7759/cureus.19887Gupta, Kesavadev, Krishnan, COVID-19 associated mucormycosis: a descriptive multisite study from India, Diabetes Metab Syndr, 
doi:10.1016/j.dsx.2021.102322John, Jacob, Kontoyiannis, When uncontrolled diabetes mellitus and severe COVID-19 converge: the perfect storm for mucormycosis, J Fungi, 
doi:10.3390/jof7040298Kumar, Dronamraju, Acharya, COVID-PIRO (predisposition, insult, response, organ dysfunction) score: a reliable predictor of outcomes in COVID-19 patients admitted in intensive care unit, Cureus, 
doi:10.7759/cureus.18960Leonardelli, Macedo, Dudiuk, Theill, Cabeza et al., In vitro activity of combinations of zinc chelators with amphotericin b and posaconazole against six Mucorales species, Antimicrob Agents Chemother, 
doi:10.1128/AAC.00266-19Mishra, Prashar, Sharma, Akash, Kumar et al., Diabetes, COVID 19 and mucormycosis: clinical spectrum and outcome in a tertiary care medical center in Western India, Diabetes Metab Syndr, 
doi:10.1016/j.dsx.2021.102196Muthu, Kumar, Paul, Is there an association between zinc and COVID-19-associated mucormycosis? Results of an experimental and clinical study, Mycoses, 
doi:10.1111/myc.13365Salehi, Ahmadikia, Badali, Khodavaisy, Opportunistic fungal infections in the epidemic area of COVID-19: a clinical and diagnostic perspective from Iran, Mycopathologia, 
doi:10.1007/s11046-020-00472-7Selarka, Sharma, Saini, Mucormycosis and COVID-19: an epidemic within a pandemic in India, Mycoses, 
doi:10.1111/myc.13353Sen, Honavar, Bansal, Epidemiology, clinical profile, management, and outcome of COVID-19-associated rhino-orbital-cerebral mucormycosis in 2826 patients in India -collaborative OPAI-IJO study on mucormycosis in COVID-19 (COSMIC), report 1, Indian J Ophthalmol, 
doi:10.4103/ijo.IJO_1565_21Singh, Singh, Joshi, Misra, Mucormycosis in COVID-19: a systematic review of cases reported worldwide and in India, Diabetes Metab Syndr, 
doi:10.1016/j.dsx.2021.05.019Talwar, Kumar, Acharya, Interleukin 6 and its correlation with COVID-19 in terms of outcomes in an intensive care unit of a rural hospital: a cross-sectional study, Indian J Crit Care Med, 
doi:10.5005/jp-journals-10071-24075Thomas, Patel, Bittel, Effect of high-dose zinc and ascorbic acid supplementation vs usual care on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection. The COVID A to Z randomized clinical trial, JAMA Netw Open, 
doi:10.1001/jamanetworkopen.2021.0369DOI record:
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      "volume": "8",
      "year": "2020"
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      "DOI": "10.1111/myc.13256",
      "article-title": "The double-edged sword of systemic corticosteroid therapy in viral pneumonia: A case report and comparative review of influenza-associated mucormycosis versus COVID-19 associated mucormycosis",
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      "volume": "64",
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      "volume": "15",
      "year": "2021"
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      "DOI": "10.1111/myc.13353",
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      "year": "2021"
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      "DOI": "10.1016/j.cbpa.2009.11.008",
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      "key": "ref9",
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      "volume": "14",
      "year": "2010"
    },
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      "DOI": "10.1111/myc.13365",
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      "author": "Muthu V",
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      "volume": "64",
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      "key": "ref11",
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      "volume": "12",
      "year": "2020"
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      "author": "Jothimani D",
      "doi-asserted-by": "publisher",
      "journal-title": "Int J Infect Dis",
      "key": "ref13",
      "unstructured": "Jothimani D, Kailasam E, Danielraj S, et al.. COVID-19: poor outcomes in patients with zinc deficiency. Int J Infect Dis. 2020, 100:343-9. 10.1016/j.ijid.2020.09.014",
      "volume": "100",
      "year": "2020"
    },
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      "key": "ref14",
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      "volume": "4",
      "year": "2021"
    },
    {
      "DOI": "10.1128/AAC.00266-19",
      "article-title": "In vitro activity of combinations of zinc chelators with amphotericin b and posaconazole against six Mucorales species",
      "author": "Leonardelli F",
      "doi-asserted-by": "publisher",
      "journal-title": "Antimicrob Agents Chemother",
      "key": "ref15",
      "unstructured": "Leonardelli F, Macedo D, Dudiuk C, Theill L, Cabeza MS, Gamarra S, Garcia-Effron G. In vitro activity of combinations of zinc chelators with amphotericin b and posaconazole against six Mucorales species. Antimicrob Agents Chemother. 2019, 63:10.1128/AAC.00266-19",
      "volume": "63",
      "year": "2019"
    },
    {
      "DOI": "10.5005/jp-journals-10071-24075",
      "article-title": "Interleukin 6 and its correlation with COVID-19 in terms of outcomes in an intensive care unit of a rural hospital: a cross-sectional study",
      "author": "Talwar D",
      "doi-asserted-by": "publisher",
      "journal-title": "Indian J Crit Care Med",
      "key": "ref16",
      "unstructured": "Talwar D, Kumar S, Acharya S, et al.. Interleukin 6 and its correlation with COVID-19 in terms of outcomes in an intensive care unit of a rural hospital: a cross-sectional study. Indian J Crit Care Med. 2022, 26:39-42. 10.5005/jp-journals-10071-24075",
      "volume": "26",
      "year": "2022"
    },
    {
      "DOI": "10.7759/cureus.19887",
      "article-title": "Hematological manifestations of COVID-19 and their prognostic significance in an intensive care unit: a cross-sectional study",
      "author": "Bawiskar N",
      "doi-asserted-by": "publisher",
      "journal-title": "Cureus",
      "key": "ref17",
      "unstructured": "Bawiskar N, Talwar D, Acharya S, Kumar S. Hematological manifestations of COVID-19 and their prognostic significance in an intensive care unit: a cross-sectional study. Cureus. 2021, 13:e19887. 10.7759/cureus.19887",
      "volume": "13",
      "year": "2021"
    },
    {
      "DOI": "10.7759/cureus.18960",
      "article-title": "COVID-PIRO (predisposition, insult, response, organ dysfunction) score: a reliable predictor of outcomes in COVID-19 patients admitted in intensive care unit",
      "author": "Kumar S",
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      "volume": "13",
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      "article-title": "When uncontrolled diabetes mellitus and severe COVID-19 converge: the perfect storm for mucormycosis",
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