The double trouble: COVID-19 associated mucormycosis a focused review and future perspectives

INTRODUCTION

Mucormycosis, formerly known as zygomycosis, a disease caused by the many fungi that belong to the family “Mucorales.” Fungi in this family are usually found in the environment – for example, in soil and are often associated with decaying organic material such as fruit and vegetables. The fungus that is often responsible for infections in humans is Rhizopus oryzae. However, the family Apophysomyces found in tropical and subtropical climates (as in India), are commonly identified as the infective agents. Although mucormycosis epidemiology has been challenging to study due to its low incidence and diagnostic limitations, cases have continued to rise in diverse populations.^[1-6] Given that the immunocompromised patients with hematological diseases and patients with a metabolic syndrome characterized by diabetes mellitus (DM) are at particular risk of mucormycosis. COVID-19 has raised a primary global concern of COVID-19 Associated Mucormycosis (CAM) outbreak.^[7]

SARS-CoV-2 infection has rapidly spread worldwide, infected over 178,566,293 people, caused more than 3,865,904 deaths in 220 countries, and is still spreading at the time of manuscript preparation (worldometers.info).^[8] So far, there is no definite line of the approved treatment for this disease except for the vaccines (based on the mRNA and adenovirus technology) that have been approved for emergency use and several candidate vaccines under investigation. Early in the outbreak, concerns have been raised regarding the use of non-steroidal anti-inflammatory drugs (NSAIDs) associated with an increased risk of adverse effects in COVID-19 patients. However, the WHO concluded no evidence of adverse events resulting from NSAIDs use in COVID-19 patients in April 2020.^[9] Several antiviral drugs and immunotherapies have been evaluated and are under clinical trials. As of October 22, 2020, the antiviral drug Veklury (remdesivir) is the only drug fully approved for the treatment of COVID-19 in hospitalized adults and children of age 12 years and older who weigh at least 40 kg (fda.gov).^[10] The FDA issued an emergency use authorization (EUA) for convalescent plasma on August 23, 2020 and the monoclonal antibodies (bamlanivimab plus etesevimab) as of April 2021 (www.fda.gov).^[11,12] The FDA note stated that COVID-19 convalescent plasma is human plasma collected from individuals whose plasma contains anti-SARS-CoV-2 antibodies, and who meet all donor eligibility requirements (21 CFR 630.10 and 21 CFR 630.15) and qualifications.^[11] It is an investigational product and is not currently approved or licensed for any indication. The initial issuance of this EUA for COVID-19 convalescent plasma was based on review of historical evidence using convalescent plasma in prior outbreaks of respiratory viruses, certain preclinical evidence, results from small clinical trials of convalescent plasma conducted during the current outbreak, and data obtained from the National Convalescent Plasma Expanded Access Protocol sponsored by the Mayo Clinic.^[11] Systemic corticosteroids are indicated in patients with severe and critical COVID-19.^[13,14]

In late May 2021, according to the articles published in the lay press – Business Standards,^[15] Times of India,^[16] the surge of the number of cases of mucormycosis (black fungus) in people recovering from COVID-19 led to the declaration of the black fungus an epidemic in four states in India by making it a notifiable disease under the Epidemic Diseases Act 1897.^[16] Mucormycosis occurs most commonly in immunocompromised patients and patients with uncontrolled diabetes.^[17,18] The patients with iron overload are also susceptible to mucormycosis.^[19] Clinical evidence suggests that both mononuclear and polymorphonuclear phagocytes are the principal host defense mechanism against Mucorales.^[1] The patients with neutropenia and dysfunctional phagocytes are at high risk of developing mucormycosis. Hyperglycemia and acidosis allow the proliferation of the fungus by impairing the chemotactic ability of phagocytes toward the organism.^[20] Corticosteroid therapy also enhances the patient’s susceptibility to mucormycosis by impairing the role of bronchoalveolar macrophages in preventing spore germination following nasal inoculation and causing functional defects in circulating neutrophils.^[21]

ASSESSMENT OF THE CAM OUTBREAK

Based on the anatomical locations, mucormycosis can be divided into the following categories – rhino-cerebral, pulmonary, cutaneous, gastrointestinal, disseminated, and miscellaneous.^[1,2] The emerging case of mucormycosis in association with COVID-19 from the published studies has been reviewed with outcomes that will benchmark and provide an avenue for both treatment and management of the conditions.^[22-26] Table 1 summarizes the characteristics of the mucormycosis cases. The studies show that the prevalence of mucormycosis is more in male patients compared to female patients.^[22-26] Singh et al.,^[22] in their systemic review on 101 cases of mucormycosis in COVID-19 patients, identified DM (83.3%) and corticosteroid therapy (76.3%) as the most common risk factors, and upper respiratory tract involvement (88.9%) as most common findings and reported the mortality in 30.7% cases. Similarly, John et al.,^[23] reported a mortality rate of 48.7%. It was interesting that of all the cases of COVID-19 associated mucormycosis about 80.4–96.7% of the patients had the DM (mean HbA1C ~10) and 87.8% patients were on corticosteroid therapy.^[22-24] Ravani et al.,^[24] in their retrospective study, reported uncontrolled DM (97.7%), COVID-19 infection (61.2%), and corticosteroid use (61.2%) as significant risk factors, whereas pansinusitis (77.41%) and orbital cellulitis (61.29%) were common presentation. In addition, authors also reported the mortality rate of 9.78%. Sharma et al.,^[25] in their study, reported 23 cases of mucormycosis. They found that all cases were related to COVID-19 and ethmoids were the most common affected sinus. There was an intra-orbital extension in 43.47% of cases and intracranial extension in 8.69% cases.^[25] They also reported that the diabetes and steroids as risk factors. Interestingly, Pakdel et al.,^[26] reported CAM cases during the first wave (April–September 2020) of the COVID-19 pandemic compared to most of the other studies. A case of gastrointestinal mucormycosis in an elderly patient of COVID-19, which is a rare disease but has a mortality up to 85% had been reported.^[27] The reader is referred to the review of Singh et al. which articulates that those individuals with diabetes and obesity tend to develop more severe COVID-19 infections, and subsequent addition of corticosteroids will increase the risk of mucormycosis.^[22] Caution regarding any conclusion is of the essence, given that there are currently no studies that compare patients of mucormycosis in non-diabetic COVID-19 who did not receive steroids versus COVID-19 patients who received steroids and developed mucormycosis.^[22] It is not easy to establish a cause-and-effect relationship between SARS-CoV-2 infection, mucormycosis, and corticosteroids.^[22]

PATHOPHYSIOLOGY AND MANAGEMENT OF CAM

COVID-19 can trigger mucormycosis by alterations in cell-mediated immunity, such as chemotaxis, phagocytosis, and cytokine secretion in susceptible patients.^[28] Certain conditions such as uncontrolled DM with or without diabetic ketoacidosis, hematological malignancies, corticosteroid therapy, organ transplantation, prolonged neutropenia, immunosuppressive agents, and iron overload increase the patients’ risk for developing mucormycosis.^[29] Song et al.,^[30] suspected the fungal co-infection association with global COVID-19 pandemic in a retrospective analysis, especially in severely ill or immunocompromised patients and provided a diagnostic/therapeutic pathway in the management of aspergillosis, candidiasis, mucormycosis, or cryptococcosis as co-morbidities in COVID-19 patients. Pandiar et al.,^[31] asserted that SARS-CoV-2 crafts a suitable microenvironment for opportunistic infections like mucormycosis by dysregulation of Angiotensin-Converting Enzyme-2 (ACE-2) expression not only in lungs but also in esophagus, pancreas, ileum, colon, cardiovascular, and renal tissues. COVID -19 produces an acute diabetic like state due to its effects on ACE-2 in the pancreatic beta cells and produces hyperglycemia.^[32,33] Lactic acidosis due to damage to type II alveolar cells causing the cell to convert to anaerobic glycolysis, which is a known risk factor for mucormycosis. Dysregulation of ACE-2 in the vascular endothelium leads to endothelial damage and vascular thrombosis. Many ICU-related vascular interventional procedures (like central venous access) and ventilatory support can also lead to vascular endothelial injury and venous stasis. An elevated serum ferritin and serum iron level due to hemolysis and acidosis, respectively, provides a source of nutrition to Mucorales.^[34] Lymphopenia is also a feature of COVID-19 infection.^[32,35] In addition, R. oryzae is a fast-growing organism at 3 mm/h at 36°C that allows mucor to grow first when optimal conditions are met.^[31,36] Mucor species are thermotolerant and can efficiently survive the raised temperature associated with COVID-19 infection.^[31] No similar mucor outbreaks in immunocompromised patient populations, like those with diabetes, cancer, receiving chemotherapy, and steroids, prompt toward the unique cascade triggered during COVID-19 as the likely causative for CAM. Similarly, the hypothesis of the use of industrial oxygen as the trigger for mucormycosis outbreak seems weak, as causative fungi are ubiquitous so may not be directly affected by additional carrier like oxygen. In addition, mucor cases recorded in patients without oxygen use further bolsters alternate reasoning for the outbreak rather than the industrial oxygen usage. Overall, from the above observations, we believe that COVID-19 itself produces immunosuppression, insulin resistance, and an independent risk factor for mucormycosis.

Direct microscopy, histopathology using H and E staining and culture are the cornerstones of diagnosis.^[37] Mucormycosis is suspected on direct microscopic examination of clinical specimens such as sputum, paranasal sinus secretions, bronchoalveolar lavage and skin lesions, preferably using optical brighteners. The fungi are characterized by broad and non-septate hyphae. The culture of a specimen is strongly recommended to confirm the diagnosis. High-dose liposomal amphotericin B is the first line of drug, while new oral antifungal posaconazole is recommended for step-down or salvage therapy after initial amphotericin B treatment.^[38] Delaying amphotericin B therapy increases mortality significantly.^[39,40] Prompt surgical debridement remains the cornerstone for better survival outcomes.^[38-40]

A few studies have suggested the role of nutraceuticals in the treatment of COVID-19. The natural compounds andrographolide, berberine, curcumin, mangiferin, nimbin, piperine, theaflavin, withaferin A, gallic acid, luteolin, naringenin, quercetin, resveratrol, and zingiberene exhibited a binding affinity for the ACE-2 receptors and inhibit the attachment of the SARS-CoV-2 virus to the host cell.^[41,42] The anti-inflammatory properties of the spices can be exploited to reduce the cytokine storm in COVID-19 patients.^[42,43] Diet may have the ability to mitigate inflammation, and nutraceuticals may become accountable to inhibit viral entry. The role of dietary nutraceuticals can be evaluated as an additional measure in the management of CAM.

CONCLUSION

Mucormycosis is an invasive opportunistic infection leading to rhino-orbito-cerebral infection as the most common presentation. Studies show a rising trend of the life-threatening CAM in affected and recovered patients globally and more so in India. A significant increase in the CAM cases is strongly associated with systemic corticosteroid administration in the diabetic patients treated for COVID-19. SARS-CoV-2 directly triggering immunosuppression, insulin resistance through the cytokine cascade should be explored as an independent risk factor for CAM. Whenever mucormycosis is suspected, due to rapid progression and angioinvasive nature, swift diagnosis and treatment should be initiated. Hence, a high index of suspicion, early diagnosis, tight glycemic control, and elimination of steroid use are recommended. Prompt radical surgical debridement, liposomal amphotericin B, and posaconazole are the standard of care as of now. The role of dietary nutraceutical can be evaluated as a supplemental measure.