A review of COVID-19-associated mucormycosis in India

INTRODUCTION

Mucormycosis is a rare angio-invasive fungal infection with a worldwide prevalence of 0.005 to 1.7 per million population.¹ In India, the estimated baseline prevalence is 140 per million population, which is about 80 times greater than the global average.^1,2 Respiratory viral infections have been associated with invasive mucormycosis in the post-infectious phase in both immunocompetent and immunosuppressed patients. With the COVID-19 pandemic, there has been an unprecedented wave of COVID-19 associated mucormycosis (CAM) in the year 2020.³ The total number of cases reported in India between May to August 2021 was 47,508 cases and had 4,425 deaths during the same period of study.⁴ During the same period of study, Nepal reported twenty-two cases with four deaths, Bangladesh and Mexico reported three cases with one death.4 During our review, we wanted to explore the reasons behind the unusual rise in the cases and mortality figures.

We conducted a literature search on PubMed, Google Scholar, Embase, Harvard library databases and restricted our study to articles in the English literature on mucormycosis. Our search terms included “COVID-19 and mucormycosis”, “COVID-19 associated mucormycosis”, “mucormycosis” and “COVID-19”. We excluded articles related to pregnancy and pediatrics. All relevant articles were included in the study due to the rare clinical presentation of the fungus. This article aims to review the epidemiology, clinical presentation, treatment strategies for CAM in India.

Epidemiology and risk factors

The cases of COVID-19 have exponentially increased in India during the second wave, which began in March 2021. The most recent surge is believed to be due to newer strains such as B.1.617 +, B.1.1.7, B.1.351, and P.1.⁵ A few studies estimate a 71% CAM case contribution from India in the backdrop of COVID-19 second wave.⁶ According to a multicenter study conducted in India, the prevalence of mucormycosis doubled in the year 2020.³

A retrospective study on 2826 CAM patients in India identified the mean age of the patients as 51.9 years with a male predominance of 71%.⁷ Immunosuppressive individuals, uncontrolled diabetes, chemotherapy-induced immunosuppression, autoimmune conditions, chronic kidney disease, infectious causes of immunosuppression are at risk of CAM. In the above-cited study, a majority (87%) of the patients had a recent history of corticosteroid treatment and 78% of the patients had diabetes mellitus irrespective of the severity.⁷ The second most common comorbidity associated with CAM was hypertension followed by acute kidney injury.⁷ Additional risk factors for CAM include the use of tocilizumab and itolizumab along with the steroid therapy used in COVID-19 therapy, prolonged hospital stay or ICU, recent organ transplantation, and history of newly diagnosed malignancies, and the use of Voriconazole therapy to treat other fungal infections.⁸

Pathogenesis

Mucorales spores are inhaled, cutaneous inoculation, or ingestion to cause infection.¹⁰ Spores then transform into hyphae leading to angioinvasion, hematogenous dissemination, and multiorgan involvement. Angioinvasion leads to vascular thrombosis and tissue necrosis that prevent the penetration of leukocytes in the foci of infection.¹⁰

COVID-19 infection in diabetics leads to an imbalance in angiotensin-converting enzyme-2 (ACE-2) activation pathways creating an inflammatory response in the pancreas causing beta-cell dysfunction and hyperglycemic state.¹¹ This leads to rapid increase in glucose levels that are linked to insulin resistance and cytokine storm.^14,15 Potential similarities with severe acute respiratory syndrome coronavirus-1 (SAR-CoV-1) infection, which had long-term damage to pancreatic beta cells, and in a small subset of the population, SAR-CoV-2 can trigger diabetic ketoacidosis that persists for weeks to months after recovery from COVID infection. This could be a possible link to the late onset of mucormycosis.^1,16

Growth and dissemination of fungus

Mucorales survive by deriving host nutrition and spread by eluding recognition and response from the host immune system.¹⁵ Iron is essential for Mucorales to grow as they undergo apoptosis in iron-deprived conditions.¹⁶ Iron is acquired from the host through high-affinity iron permeases (rFTR1) secreted by fungi.¹⁷ Mucorales also use iron chelators such as ferrioxamine (an iron-rich form of deferoxamine) as xenosiderophores to capture iron.¹⁸ Iron chelator therapy with deferoxamine (DFO) enhances angioinvasion because DFO acts as a xenosiderophore after free iron is bound.¹⁹ Hyperglycemia leads to glycosylation of ferritin, transferrin, and lactoferrin, thus decreasing their iron affinity and increasing free iron. Ketone bodies and acidosis decrease the chelation ability of transferrin.²⁰ Ketoacidosis also affects neutrophil chemotaxis and phagocytosis, thus favoring the dissemination of fungus.^22,24

COVID-19 infection is associated with a cytokine storm, particularly IL-6, which stimulates the synthesis of ferritin and hepcidin synthesis.²⁶ Hepcidin seizes iron in enterocytes and macrophages by preventing its efflux.²⁵ Increased free iron reacts with oxygen, nitrogen, and sulfur to generate reactive species which leads to oxidative damage.²⁴ A hallmark of iron overload is interaction with proteins of coagulation cascade resulting in coagulopathy.²⁴

Epithelial and endothelial interactions

Spores of mucorales attach to extracellular matrix proteins, laminins, and collagen IV of damaged epithelium. Mucorales invade the host by secreting proteases, lipolytic enzymes, and subtilases.^22,30 Spore coat homolog (CotH) proteins are exclusive to mucorales and facilitate endothelial adherence.²⁷ CotH proteins help in invasion by attaching to the glucose-regulated protein 78 (GRP78) present in endothelial cells.²⁸ A study has shown ineffective endothelial invasion by Rhizopus oryzae (R. oryzae) with the use of anti-GRP78 antibodies or anti-CotH antibodies.²⁹ Hyperglycemia and acidic pH-induced availability of iron also enhance cellular expression of CotH and GRP78 proteins.²⁷ Figure 1 shows a summary of the above-mentioned pathologic mechanisms.

Downregulation of host defenses

The innate immune system like the neutrophils, macrophages, and dendritic cells forms the first layer of defense.^25,30 Toll-like receptors (TLR) recognize R. oryzae and upregulates the secretion of chemokines and cytokines from phagocytes including TNF-alpha and IL-6.^33,34 Adaptive immunity is vital in host defense, Th-1 cells by increasing the activity of phagocytes and natural killer cells by secretion of immunoregulatory molecules like INF-gamma and RANTES (CCL5).³⁰ Platelets secrete granules containing TGF-beta and thrombocidins which contain fungicidal properties, and expression of CD-154 and platelets TLR which bind to and activate macrophages and lymphocytes.^36-38 Additionally, platelet adherence and aggregation suppress hyphal growth and prevent fungal dissemination.³¹

Mucorales down-regulate the genes responsible for pathogen identification, innate immune defenses, and tissue repair mechanisms.³⁹ Neutropenia, hyperglycemia, acidosis, and iron overload are some host factors that impair phagocytic functions.²² Patients with endogenous Cushing syndrome or exogenous glucocorticoids therapy, are at increased risk of fungal infections. Decreased lymphocyte proliferation and migration of lymphocytes, impaired NK cell cytotoxicity, and impaired phagocytosis are among the mechanisms responsible for decreased immune response in these groups.³⁶

Clinical manifestations

Rhino-orbital cerebral mucormycosis

Rhino-orbital cerebral mucormycosis (ROCM) is the most common presentation in CAM patients.7 According to a study carried out in CAM patients in India, the mean interval for developing ROCM was 14.5±10 days post-COVID infection.⁷ Delayed manifestation after 14 days was observed in 44%.⁷ The most common symptoms of ROCM are orbital/facial pain (23%), orbital/facial edema (21%), loss of vision (19%), ptosis (11%), and nasal block (9%) as shown in Table 1.⁷

The diagnosis of ROCM is graded as possible, probable, and proven. Symptomatic patients with a history of less than 6-weeks post COVID-19 treatment, diabetes, steroid therapy, tocilizumab, supplemental oxygen, and mechanical ventilation can be considered as a possible case of ROCM.³⁸ Once symptoms are verified by nasal endoscopy or contrast-enhanced magnetic resonance imaging or computed tomography (CT), the patient can be classified as probable ROCM.⁴⁰ Further microbiological tests like direct microscopy, culture, biopsy with histopathology with special stains along radiological tests should be considered to term a proven case of ROCM.³⁸ The first sign seen in magnetic resonance imaging (MRI) in earlier stages of ROCM is the ‘black turbinate sign’, as shown in an axial scan in Figures 2a and 2b.⁷

Cerebral invasion and infarction are best diagnosed by magnetic resonance imaging. Imaging findings include rim enhancement on T1 post-contrast imaging, central hyperintensity on T2 sequences, and diffusion restriction, usually seen in the basal ganglia. Mucormycosis has an established affinity for this area.³⁹ ROCM is best managed by a combination of medical and surgical therapy. Medical therapy include a combination of liposomal amphotericin B and posaconazole or isavuconazole.³⁷

Surgical therapy includes functional endoscopic sinus surgery (FESS) or paranasal septal debridement.⁷ Orbital involvement may require eye exenteration and is sometimes the initial option to curb rapid fungal spread to the brain.⁷

Pulmonary mucormycosis

Pulmonary mucormycosis (PM) is the second most common form of mucormycosis after ROCM in COVID-19 patients.⁴⁰ Risk factors for PM include heme malignancies, particularly leukemia, bone marrow transplant, solid organ transplant, neutropenia, deferoxamine, and corticosteroid therapy.⁴¹ Taking into account the angioinvasive properties of the disease, patients present with fever, cough, shortness of breath, chest pain, and hemoptysis.³ PM can also present with peripheral lung cavities as shown in Figures 3a and 3b.

Imaging signs suggesting PM as described in the literature are: the “halo sign” on CT viz. is defined as a ground-glass opacity encompassing a pulmonary mass or a nodule, which pathologically represents an area of necrosis; and a focal round area of ground-glass opacity but surrounded by a crescent or a complete consolidation ring refers to the ‘reverse halo sign’ or ‘atoll sign’.⁴²

It should be emphasized that no radiological features are diagnostic of PM.³⁷ A decrease in the intensity of ground-glass opacities serves as a radiological sign of improvement in clinical status.³⁷

PM is also known to present as hydropneumothorax as shown in Figures 4a and 4b. In the only clinical trial ever conducted on mucormycosis, no radiological signs were present indicating a recovery in the first 30 days did not show negative outcomes at the end of 90 days.³⁷ This indicates that physicians should not change their decisions based on mere radiological recovery signs.³⁷ A CT-guided needle biopsy was found to be superior to BAL in diagnosing PM. CT-guided needle biopsy is contraindicated in patients with thrombocytopenia and coagulopathies, and therefore BAL is used in hematological malignancies.³⁷ Less than 50% of patients are diagnosed before death.⁴⁰ PM is usually treated with liposomal amphotericin B, in combination with isavuconazole or posaconazole. The lipid formulations have a favorable side effect profile compared to other formulations.

However, even liposomal amphotericin B causes nephrotoxicity and hypokalemia when dosed 10 mg/kg in up to 30% of cases.³⁷

Several complications have been observed, such as extensive bronchial necrosis, broncho-mediastinal fistula, and life-threatening hemorrhage.⁴²

Treatment of CAM in India

The National Center for Disease Control under the Directorate General of Health Services India emphasizes the treatment recommendations of the fungal infection study forum (FISF) to treat CAM when the availability of antifungal drugs is limited.⁴⁵ The recommendations are summarized in Table 2.⁴⁶

Steps taken to check the spread of CAM in India

FISF recommended aggressive glycemic control, steroids use to be limited to hypoxemic patients, oral steroid medications are contraindicated in patients with normal oxygen saturation in room air, glucose monitoring if a steroid is prescribed, dose and duration of steroid therapy to be limited to dexamethasone 0.1 mg/kg/day for 5-10 days.⁴⁶

Proper patient education with early signs of CAM such as facial pain, nasal blockage, excessive discharge, loosening of teeth, and respiratory difficulty should be given while leaving the COVID care facility.⁴⁶

UNIQUE CHALLENGES IN DIAGNOSIS AND TREATMENT OF CAM IN INDIA

Increasing incidence of with tuberculosis associated CAM in India

India accounts for 1.4 million global deaths due to TB annually.⁴⁷ Continuous lockdown imposed nationwide has severely affected health care services in India. The country had a severe 24% reduction in GDP from April to June 2020.⁴⁷ While the COVID-19 cases grew, the public health sector collapsed with the TB notification rate falling by 60%, and the private health sector became costlier day by day.⁴⁷ Many hospitals turned into COVID treatment facilities where only COVID patients were admitted. This led to the abrupt withdrawal of TB patients seeking healthcare. Due to the increase in the prevalence of active cases of TB, some patients with mucormycosis were co-diagnosed with TB upon presentation as depicted in the above image.⁴⁷ Poor quality of TB healthcare and high case fatality of TB can be a major driving force in the spread of mucormycosis.⁵

Co-management challenges of tuberculosis and diabetes

The coexistence of TB or DM with CAM can pose peculiar problems such as nonspecific physical signs of extensive pulmonary TB and can present as hemoptysis.⁴⁸ Treatment challenges such as the lower likelihood of sputum conversion in patients with DM, an increased risk of multidrug resistance, treatment failure or relapse is possible, polypharmacy in the elderly can cause serious unwanted side effects and decrease patient compliance.⁴⁸ Rifampicin used for TB treatment interferes with oral antifungal drug (azoles) metabolism, reducing the efficacy of treatment unless the dose is adjusted using therapeutic drug monitoring.⁴⁸

About 75 million people in India have diabetes.⁴⁸ COVID-19 can worsen diabetic control and can increase the risk of opportunistic infections. Several cases of new-onset diabetes have been reported with admissions to COVID-19, which could indicate diabetic ignorance of the Indian diaspora.⁴⁸ The unchecked use of steroids could have exacerbated hyperglycemia.⁴⁸ Inability to access pharmacy or healthcare services for routine diabetic care, inability to exercise with the closure of gyms, inability to buy medications, long pause in patient-physician interaction along with economic challenges forced many people to face diabetes or COVID-19.⁴⁸

Isavuconazole: an alternative to amphotericin

A new drug called isavuconazole showed comparable efficacy to amphotericin B and is newly approved for mucormycosis in India in February 2020 by CDSCO for adults >18 years.⁴⁹ Isavuconazonium is available in injection and oral formulation. As a loading dose, 372 mg of isavuconazonium is bioequivalent to 200 mg of isavuconazole and can be given every 8 hours to the maximum of 6 doses requiring 48 hours.⁵⁰ Maintenance dosage is similar to loading dose, given once daily via the oral route (2 capsules) or intravenous route (1 reconstituted vial) starting 12-24 hours after last loading dose.⁵⁰ Hypersensitivity to the drug is possible like Steven-Johnson syndrome which mandates discontinuation.⁵⁰ It is a substrate of CYP 3A4 and coadministration with CYP 3A4 inhibitors like ketoconazole and high-dose ritonavir is not indicated.⁵⁰ Serious hepatic adverse reactions like elevated liver function tests (LFT) have been reported.⁵⁰ Common adverse reactions are nausea, vomiting, diarrhea, headache, and elevated LFT, hypokalemia, constipation, peripheral edema, cough, and back pain.⁵⁰

CONCLUSION

Optimal treatment of CAM requires coordinated teamwork of doctors from various specialties of medicine. A high index of suspicion along with rapid screening tests should be employed to avoid devastating consequences. The long-term effects of corticosteroids on mortality and functional outcome in survivors of CAM are unknown and will be the subject of future research. As new immunomodulatory treatment strategies have evolved, it is important to investigate their interaction with steroid therapy in patients with COVID-19. Future clinical trials should focus on the adequate representation of low and middle-income areas of India to ensure the generalizability of study results adjusted to prevalent comorbidities.

It is hypothesized that cloth-based masking or double masking has a role in chronic exposure to mucormycosis infection, (as most patients with ROCM have necrotic signs on the hard palate with sinus invasion) leading to soft tissue invasion which is a subject of research. Although we have made a sincere effort to summarize the causes, there could be several confounding factors which need to be evaluated and should be considered for further research. We should form a rapid task force and employ scientific personnel to check any such surge in India in the near future.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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