Review on mucormycosis – A gloom epoch

COVID-19-associated mucormycosis

Mucormycosis is one of the numerous opportunistic infections seen during COVID-19. Several studies have shown that uncontrolled diabetes mellitus and diabetic ketoacidosis are the major risk factors to develop this disease. Increased free iron levels in the serum as a result of hyperglycaemia and a hyperacidic state can predispose to mucormycosis. COVID-19 creates some favorable conditions for mucormycosis. Hyperglycemia, hyperferritinemia, hypoxia, attenuated phagocytic activity, etc., are the favorable conditions produced by COVID-19 and cause immunosuppression.^[16] Artis et al. reported that the susceptibility of endothelial cells to Rhizopus is increased by high glucose and iron levels.

The immune system of the individual is suppressed by the corticosteroids that were given during the COVID-19 treatment.^[17] Mucormycosis together with COVID-19 is actually a deadly companion. The nose, sinuses, orbit, CNS, lungs, mediastinum, GIT, jaw bones, skin, heart, kidney, joints, and abdominal portion are the target sites of mucormycosis. In both diabetic and non-diabetic patients, the species found was Rhizopus. Rhizopus thus plays an important role in the mucormycosis caused by COVID-19. Patients are more prone to secondary infections such as mucormycosis due to the series of events that are caused by COVID-19. In severe cases of COVID-19, there is a decrease in CD4+ and CD8+ groups, which predisposes to mucormycosis as a result of immunosuppression. The mortality rate of 30.73% in patients with COVID-19 and mucormycosis was reported by SeyedAlinaghi, S et al.^[18] AIDS, organ transplantation, malignancies, neutropenia, iron overload, malnutrition, etc., can also predispose to mucormycosis. Through the enhanced production of stress hormones, insulin resistance increases in severe COVID-19. Steroids play an unavoidable role in COVID-19-associated mucormycosis.

Diabetes and mucormycosis

From various studies conducted on different geographical areas, it is seen that different geographical areas have considerably different risk factors. Diabetes mellitus was a risk factor in India, Iran, and Mexico, as well as hematological malignancy in Europe. Stemler et al. conducted studies in countries in the Middle East and North Africa. This study reveals that diabetes mellitus was one of the leading underlying conditions for mucormycosis. As the number of diabetes mellitus cases increases, it is expected that there will be an increase in mucormycosis cases. In India, the majority of the mucormycosis cases were reported and also in patients with uncontrolled diabetes mellitus as the major risk factor in these cases. A multicenter study was conducted on mucormycosis in India recently. This study reveals that 57% of patients have uncontrolled diabetes and an additional 18% have diabetic ketoacidosis.^[19] The morbidity and mortality of COVID-19 increase when diabetes mellitus acts as the major risk factor. In his review, Jeong et al. revealed that in 40% of cases, the underlying condition is diabetes mellitus and diabetic ketoacidosis in 20% of cases.

In patients with uncontrolled diabetes mellitus, the most common occurrence is rhino-orbital cerebral mucormycosis, because high blood sugar is a favorable environment for growth and flourishment of Rhizopus.^[20] The acidic pH and increased free iron concentration will be an important factor for rhino-orbital cerebral mucormycosis. Diabetic ketoacidosis leads to uncontrolled hyperglycemia, which causes a drastic change in the immune response of the individual. In addition to that, the enzyme ketone reductase from Mucorales will increase the glucose level and diabetic ketoacidosis. According to a review by John et al., diabetes mellitus was an underlying condition in 93% of cases of mucormycosis. In some patients, a euglycemic state was also found. In all the aspects of COVID-19 infection, diabetes stands as a separate or independent risk factor for mucormycosis specifically in rhino-orbital cerebral mucormycosis.

Overall mortality is high for rhino-orbital cerebral mucormycosis. It is an angioinvasive fungal infection that affects brain and paranasal sinuses. Immunocompromised patients are at high risk for developing rhino-orbital cerebral mucormycosis,^[21] as depicted in [Figures 1 and 3].

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Figure 3:

Mucormycosis invasion in hard palate.

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Earlier diagnosis is needed for this type of mucor invasion. Clinical manifestations, radiological findings and Histological analysis aid in diagnosis. The most important microscopic feature is broad-based ribbon-like non-septate hyphae with irregular right-angled branching, which acts as a key diagnostic feature.^[22] To find out the extent of the disease, computed tomography (CT) imaging should be done. Internal carotid artery and cavernous sinus thrombosis, bony erosions, and ethmoid or sphenoid sinusitis with orbital or intracranial extensions are the associated pathological findings.^[23] Glycemic control should be strictly followed for the management of rhinocerebral mucormycosis.

Investigations

Clinical signs, histological findings, and radiological results aid in diagnosis. The most frequent locations for specimen collection are the paranasal sinus and nasal cavity. Broad aseptate hyphae are visible histologically.^[24] The visualization of fungal hyphae is improved with the use of flurorescent brightners,potassium hydroxide and Lactophenol cotton blue stain. Also for the histological examination hematoxylin and eosin, Periodic acid schiff, Grocott-Gomori methanamine silver stains are used. In computed tomography the classical finding of mucor invasion is seens as reverse halo sign and in immunodeficient mucormycosis affected patients the CT will show nodules with a halo of ground-glass opacity around them. In addition, a number of molecular techniques are becoming available for fungal diagnosis. Several PCR-based methods have been developed for the detection of fungal spores.^[25] Burnha-Maurish et al. have stated that in the sandwich ELISA technique, a monoclonal antibody is found to be highly reactive with purified glucomannan of species mucor. Afterward, lateral flow immunoassays were developed, which are more convenient than ELISA for the detection of fungal spores.

Management

The first important matter for the management of mucormycosis is the removal of predisposing factors. Metabolic abnormalities should be corrected as earlier as possible. Intravenous antifungal drugs are given. Amphotericin B at a dosage of 5–10 mg/kg/day is the first-line treatment for mucormycosis. Posaconazole intravenously is given as a second line of treatment. Isavuconazole is the other active antifungal drug which can be administered with surgical drainage and debridement to be done.

Limitations of the review

However, there are a few limitations to this review wherein the entire aspect of mucormycosis is not covered related to studies conducted and epidemiology of mucormycosis.