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 Table of Contents  
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 69-74

Epidemiology and management of mucormycosis in India – Pre- and Post-COVID-19

Department of Microbiology, Apollo Hospitals, Chennai, Tamil Nadu, India

Date of Submission07-Oct-2021
Date of Decision22-Oct-2021
Date of Acceptance18-Dec-2021
Date of Web Publication21-Jan-2022

Correspondence Address:
Nandini Sethuraman
Department of Microbiology, Apollo Hospitals, Greams Road, Chennai, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/japt.japt_42_21

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Mucormycosis is a spectrum of highly invasive infections caused by filamentous fungi belonging to the order Mucorales. Typically known as a disease of the immunocompromised and uncontrolled diabetic host, the COVID-19 pandemic uncovered new and hitherto unknown facets of this disease. A thorough knowledge of its epidemiology, methods of diagnosis, and treatment options available is important to manage the carnage this disease has unveiled upon us in current times. This review provides an updated understanding of the existing problem of mucormycosis in India and the added burden due to the COVID-19 pandemic and provides an insight into the challenges involved in making a diagnosis and managing these debilitating infections.

Keywords: Amphotericin B, COVID-associated mucormycosis, Mucorales, mucormycosis

How to cite this article:
Sethuraman N. Epidemiology and management of mucormycosis in India – Pre- and Post-COVID-19. J Assoc Pulmonologist Tamilnadu 2021;4:69-74

How to cite this URL:
Sethuraman N. Epidemiology and management of mucormycosis in India – Pre- and Post-COVID-19. J Assoc Pulmonologist Tamilnadu [serial online] 2021 [cited 2022 May 16];4:69-74. Available from: http://www.japt.com/text.asp?2021/4/2/69/336172

  Introduction Top

Mucormycosis is a highly invasive fungal infection which, albeit rare, is associated with a very high mortality rate or diminished quality of life among survivors. Classically described as a disease that occurs in patients with hematological malignancies (HMs) and those undergoing hematopoietic stem cell transplantation (HSCT) or solid organ transplantation, it is increasingly being described in patients with uncontrolled diabetes with or without diabetic ketoacidosis (DKA), especially in India. The disease is caused by a group of fungi classified under order Mucorales which are characterized by their aseptate or pauciseptate hyphae and rapidity of growth. They are frequently found on decaying organic material like bread and fruit. Spores of these fungi are found ubiquitously in tropical climates both indoors and outdoors, especially in settings of high soil exposure like agriculture and construction work. With the advent of COVID-19 in India, the prevalence of this disease has spiraled out of control due to a myriad of possible reasons discussed below. Diagnosis is a challenge, especially in pulmonary mucormycosis due to nonspecific radiological signs, lack of reliable biomarkers, and requirement of invasive sampling for tissue diagnosis, and requires a high index of suspicion in the appropriate host. Treatment commonly involves a combination of surgery to debride all infected tissue along with antifungal agents with very limited options. This review will outline the various aspects of this disease, especially with respect to what has been known so far prior to COVID-19 and what new data have emerged ever since.

  Disease Burden Pre-COVID-19 Top

In a recently published meta-analysis of 851 cases reported between 2000 and 2017, a majority of cases were from Europe (290/851; 34%), followed by Asia (267/851; 31%) and the Americas (239/851; 28%).[1] This may have been due to gross underreporting from Asia. India in particular has reported large numbers of cases, especially from a single center.[2],[3],[4],[5] That center reported 129 cases between 1990 and 1999, 178 cases during the next 5 years (2000–2004) and then 75 cases during 2006–2007. Another center from Tamil Nadu reported 184 cases in the period between 2005 and 2015.[6] Later on, a couple of multicentric studies reported several hundreds of cases between 2013 and 2019 from India.[7] These data indicate that mucormycosis is being increasingly reported possibly because it is being increasingly well recognized. Susceptible populations are also increasing with advances made in medicine and overall burden of lifestyle diseases like diabetes. Although multicentric studies provide a window into the possible burden of the disease, population-based or large-scale community data are only emerging from India.

Population-based incidence data are available in some countries with the help of large multicentric studies. Such a study from Spain reported the prevalence of mucormycosis at 0.43 cases per million population per year and 0.62 cases per 100,000 hospital admissions.[8] In France, a nationwide population-based study revealed that the prevalence rate of 0.7 cases per million in 1997 rose to 1.2 per million in 2006.[9] In other cases, estimated incidence was calculated with the help of mathematical modeling to reflect true incidence considering that reported cases may only be a proportion of actual cases occurring. According to the Leading International Fungal Education (LIFE) portal, prior to the COVID-19 pandemic, the annual prevalence of mucormycosis in the world apart from India was around 10,000 cases.[10] Another computational modeling study suggested that the population prevalence in India is about 14/100,000 population in India.[11] This put the pre-COVID-19 prevalence of mucormycosis in India at around 70 times higher than the global average.

  Risk Factors Top

Some of the first insights into invasive mucormycosis were provided by the review of 929 cases by Roden et al. in 2005.[12] Following this review, many other large case series and systematic reviews of literature have been published.[2],[13] The disease most commonly affects individuals with lowered immunity due to uncontrolled diabetes with or without diabetic ketoacidosis (DKA), neutropenia, hematological or solid organ malignancies, hematopoietic stem cell, or solid organ transplant recipients and those receiving high-dose, long-term corticosteroid therapy.[13] Breakthrough mucormycosis may also occur in hematological patients on voriconazole prophylaxis to prevent aspergillosis.[14] In India, uncontrolled diabetes remains the most important risk factor and proportion of mucormycosis reported from other vulnerable populations remains relatively low.[7] A minority of patients may not have any underlying risk factor, especially in the case of cutaneous and renal mucormycosis.[15] Rhino-orbito-cerebral mucormycosis (ROCM) has also been occasionally described in immunocompetent individuals.[16] Cutaneous mucormycosis often follows traumatic injury to skin and consequent soil exposure. Cutaneous variety has also been reported in health-care settings where the source was identified as contaminated elastoplast adhesive bandages and contaminated hospital linens.[17],[18]

There is some variation in the risk factors associated with the different forms of mucormycosis. For example, the ROCM form is most associated with diabetes followed by HMs. Whereas the pulmonary variety is more common among those with HM. Gastrointestinal (GI) mucormycosis was seen in a large number of neonates following surgery for necrotizing enterocolitis in a single center.[19] There are also reports of hospital-acquired GI mucormycosis due to contaminated wooden tongue depressors and karaya ostomy bags.[20],[21]

Iron overload states and deferoxamine therapy have an important role in the pathogenesis of mucormycosis. The iron chelated by deferoxamine is used up by siderophores on Rhizopus species, thereby promoting its growth. An international registry on dialysis patients with 70% of them having no other comorbidity had a total of 59 cases of mucormycosis. The common feature among 78% of these patients was deferoxamine therapy which was then identified as the risk factor.[22] Other iron chelators were not associated with higher risk of mucormycosis.

  Etiology Top

The most common species causing mucormycosis include Rhizopus arrhizus, Rhizopus microsporus, Rhizomucor pusillus, Lichtheimia spp., Cunninghamella bertholletiae, Apophysomyces elegans, Mucor racemosum, and Saksenaea vasiformis. In India, a few rare species including Apophysomyces elegans, Mucor irregularis, Rhizopus homothallicus, and Thamnostylum lucknowense have been described.[15] These fungi are found ubiquitously in both indoor and outdoor environments. The spore counts have been found to be higher during construction activities due to soil disruption.[23] Infection is acquired mainly by inhalation of sporangiospores and occasionally by ingestion or inoculation of spores.[24] Spore counts in Indian air reveal a high burden of Mucorales, especially more so in outdoor air and near construction activities.[23]

  Clinical Types Top

Rhino-orbito-cerebral mucormycosis

This is the most common clinical variety of mucormycosis world over and India in particular. The spectrum ranges from involvement of the nasal turbinates and paranasal sinuses alone (rhinosinusitis), expansion into the orbit and ocular structures (rhino-orbital) to involvement of the brain (rhinocerebral). Cerebral involvement often results in poor prognosis and high mortality rate of over 50%. As the fungus is highly angioinvasive, this progression can happen in a span of days, especially in patients with DKA or profound neutropenia which makes early recognition of the infection vital. In India, this is often the presenting complaint for diabetes as the latter remains undiagnosed in a vast majority of the population without access to regular screening and diabetogenic diet and lifestyle.[4]

Symptoms may start with facial pain, congestion, and headache. With further tissue invasion, affected tissues become red and necrotic and patients may present with facial, nasal, or palatal necrotic eschars. Concomitant cough may indicate further pulmonary involvement. Further invasion of contiguous structures by the fungal hyphae can result in complications such as cranial nerve involvement and cavernous sinus thrombosis and cerebral involvement. Imaging can reveal severe sinusitis and bony erosion but may not be specific enough to diagnose ROCM. Computed tomography and magnetic resonance imaging scans are more sensitive and can reveal mucosal thickening, air-fluid levels, bony erosion, and extent of involvement. Extraorbital muscle thickening is an early sign of orbital involvement. Definitive diagnosis requires appropriate sampling of affected tissues including the necrotic eschars if present and subjecting them to microscopy, histopathology, and fungal cultures.

  Pulmonary Infections Top

Pulmonary mucormycosis is most encountered in patients with profound neutropenia, HMs, and hematopoietic stem cell transplantation. It may also occur as an extension of ROCM. Diagnosis is of paramount importance as the disease is not immediately apparent and may radiologically mimic other fungal pneumonias. They are associated with high mortality rates of over 50%, especially when diagnosis and appropriate antifungal therapy is delayed.[25] A common radiological finding in early stages of pulmonary mucormycosis is the reversed halo sign, but this is not specific to mucormycosis and can be seen in pulmonary aspergillosis, organizing pneumonia, and more recently in COVID-19 as well.[26],[27],[28]

Symptoms do not become apparent until much later in the disease where large parts of the lung get involved, especially in patients whose immunity is already depressed due to HM/HSCT or their treatments. Symptoms include nonresponsive fever, nonproductive cough, dyspnea, and pleuritic chest pain. The fungus can invade neighboring structures and, being highly angioinvasive, result in large cavitary lesions with hemoptysis. Clinical clues more suggestive of pulmonary mucormycosis rather than aspergillosis include nonresponsiveness to voriconazole, multiple nodular infiltrates (>10), reverse halo sign, pleural effusion, and nonelevation of fungal biomarkers such as beta-D-glucan or galactomannan in serum or bronchoalveolar lavage (BAL).[26],[29] Other imaging findings include predominant upper lobe and often bilateral involvement.[30] Pulmonary vessel thrombosis results in wedge-shaped infarcts. Endobronchial fine-needle aspiration of lesions can aid in the diagnosis.

  Skin and Soft-Tissue Mucormycosis Top

These are often a result of extensive trauma and resultant inoculation of spores into the injured tissue. This clinical form may be seen even in immunocompetent individuals. Cutaneous mucormycosis is also the most common type of hospital-acquired mucormycosis, and outbreaks have been reported from the use of contaminated linen and adhesive bandages.[17],[18] The spectrum and progression of cutaneous mucormycosis ranges from erythema and induration with eschar formation. This may quickly progress to involve deeper layers of cutaneous and subcutaneous tissues leading to necrotizing fasciitis. The rate of progression may be even more among neutropenic patients.

  Gastrointestinal Mucormycosis Top

This is a less common form of mucormycosis seen in relation to outbreaks due to contaminated tongue depressors and karaya ostomy bags. Preterm neonates with necrotizing enterocolitis are also at high risk of GI mucormycosis. GI tract may also get secondarily involved because of hematogenous invasion. It is often diagnosed late due to subtle signs and symptoms. Clinical presentation may start as a fever with enterocolitis and progress to severe colonic ischemia, peritonitis, and gut perforation.

  COVID-19-Associated Mucormycosis Top

An unexpected by-product of the COVID-19 pandemic, especially in India, has been the exponential surge in mucormycosis cases. Even though the baseline mucormycosis rate in India was 70 times more than the Western world, the first wave of COVID-19 was closely followed by a doubling in the number of cases compared to 2019, as per a multicentric study from 16 centers in India between September and December 2020.[31] An estimated total of 287 cases were reported in India in 2020 in this study period. However, the massive second wave in 2021 was immediately followed by a deadly wave of mucormycosis cases. An early global study on COVID-19-associated mucormycosis (CAM) conducted in 2020 showed that 53% of reported cases were from India, followed by the USA (10%) and Pakistan (6.3%).[32] The health-care system was caught unawares by this surge to such an extent that essential antifungals needed to treat mucormycosis like liposomal and conventional amphotericin B were in short supply. By the 3rd week of July 2021, over 45000 cases had been reported and the disease had claimed over 4300 lives and a majority of the survivors continued to have significant morbidity with loss of vision and disfigurement.[33]

Apart from the known risk factors of diabetes, COVID-19 itself and its treatments are now seen as strong risk factors for mucormycosis. The RECOVERY trial concluded that the usage of corticosteroids at a dose of 6 mg dexamethasone or equivalent a day for 7–10 days in patients with moderate-to-severe COVID-19 requiring oxygen would result in better clinical outcomes.[34] However, an uncontrolled use of higher and longer doses of steroids was shown to be a strong risk factor in many of the cases.[31] Unavailability of other drugs such as tocilizumab, remdesivir, and even oxygen may have led to the overuse of steroids to compensate. The virus per se is also an independent risk factor, as was witnessed in a few patients without prior diabetes or requiring steroids, albeit to a smaller extent. This is postulated to be due to destruction of beta-cells of pancreas which also carry the ACE-2 receptors.[35] Hyperglycemia that goes unchecked during high-dose corticosteroid therapy for COVID-19 is a contributing factor. The resultant hyperglycemia and hyperferritinemia (especially in DKA) are fertile ground for mucormycosis. Hyperglycemia upregulates GRP78 receptor on endothelial cells which also acts as a co-receptor for COVID-19, thus forming a vicious circle. CotH3 (spore coat protein) located on the surface of R. arrhizus cell surface is the fungal ligand for the GRP78 receptor.[36] The CotH3–GRP78 binding is responsible for entry of mucormycosis into the nasal epithelial and endothelial cells, probably leading to the high incidence of ROCM in COVID-19.

Dysregulation of iron homeostasis is a hallmark of moderate-to-severe COVID-19, as is witnessed by increased levels of serum ferritin in response to inflammation. This consequently elevates free serum iron as well as intracellular iron. Increased interleukin-6 levels and macrophage activation further elevate ferritin levels. Intracellular iron leads to the formation of reactive oxygen species and free radicals that lead to cellular, especially endothelial destruction termed as “endothelialitis.”[37] Growth of Rhizopus is spurred on by this increased serum iron, and endothelial damage encourages hyphal invasion.[38]

The incidence of pulmonary mucormycosis in COVID-19 has been comparatively low even though the latter is a pneumonia-causing damage to lung tissue. This may also be because pulmonary mucormycosis is difficult to diagnose, especially in the setting of COVID-19 where there is hesitancy to do bronchoscopy to prevent COVID-19 transmission.

  Laboratory Diagnosis Top

Microscopy is a crucial rapid test for the immediate diagnosis of mucormycosis from a well-collected specimen. A simple potassium hydroxide (KOH) mount, supplemented by a fluorescence brightener such as calcofluor or Blankophor white, are preferred techniques for rapid visualization of broad (6 to 25μm), irregular, aseptate or pauciseptate, hyaline, ribbon-like hyphae, within a few hours of sample collection. Invasive specimens are usually required for increasing the yield – such as nasal or palatal lesion scrapings, endoscopic sinus debrided tissues for ROCM, or a concentrated BAL or FNA of lung lesions. The hyphae are apparent on hematoxylin and eosin stains, however, special stains such as periodic acid–Schiff and Gomori's methenamine silver are needed for clear morphological evaluation.

Cultures are needed to confirm mucormycosis as microscopy may occasionally not differentiate aseptate from septate hyphae on histopathology. Culture is also needed for speciation of the Mucorales which can have therapeutic implications. For example, species like Cunninghamella have higher minimum inhibitory concentrations (MICs) to amphotericin B and Mucor circinelloides have higher MICs to isavuconazole.[39] Mucorales grow rapidly on Sabouraud's dextrose agar at 37°C. However, the sensitivity of culture may be only about 50% despite visualization of hyphae on microscopy. Excessive tissue homogenization or prior antifungal therapy reduces sensitivity.

Molecular techniques like polymerase chain reaction have been studied for mucormycosis, and a few commercially available and several in-house tests have been evaluated. A big limitation for these highly sensitive techniques is the ubiquitous presence of fungi that may lead to false-positive results in unsterile specimens. DNA extraction is also challenging from tissues and formalin fixed paraffin embedded (FFPE) specimens which limit the utility of this technique routinely, not to mention the associated cost. Available tests require further standardization to be reproducible across laboratories. Therefore, these techniques when available must be used in combination with conventional techniques and not as standalone tests. Other molecular techniques like matrix-assisted laser desorption ionization–time of flight can be utilized to identify fungal species from culture with the ever-expanding database. Mucorales-specific labeled antibodies in immunohistochemistry and probes in fluorescent in situ hybridization can aid in differentiation from other fungi in tissues.

  Treatment Top

To successfully manage mucormycosis, a multidisciplinary approach is crucial and includes early diagnosis, correction of risk factors, early antifungal therapy, thorough removal of infected tissues, and other adjunctive therapies. Correction of risk factors includes bicarbonates to correct ketoacidosis, rapid tapering off of corticosteroids, and improving white cell counts where possible. These fungi are highly invasive, and treatment delays can result in worsening of prognosis. Early debridement of all infected tissues can avoid extensive surgery to remove large parts of the sinuses, eyes, and orbits in ROCM or involved lung lobes in pulmonary mucormycosis which may become inevitable with delays in diagnosis and institution of appropriate therapy. Chamilos et al. showed that delaying amphotericin B-based therapy in patients with mucormycosis with underlying HMs for >5 days resulted in a twofold increase in mortality at 12 weeks (82.9% compared to 48.6% for those who started treatment immediately.[25]

Immediate and rapid initiation of antifungal therapy is recommended along with complete removal of infected tissue. Among the available antifungal classes, Mucorales are intrinsically resistant to echinocandins, fluconazole, and voriconazole. The drug of choice as per the ECMM/ESCMID guideline is liposomal amphotericin B at a dose of 5–10 mg/kg/day given in 5% dextrose over 2–3 h, with the highest dose recommended for cerebral involvement.[40] Doses higher than 10 mg/kg are not associated with better outcomes and lead to significant rise of creatinine and must be avoided.[41] It is important to pre- and postload amphotericin B dose with 500-ml normal saline to reduce toxicity. When amphotericin B cannot be given due to preexisting renal compromise, isavuconazole IV (200 mg thrice daily for the first 2 days followed by 200 mg from day 3) or posaconazole IV (300 mg twice daily on day 1 followed by once daily) can be given as an alternate regimen. Weekly assessments of response to therapy should be made in terms of clinical and radiological improvement. Step-down to oral posaconazole or isavuconazole from IV amphotericin B can be done once progression of disease is arrested. There is no definitive duration for which treatment should be given and this needs to be personalized to each patient. Treatment must, however, be continued until complete reversal of immunosuppression or achievement of glycemic control and resolution of symptoms.[40]

COVID-19 posed a unique challenge resulting in unavailability of antifungal drugs for mucormycosis. A guideline was proposed for CAM by the ECMM/ISHAM group suggesting amphotericin B deoxycholate at 1–1.5 mg/kg/day infused slowly over 6–8 h in the absence of liposomal form.[42] Conventional amphotericin B is significantly more toxic than the liposomal form and requires stringent monitoring of renal parameters, serum potassium and magnesium. Posaconazole or isavuconazole monotherapy have also been sugegsted as alternatives.

Experimental therapies including combination of polyenes with caspofungin and terbinafine require further research. Combination of deferasirox for iron chelation has been studied under two small randomized controlled trials and found to have no benefit, probably warranting larger studies.[43]

  Concluding Remarks Top

Mucormycosis though previously considered rare has unveiled itself in the course of the COVID-19 pandemic. The increasing prevalence of vulnerable populations including diabetics and patients on immunosuppressive medication has led to increased recognition of this entity. Clinical diagnosis requires a high index of suspicion. Appearance of classical symptoms such as ptosis and palatal ulcers usually means that it is already very late. In the COVID-19 setting, high-risk patients getting discharged after treatment for COVID-19 must be apprised of the early warning symptoms of mucormycosis such as facial swelling, headaches, and facial or tooth pain. Early diagnosis with availability of skilled microscopists is pivotal for management. Multimodal approach to therapy is needed including reversal of risk factors, surgery, and antifungal medications. A better understanding of disease pathogenesis with specific biomarker development, targeted immunotherapy, and newer antifungal targets are our hope for the future for dealing with this deadly disease.

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Conflicts of interest

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