key: cord-0929015-0m73c5kv
authors: Rudramurthy, Shivaprakash M.; Hoenigl, Martin; Meis, Jacques F.; Cornely, Oliver A.; Muthu, Valliappan; Gangneux, Jean Pierre; Perfect, John; Chakrabarti, Arunaloke
title: ECMM/ISHAM recommendations for clinical management of COVID‐19 associated mucormycosis in low‐ and middle‐income countries
date: 2021-07-26
journal: Mycoses
DOI: 10.1111/myc.13335
sha: 55817f7a2b8b3ef10aeb449df2e0e4341c30fdbc
doc_id: 929015
cord_uid: 0m73c5kv

Reports are increasing on the emergence of COVID‐19–associated mucormycosis (CAM) globally, driven particularly by low‐ and middle‐income countries. The recent unprecedented surge of CAM in India has drawn worldwide attention. More than 28,252 mucormycosis cases are counted and India is the first country where mucormycosis has been declared a notifiable disease. However, misconception of management, diagnosing and treating this infection continue to occur. Thus, European Confederation of Medical Mycology (ECMM) and the International Society for Human and Animal Mycology (ISHAM) felt the need to address clinical management of CAM in low‐ and middle‐income countries. This article provides a comprehensive document to help clinicians in managing this infection. Uncontrolled diabetes mellitus and inappropriate (high dose or not indicated) corticosteroid use are the major predisposing factors for this surge. High counts of Mucorales spores in both the indoor and outdoor environments, and the immunosuppressive impact of COVID‐19 patients as well as immunotherapy are possible additional factors. Furthermore, a hyperglycaemic state leads to an increased expression of glucose regulated protein (GRP‐ 78) in endothelial cells that may help the entry of Mucorales into tissues. Rhino‐orbital mucormycosis is the most common presentation followed by pulmonary mucormycosis. Recommendations are focused on the early suspicion of the disease and confirmation of diagnosis. Regarding management, glycaemic control, elimination of corticosteroid therapy, extensive surgical debridement and antifungal therapy are the standards for proper care. Due to limited availability of amphotericin B formulations during the present epidemic, alternative antifungal therapies are also discussed.

The current pandemic of Coronavirus disease (COVID-19) caused by the novel Coronavirus SARS-CoV-2 has already affected more than 174 million and has killed 3.8 million people across the world.

Mortality is causally related to the severe pneumonia caused by SARS-CoV-2 along with an aberrant host immune response in the form of a cytokine storm. Secondary infections due to bacteria and fungi increase the mortality rate. 1,2 Among fungal infections, COVID-19-associated pulmonary aspergillosis (CAPA) carries a high mortality, with an all-cause mortality ranging between 33%-80%, as the diagnosis of CAPA is difficult. [3] [4] [5] Due to overlapping clinical features of CAPA and COVID-19-associated acute respiratory distress syndrome (ARDS), the European Confederation of Medical

Mycology (ISHAM) jointly defined diagnostic criteria and management protocol of patients with CAPA. 3 Mucormycosis did not draw similar attention, as the disease was considered rare. Recent reviews on worldwide cases highlighted the importance of COVID-19associated mucormycosis (CAM) globally. [6] [7] [8] [9] Particularly the recent unprecedented surge of CAM in India has drawn worldwide attention. 10, 11 During the last year, a 2.1 time increase of mucormycosis prevalence was reported due to COVID-19 in a multicentre study in India. 10 However, this year those numbers have been exploding:

Already more than 28,252 mucormycosis cases have been reported and mucormycosis has been declared a notifiable disease in India. 12 Although the ECMM and the Mycoses Study Group (MSG) together developed a global guideline for diagnosis and management of mucormycosis, 13 we felt the need to address the specific issues related to CAM such as any misconceptions on the management, diagnosing and managing this infection that more frequently occur in low and middle-income countries (LMIC). Experts from ISHAM and ECMM prepared recommendations to help clinicians manage this infection.

Mucormycosis is caused by few genera of fungi in the order Mucorales of the phylum Mucormycota. The phylum Mucormycota comprises 55 genera with 261 species of which 38 are known to be human pathogens. 14 Common species causing mucormycosis include Rhizopus spp., Rhizomucor spp., Mucor spp., Lichtheimia spp., Apophysomyces spp., Cunninghamella spp. and Saksenaea spp. Present data suggest that Rhizopus arrhizus is the predominant agent causing CAM in India. 10 The distribution of different species varies amongst different geographical regions. For instance, Rhizopus arrhizus is the most common species in India 15, 16 and France 17 but Cunninghamella spp.is the most common in Spain. 18 Mucorales are thermo-tolerant fungi with a ubiquitous distribution. They are found on organic substrates such as decaying fruit and vegetable matter, crop debris, bread, compost piles, animal excreta and soil within indoor and outdoor environments. 19 An ecological study conducted in India revealed the presence of many species of Mucorales in soil. 20 Mucorales are also present in indoor environments such as air conditioning filters. 21, 22 A recent study from North India reported large numbers of Mucorales spores in both hospitals and outdoor air. 21 The mean spore count of Mucormycetes in outdoor samples ranged between 0.73 to 8.60 cfu/m 3 across different seasons. Within the hospital, the mean spore count was slightly higher in an airconditioned area (0.88-1.72 cfu/m 3 ) compared to a nonairconditioned area (0.68-1.12 cfu/m 3 ). 21 R arrhizus was the predominant Mucorales isolated in both indoor and outdoor air. 21 Rhino-orbito-cerebral mucormycosis (ROCM) and pulmonary mucormycosis are generally observed in patients with uncontrolled diabetes or having immunosuppressive conditions such as patients receiving corticosteroid treatment, cancer chemotherapy or immunotherapy, haematological stem cell transplants, those with prolonged neutropenia or solid organ transplants. 13, 15 In contrast cutaneous or subcutaneous mucormycosis is generally observed after trauma. 15 

The sporangiospores of Mucorales vary in size depending on species (range 3-11 µm). These spores are released from the sporangium and dispersed into the air, where a vulnerable host population may acquire an infection. Inhalation is the major route of acquiring mucormycosis. The relatively larger spores of R arrhizus get trapped in the nasal epithelium and sinuses and thus may lead to ROCM, whereas the relatively smaller spores of Cunninghamella spp. can reach the lower respiratory tract leading to pulmonary mucormycosis. 15 However, available evidence suggests that any pathogenic Mucorales species can produce any type of clinical presentation. 23 Recommendations are focused on the early suspicion of the disease and confirmation of diagnosis. Regarding management, glycaemic control, elimination of corticosteroid therapy, extensive surgical debridement and antifungal therapy are the standards for proper care. Due to limited availability of amphotericin B formulations during the present epidemic, alternative antifungal therapies are also discussed.

corticosteroids, COVID-19, diabetes, infection, Mucorales, mucormycosis, SARS-CoV-2

The major underlying disease noted in mucormycosis cases in LMICs such as India, Iran or Mexico is uncontrolled diabetes with or without ketoacidosis. 14, 21, 22, 24 Among COVID-19 patients, uncontrolled diabetes had been reported at 7%-21%. However, the prevalence in India is above 30%, with 2% of patients developing diabetic ketoacidosis. Acute or stress-induced hyperglycaemia has been noted in 50% of hospitalised COVID-19 patients. 25, 26 SARS-CoV-2 itself can induce acute diabetes and diabetic ketoacidosis by damaging pancreatic islets cells, which have a high expression of angiotensin converting enzyme-2 receptors, as has been noted with SARS-CoV-1, and indirectly by damaging small blood vessels supplying pancreatic beta cells. 27, 28 Increased resistance to insulin due to the profound inflammatory reaction, may also play some role in the induction of hyperglycaemia. 8, 29 In addition, a few cases of euglycemic diabetic ketoacidosis have been reported in COVID-19 cases, especially those receiving sodium-glucose co-transporter-2 inhibitors (SGLT2). 30, 31 Type 2 diabetes mellitus itself is an immunocompromised state which leads to dysregulated, dysfunctional innate and adaptive immune cells making the host susceptible to infections by Mucorales. 32 Due to increased glycosylation, IL-10 production by lymphocytes and macrophages is significantly reduced. Diabetes mellitus also reduces polymorphonuclear leukocyte mobilisation and chemotaxis. 32 Hyperglycaemia and acidosis can induce phagocytic cell dysfunction leading to increased risk of Mucorales infections.

In a multicentre study from India, inappropriate corticosteroid use was noted in 63.3% patients. 10 The situation was aggravated further during the second wave of COVID-19, when steroids were used indiscriminately and inappropriately to overcome the challenge of the oxygen acquisition crisis and resulting oxygen desaturation in patients. The over-the-counter availability and the practice of selfmedication with corticosteroids complicates the situation even further. The use of corticosteroids in the treatment of COVID-19 may act as a double-edged sword. Firstly, corticosteroids can increase blood glucose levels by acting as a substrate for oxidative stress metabolism with lipolysis, proteolysis and hepatic glucose production.

They also increase insulin resistance in up to 60%-80% of patients depending on the dose and type used. 33 Secondly, they affect virtually all immune cells. Some major immune suppressive actions of corticosteroids are given as: (i) antagonism of macrophage maturation and differentiation, (ii) decrease of interleukin-1, interleukin-6, tumour necrosis factor, proinflammatory prostaglandins and leukotrienes production by macrophages, (iii) suppression of microbicidal activity of activated macrophages. 34 They also suppress neutrophil adhesion to endothelial cells and impair lysosomal enzyme release, respiratory burst and chemotaxis to the site of infection. 34 Increased risk of infection following glucocorticoid therapy is well established, but the dose and the duration of steroid therapy required to increase the risk of different infections is not as well defined. 35 

Iron overload and deferoxamine therapy are well-known risk factors for mucormycosis. 36 The free iron captured by siderophores of Rhizopus species helps in its growth. 36 Severe COVID-19 is a hyperferritinaemic state due to hyperinflammation. 37 In severe COVID-19 patients, ferritin level rises 1.5 to 5 times higher than in non-severe cases (average ferritin concentration of >800 μg/L). 37 High IL-6 concentrations in COVID-19 patients have been correlated to disease severity. 38 IL-6 directly stimulates ferritin production and increases the synthesis of hepcidin which in turn sequesters iron in enterocytes and macrophages thus preventing them to efflux from these cells leading to increased intracellular iron load. 39 This excess intracellular iron generates reactive oxygen species (ROS) causing damage to the tissue and free iron is released in the circulation and available to Mucorales. 8, 9, 38 

Comparison of autopsy lung specimens obtained from expired patients due to COVID-19 and those with acute respiratory distress syndrome (ARDS) secondary to influenza A (H1N1) infection, has revealed severe vascular endothelial injury along with the presence of intracellular virus and disrupted cell membranes in COVID-19 deceased patients. Pulmonary vessels show widespread thrombosis along with significantly higher (9 times, p < .001) alveolar capillary microthrombi in COVID-19 patients compared to patients with influenza. 40 Thrombosis can also occur in small veins supplying the pancreas, thereby damaging it and causing insulin deficiency leading to diabetes mellitus. 41 As endothelial adhesion and penetration is an early step in establishing mucormycosis, 36 endothelial damage observed in severe COVID-19 disease may play an important pathogenic role. 8

Hyperglycaemia is a stress condition that induces the overexpression of the glucose regulated protein (GRP78) which is present in the lumen of the endoplasmic reticulum and expressed in mammalian cells. 42 The CotH protein kinase belonging to the spore coating protein family in Rhizopus acts as the ligand for GRP78, which helps the fungus to adhere and invade endothelial and nasal epithelial cells. 43 Sabrili et al demonstrated significantly higher serum GRP78 levels in COVID-19 patients compared to a COVID-19 negative control group. These findings suggest amplified pathogenetic role of GRP78 in CAM. 44 Therefore, the pathogenesis of CAM is a complex issue, in which environment, vulnerable patients, corticosteroid use and COVID-19 play synergistic roles in the disease pathogenesis ( Figure 1 ).

During the present epidemic nearly 90% of cases presented as ROCM and <10% as pulmonary or disseminated disease. 10 Cutaneous mucormycosis is rarely reported in SARS-CoV-2 infected patients. 9, 10 Early diagnosis of CAM cases helps in prompt treatment which, in turn, reduces the mortality or morbidity of this infection. CAM can occur while the patient is actively suffering from the disease, during the in-hospital recovery stage or post-discharge after recovering from SARS-CoV-2 infection. 9,10 Some important points to be considered while clinically diagnosing these conditions are described below. One should suspect CAM in any SARS -CoV-2 infected (present or past) uncontrolled diabetic patient who received corticosteroid therapy and develop the following features.

Early warning signs of ROCM include facial pain, nasal blockade or congestion, bloody/brown/black discharge with or without local tenderness or pain. This can be associated with fever, nausea and headache. Nasal ulcers or crusts turning black later in the course of disease are often noted. Furthermore, patients may develop facial numbness or oedema during involvement of the maxillary, frontal or ethmoidal paranasal sinuses. Palatal involvement may be noted in the form of an ulcer over the upper palate leading to a dark necrotic area ( Figure 2A ). It may also present as toothache and/or loosening of maxillary teeth and restriction of jaw movement which was not noted during pre-COVID-19 times. 10 With invasion into the orbit the patient may initially have blurring of vision or diplopia, orbital pain, paraesthesia or proptosis ( Figure 2B ). The orbital apex syndrome without pain has also been well described. An eschar may be seen in the nasal septum, palate, eyelid, face or orbital areas. Cranial nerve palsies are also common. With invasion of the brain the patient may present with features of cerebral oedema such as coma, and vascular invasion may lead to cerebral infarcts. Another common presentation includes sinus cavernous thrombosis a loss of vision.

Solitary pulmonary CAM is difficult to diagnose and a radiological imaging is needed as several symptoms may overlap with pulmonary features of COVID-19 and of invasive aspergillosis. 6 Fever, cough, haemoptysis, chest pain and pleural effusions are generally present.

However, features such as haemoptysis, and tissue infarction are particularly characteristic of pulmonary mucormycosis. 6,10 Pulmonary mucormycosis is usually the form observed in neutropenic patients. 

In case of suspicion of ROCM, patients should undergo imaging studies such as computed tomography (CT) or magnetic resonance F I G U R E 1 Schematic representation of pathogenesis of COVID-19-associated mucormycosis. This illustration was prepared using BioRender software imaging (MRI) of brain and paranasal sinuses. MRI has an advantage over CT as it can determine the extent of fungal invasion whereas CT is better in identifying the bony erosion, which is noted in advanced stages of infection. 13 Radiological features of ROCM are mucosal thickening and opacification of the sinuses, oedema, inflammation or infarction of the brain ( Figure 2C,D) .

Radiological features of pulmonary mucormycosis are nonspecific and difficult to interpret as many features overlap with other fungal pneumonias such as pulmonary aspergillosis. The reversed halo sign is commonly associated with pulmonary mucormycosis. 9 Other features include signs of pleural effusions and multiple nodules. Lung CT may be confused with COVID-19 related shadows. In such cases, mucormycosis should be suspected when there is a thickwalled lung cavity (need to differentiate from COVID-19-associated pulmonary aspergillosis), reverse halo sign, multiple nodules and pleural effusions 13 (Figure 3 ). 

Early and aggressive surgical resection and debridement of the affected tissues is necessary for local control of mucormycosis. 13 In ROCM infection complete debridement of the external infected tissues including bones as well as internal tissues by endoscopic debridement or orbital exenteration results in higher survival rates. 13 In cases of recurrence, repeated resection and debridement is necessary.

In pulmonary mucormycosis, resection of the affected lung (if localised or single lobe is involved) may be beneficial to the patient by preventing him/her from undergoing emergency surgery for controlling bleeding in a later course of disease further increasing the chance of survival. However, we recommend to follow the global guideline on mucormycosis after the availability of antifungal drugs. 13 Itraconazole is generally not recommended for the management of mucormycosis.

In fact, there are only few case reports available using itraconazole either alone or in combination with amphotericin B for mucormycosis. 52 

Steps to prevent or reduce the occurrence of COVID-associated mucormycosis and misconception on the terminology and acquisition of infection is depicted in Figure 6 .

An urgent attention is essential to curb the epidemic of CAM in (Figures 1 and 6 ). 

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COVID-19-associated pulmonary aspergillosis

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Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes

SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas

COVID-19 Endocrinopathy with hindsight from SARS

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Iron: innocent bystander or vicious culprit in COVID-19 pathogenesis?

Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19

COCID-19 and diabetes mellitus: from pathophysiology to clinical management

The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice

CotH3 mediates fungal invasion of host cells during mucormycosis

High GRP78 levels in Covid-19 infection: a case-control study

Molecular diagnosis of rhino-orbito-cerebral mucormycosis from fresh tissue samples

Molecular identification of pathogenic fungi in formalin-fixed and paraffin-embedded tissues

Conventional PCR as a reliable method for diagnosing invasive mucormycosis in resource-limited settings

Challenges in the diagnosis and treatment of mucormycosis

Evaluation of MucorGenius® mucorales PCR assay for the diagnosis of pulmonary mucormycosis

Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis

Fungal Infections Study Forum. Treatment of Covid associated mucormycosis

Rhinocerebral mucormycosis in an adolescent with type 1 diabetes mellitus: case report

Zygomycosis caused by Cunninghamella bertholletiae in a kidney transplant recipient

Paranasal mucormycosis: Unusual presentation in otherwise healthy child

A multicentre observational study on the epidemiology, risk factors, management and outcomes of mucormycosis in India

Multicenter evaluation of MIC distributions for epidemiologic cutoff value definition to detect amphotericin B, posaconazole, and itraconazole resistance among the most clinically relevant species of Mucorales

ECMM and ISHAM. ECMM/ISHAM recommendations for clinical management of COVID-19 associated mucormycosis in low-and middle-income countries