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Resurgence of mucormycosis during COVID-19 pandemic

Objective To explore the literature on corona-associated mucormycosis and explain its relevance to dentists and oral surgeons. Methods A literature search was carried out to identify reported cases on corona-associated mucormycosis since the start of COVID-19 pandemic. Results A review of literature identified 265 published papers on CAM between March 2020 and September 2021. Careful screening of abstracts and full texts revealed 29 studies reporting case series of CAM and, 27 case reports on CAM. Conclusions A multitude of factors may be responsible for the alarming rise in the incidence of corona-associated mycosis including reduced access to routine medical services during the pandemic, injudicious use of antibiotics, steroids and nutritional supplements. Risk factors contributing to corona-associated mucormycosis need to be recognized. Dentists and oral surgeons can contribute to early recognition of corona-associated mucormycosis involving the maxilla, and palate. Prioritizing research focus on optimal management of mucormycosis may reduce the morbidity and mortality associated with this debilitating infection.


Introduction
Mucormycosis is a fulminant, potentially fatal, opportunistic fungal infection. It affects immunocompromised patients, and its mortality rate has been reported to be as high as 80%. First described as Phycomycosis by Paltauf in 1885, the term mucormycosis was introduced by Baker in 1957 and still remains in use [1,2]. Currently, Mucorales fungi are the next most common mold pathogens after Aspergillus, leading to invasive fungal disease in susceptible patients.
Mucormycosis is primarily seen in patients with immunosuppression. Due to the increasing incidence of diabetes mellitus, cancer, and growing number of organ transplantations, the number of patients at risk for this deadly infection is increasing. Despite aggressive therapy including surgical debridement and adjunct antifungal therapy, morbidity and mortality following mucormycosis remains high. New strategies to prevent and treat mucormycosis are warranted. A better understanding of the pathogenesis and host response to mucormycosis may provide targets for novel therapeutic interventions in the future [3].
Based on clinical presentation and involvement of typical anatomic regions, mucormycosis is classified into five clinical types namely, (i) rhino-cerebral, (ii) pulmonary, (iii) cutaneous, (iv) gastrointestinal, and (v) disseminated. These categories of invasive mucormycosis tend to occur in patients with specific defects in host defense. For example, patients with diabetes mellitus (DM) complicated by ketoacidosis typically develop the rhinocerebral form of the disease, and much more rarely develop pulmonary or disseminated disease [4].
The rhino-orbito mucormycosis (ROM) is the most common type of mucormycosis [5,6]. The disease process starts with inhalation of the fungus into the paranasal sinuses. The fungus may spread to invade the palate, maxilla, orbit, or centrally to involve the brain. If untreated, infection usually spreads from the ethmoidal air sinuses to the orbits, resulting in the loss of extraocular muscle function and proptosis [7]. Classically, the clinical presentation has been described as an orbital cellulitis with proptosis, and neuropathies including loss of vision. ROM frequently involves the palate and maxilla (Fig. 1). Necrotic exposure of the palatal bone may the first clinically visible manifestation of the disease and patients may initially present to dentists or oral and maxillofacial surgeons. Similarly, neuropathies involving the trigeminal or facial nerve may initially present to oral and maxillofacial surgeons (Fig. 2).
Optimal management of mucormycosis is complicated due to lack of well-defined predictors of clinical response to interventions and high risk of morbidity. Mucormycosis is more commonly reported from countries with poor socio-economic profile and has not received adequate focus in contemporary clinical research. Diagnosis of mucormycosis is based on clinical assessment, and relevant laboratory investigations [8]. Imaging techniques can provide useful information regarding the extent of specific organ involvement but are not conclusive. Histopathology, microbial identification with polymerase-chain reaction (PCR) tests are the key investigations to establish a definitive diagnosis [9].
Current management options focus on control of risk factors and a combination of anti-fungal therapy and surgical debridement of infected tissues. Owing to its broad-spectrum antifungal activity, traditionally amphotericin B has been the antifungal agent of choice for the treatment of mucormycosis [8][9][10][11][12]. Other options include posaconazole and isavuconazole [13]. Adjunctive measures to manage mucormycosis include irrigation of infected tissues with Amphotericin B, hyperbaric oxygen therapy and iron chelators. However, lack of robust evidence precludes their routine use in the management of mucormycosis.
The aim of this paper is to review current evidence on Corona-associated mucormycosis (CAM) following the start of COVID-19 pandemic.

Review of literature on corona-associated mucormycosis
This paper is based on a review of published literature and did not involve collection of new data. Therefore, the study was exempt from ethics approval. Images used in this paper were obtained after an informed consent from patients.
A review of literature identified 265 published papers on CAM between March 2020 and September 2021. Careful screening of abstracts and full texts revealed 29 studies reporting case series of CAM and, 27 case reports on CAM. Table 1 summarizes the key features of CAM reported in case series. M of studies from reporting CAM were from India.
Data from a total of 3856 patients included in 29 studies showed that at least 3000 (~80%) had pre-existing DM. Other underlying conditions included hypertension, ischemic heart disease, chronic kidney disease, and steroid therapy as depicted in Table 1.
In addition, 27 case reports on CAM were also published during this period. The case reports mirror patterns observed in studies included in Table 1 and majority of the reported cases were in adult males. DM was the most common underlying health condition and the clinical presentation included ROM; RCM while pulmonary involvement was observed in seven cases.
An alarming rise in the incidence of mucormycosis has been witnessed globally following the COVID-19 pandemic. Opportunistic fungal infections such as Aspergillosis, Candidiasis and mucormycosis are being reported increasingly in patients with COVID-19 [14]. Similarly, a 26.7% rise in the incidence of invasive fungal diseases has been reported in a multicenter cohort of COVID-19 intensive care patients in the UK, including a 12.6% incidence of invasive yeast infections [15]. Recent evidence also suggests that the fungal infections in COVID-19 positive patients may actually be under-reported [16].
CAM is an emerging public health concern. Based on the published literature. Hoenigl et al. analyzed 80 cases of CAM, with over 50% cases only from India [15]. Similarly, seven countries in the American continent have reported 16 cases of CAM up to June 9, 2021 [17,18].
Based on the published literature, India contributed to approximately 71% of global cases of CAM from December 2019 to start of April 2021, with majority of the cases occurring during the second wave [19]. Mucormycosis (Black fungus) during the second wave of COVID-19 has been described as an epidemic within a pandemic More than 31,000 cases have already been reported so far across India and more than 2100 people have died as a result of the disease. Majority of cases from India have been reported from the state of Maharashtra followed by Rajasthan, Gujarat, Madhya Pradesh, Haryana, Delhi, and Punjab. Cases of mucormycosis have more than doubled in India in late 2020 compared to the corresponding months of 2019 which suggests a direct correlation between COVID-19 and mucormycosis. Cases have been reported from every state of India and it is now included in the list of "notifiable" diseases [20]. Mucormycosis in India was predominantly seen in males and included both in individuals with active infection as well as those who had recovered from COVID-19. Mucormycosis involving nose and sinuses was most common followed by rhino-orbital involvement   [21]. A prospective observational clinical study investigated clinical manifestations of rhino-orbital mucormycosis (ROM) in COVID-19 positive patients. Among 32,814 patients hospitalized with the diagnosis of COVID, 11 cases of mucormycosis were observed. The mean time-interval between COVID-19 diagnosis and ROM diagnosis was 14.4 ± 4.3 days. Seven patients (63.6%) had orbital apex syndrome, and four patients (36.4%) presented with orbital cellulitis [22].

Pathogenesis of mucormycosis in COVID-19 patients
A multitude of factors may be responsible for a sharp rise in the incidence of CAM. Injudicious use of steroids, antibiotics and nutritional supplements as self-medications increased during the COVID-19 pandemic. These trends were particularly common in countries where public has access to prescription medicines over the counter. Imprudent use of these medications may lead to immunosuppression and the dysbiosis of microbiota, rendering the high-risk groups even more vulnerable to mycotic disease [23]. Moreover, COVID-19 pandemic has impacted adversely on healthcare services globally and access to routine medical services for patients with chronic diseases has been compromised. Poor access to medical care, and inadequate monitoring of diseases such as DM may have contributed to the rising incidence of CAM.
Immune response to mucorales involves generation of oxidative free radicals and the cationic peptides such as, defensins. Tissue hypoxia secondary to COVID-19 provides a favorable environment for germination of mucorale spores and compromises phagocytic potential [23]. COVID19-mediated immune-dysregulation not only leads to a deficient innate immune response, but also leads to reduced activity of T lymphocytes [24]. High levels of pro-inflammatory cytokines developing as a result of COVID-19, promote fungal colonization and infection [18]. Furthermore, hyperglycemia and acidosis, as encountered in uncontrolled diabetics, also lead to reduced oxygen-dependent and oxygen-independent phagocytosis [4]. Finally, endothelial damage in COVID-19 may provide an additional pathway to promote mucorale adhesion and tissue penetration [25].

Conclusions and recommendations
CAM represents a double whammy and carries a poor prognosis overall. Prevention of CAM is the most fundamental strategy and hinges on vaccination, social distancing measures and reduction of risk factors such as immunosuppression secondary to DM, steroids and other immunosuppressive medications. Unlike COVID-19, mucormycosis has existed for well over a century. However, mucormycosis has not received adequate focus in clinical research and continues to show significant morbidity and high mortality in susceptible patients. Rapid advancements in medical research following the COVID-19 pandemic have enabled production of vaccines and other adjunctive therapies [26]. Mucormycosis has received a renewed focus during the COVID-19 pandemic due to high mortality rates in many countries, especially India. Whilst unfortunate, the recognition of CAM should be used as an opportunity to dedicate more resources to fund research for developing evidence-based clinical care protocols and therapies for mucormycosis. Dentists can also play their part in recognition of CAM as they may be the first members of the healthcare teams to identification of oral manifestations of COVID-19 including dry mouth, dysgeusia, oral ulcerations and opportunistic infections [27]. Additionally, involvement of the palate, maxilla may be the first signs of mucormycosis and patients may initially present to dentists and maxillofacial surgeons, providing early opportunities for diagnosis and prompt management.

Data availability statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Funding
Open access funding was provided by the Qatar National Library.

Credit author statement
Shiraz Altighani carried out the literature search. K Ali was responsible for drafting of the manuscript.

Declaration of competing interest
None of the authors have any conflict of interest to declare.