Black fungus outbreak in India - A direct consequence of COVID-19 surge: A myth or reality.

The deadly second wave of COVID-19 has seen an unprecedented surge in mucormycosis associated mortality in India, overwhelming the heath authorities with challenges beyond measure. Also known as black fungus, this life-threatening fungal infection usually manifests in the nose, spreads to the eyes, and in some cases also to the brain. Immune suppression, pre-existing conditions, prolonged and indiscriminate use of steroids, and unhygienic environments are some of the widely recognized risk factors for contracting black fungus in individuals recovered from COVID-19. However, diagnosis of the infection remains insufficient due to the lack a holistic understanding of the possible risks, symptoms, and exposure pathways and therefore no definite protocol exists for managing this fatal infection. Here, we synthesize the current state of knowledge on black fungus outbreak in India and identify key gaps in its understanding with respect to potential risk factors leading to the widespread infection. We looked at 3354 black fungus cases in India, enlisting ailment history (particularly diabetes) and steroid usage in COVID-19 patients as the key factors responsible for exacerbating risks associated with the disease. However, we also press on the possibilities that other less studied non-traditional risk factors may also have a role in causing the infection. Black fungus is therefore a reality of COVID-19, with or without diabetes or steroid use needs to be investigated. We believe such a review is imperative for making informed decisions specially around timely diagnosis and channelizing efforts in controlling the spread of COVID-19 associated mucormycosis.

Introduction

Corona Virus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a cause for national health concerns (CSSE, 2021, Changotra et al., 2021, Chelani and Gautam, 2021, Gautam and Hens, 2020, Rajput et al., 2021, Selarka et al., 2021). As India is fighting the second wave and running an active vaccination drive (20% fully vaccinated) (Our World in Data, 2021), officials are anticipating a third wave (Sen et al., 2021). Amidst these challenges, complications associated with COVID-19 including enhanced vulnerability to secondary fungal infections has crippled the countries healthcare system (Hughes et al., 2020, Mehta and Pandey, 2020). Among the many invasive fungal infections, mucormycosis, also known as black fungus, has been increasingly diagnosed in patients recovered from COVID-19 (Moorthy et al., 2021, Rao et al., 2021).

Black fungus infects the sinus, lungs, and skin, and occasionally gastrointestinal tract and other areas (Garg et al., 2021). It is among the most life-threatening infection with an overall all mortality rate of 54% (CDC, 2021, Roden et al., 2005). Death rate associated with black fungus is however subjective to underlying conditions of the patient, type of fungal species, and site of infection (Ravindra and Ahlawat, 2021). For instance, among the sinus, pulmonary, and disseminated infections, mortality rate has been observed as 46%, 76%, and 96%, respectively (Roden et al., 2005). Black fungus can spread among people of any age group, including children (Francis et al., 2018). One-sided facial swelling, headache, and shortness of breath are some commonly observed symptoms associated with the disease (Centers for Disease Control and Prevention (CDC), 2021). Facial structure abnormalities including that of the eyes and teeth are the commonly observed clinical manifestations (Arora et al., 2021, Rao et al., 2021). Occasionally, fungal infection can spread to the brain (also known as rhinocerebral mucormycosis) leading to altered consciousness, coma, and even death (Arora et al., 2021).

Immune suppression, pre-existing conditions, prolonged and indiscriminate use of steroids, and unhygienic environments are some of the widely recognized factors leading to the emergence of black fungus in patients recovered from COVID-19 (Banerjee et al., 2021, Deng et al., 2021, Duffy et al., 2014, Hughes et al., 2020, Moorthy et al., 2021). However, uncertainty still lingers around a definitive treatment protocol (Sen et al., 2021) largely because of insufficient diagnosis due to the lack a holistic understanding of the possible risks, symptoms, awareness of the possible symptoms and exposure pathways. By the means of our review, we aim to provide a comprehensive understanding of the current state of knowledge on mucormycosis outbreak in India and identify key gaps in its understanding with respect to potential risk factors leading to the widespread infection. We systematically review scientific literature for mucormycosis cases in India to explore patient demographics including gender, ailments history, and COVID-19 treatment regime and provide evidence for the factors responsible for exacerbating risks associated with the disease. We believe insights from this review can help officials in making informed decisions including timely diagnosis and channelizing their efforts in controlling the spread of black fungus in India.

Clinical forms of black fungus

Among the major invasive fungal species, mucormycetes has been found to be responsible for most infections globally. Notably, Iran, India, Australia, France, and Mexico have shown a high proportion of mucormycetes based cases (Fig. 1 ). Although mucormycetes is the prevalent species in India, apophysomyces and lichtheimia species have also been found to be associated with a significant proportion of fungal infections (Petrikkos et al., 2012, Roden et al., 2005).

Fig. 1

Major causative agents for black fungus reported worldwide.

Black fungus takes many clinical forms based on the anatomical site of involvement. The most common forms as reported by two case studies from India are shown in Fig. 2 (Jeong et al., 2019, Prakash and Chakrabarti, 2021). Rhino-orbital-cerebral mucormycosis (ROCM) is involved in 50% of the infections, 18% infections are cutaneous, pulmonary mucormycosis contributes to 8% of the cases, 4% cases are related with gastrointestinal mucormycosis, disseminated infections are usually 3%, while 2% are renal infections (Jeong et al., 2019; Prakash and Chakrabarti, 2021). Breast (Kataria et al., 2016), ear (Prakash et al., 2019), spine (Hadgaonkar et al., 2015, Shah and Nene, 2017), heart (Bharadwaj et al., 2017, Krishnappa et al., 2019), and bone infections (Bhatt et al., 2018, Urs et al., 2016) are some of the other less frequent sites of infection reported in India (Prakash and Chakrabarti, 2021).

Fig. 2

Major clinical forms of black fungus in India and their prevalence.

Black fungus outbreak in India

India accounted for around 70% of the world’s black fungus cases between December 2019 and April 2021 (John et al., 2021, Raut and Huy, 2021), with 14 of every 100,000 individuals being infected (Singh et al., 2021a, Singh et al., 2021b). Between May 6th and August 3rd, 2021, 47,508 cases and 4425 deaths were reported in India, with the total reported cases and deaths rising exponentially starting June 2021 (Fig. 3 ) (Government Stats-Mondat, 2021). However, actual figures are expected to be higher than these numbers.

Fig. 3

Total number of black fungus cases and deaths reported in India (between May and August 2021). Source: GovernmentStats.com.

By the starting of May 2021 most of the Indian states reported black fungus cases. Among the infected regions, Maharashtra, Gujrat, Andhra Pradesh, Tamil Nadu, Karnataka, Rajasthan, Telangana, Uttar Pradesh, and Madhya Pradesh accounted for over 80% of the cases (Fig. 4 ) (Government Stats-Mondat, 2021); maximum cases were reported in Maharashtra and Gujrat (9654 and 6846 respectively). Most of these states also reported comparatively higher number of deaths, except for Telangana where only 9 deaths were reported against 2449 cases of infection. Kerala and Puducherry were among the regions where few number of cases (73 and 2, respectively) and no death casualties were reported.

Fig. 4

State-wise black fungus cases and deaths reported. Grey regions in the map depict states for which data were not available. Source: GovernmentStats.com.

Methods

We conducted a systematic review of literature to identify black fungus cases in India using the Web of Science database and Google scholar using keywords “Mucormycosis” OR “Black Fungus” AND “COVID19” OR “Corona Virus” OR “SARS CoV2”. We only include articles published between January 2020 until September 2021 which restricts our review to COVID-19 associated black fungus infections only. We only included studies reporting patients from India and published in English. Publications with a single case report were excluded from the analysis to avoid ambiguity (many review articles included in our study have already accounted for these case studies). Articles focussed on only a specific form of mucormycosis were also excluded from the review. The detailed methodology flow chart for conducting the systematic review using PRIMA guidelines is provided as supplementary data, Fig. S1.

Result and discussions

Summary of patient demographics from scientific literature

The sudden spike in mucormycosis during the second wave of COVID-19 can be attributed to a synergistic interaction of numerous factors (Ong et al., 2021). To enumerate the potential risks contributing to black fungus infection in COVID-19 patients, we identified nine case studies reporting demographics for a total of 3354 mucormycosis patients in India (Table 1 ). All the patients had COVID-19 associated mucormycosis. On an average (geometric mean), patients were predominately males (72%). Prevalence of diabetes mellitus and history of corticosteroid treatment were found to be the most common predisposing risk factors among the subjects (Fig. 5 ). Four studies also reported hypertension as a common comorbid illness among patients (Meher et al., 2022, Rao et al., 2021, Selarka et al., 2021, Sharma et al., 2021). Around 78% patients were administered with corticosteroids as a part of COVID-19 treatment regime, indicating its critical role in the infection pathway. However, a comparative analysis of patient characteristics across the selected case studies shows that not all but 71% of the patients had diabetes mellitus. This also agrees with the observations by Garg, et al. 2021 where traditional risk factors like diabetes were found to be absent in 42% of the subjects (Garg et al., 2021). Nevertheless, with or without the traditional risk factors, COVID-19 is responsible for weakened immunity in patients even after recovery which make them susceptible for secondary infections. This points towards the possibility that other potential risk factors might be responsible for causing the infection in individuals with COVID-19. However, even if it is not fully understood if COVID-19 on its own increases the risk to black fungus (in the absence of diabetes or steroid use), correlation between the two is certainly not a myth. Most, if not all causative factors were some ways or the other, found to be a repercussion of COVID-19 infection.

Table 1

Summary of COVID-19 associated black fungus cases in India (reported in literature).

Number of patients	Sex ratio (M:F)	Diabetes Mellitus (% patients)	Corticosteroid treatment (% patients)	Reference
28	1:0.27	96	46	Rao et al., 2021
101	1:0.26	80	77	Singh et al., 2021a, Singh et al., 2021b
187	1:0.34	21	79	Patel et al., 2020
47	1:0.34	77	100	Selarka et al., 2021
2826	1:0.41	78	87	Sen et al., 2021
18	1:0.13	84	84	Moorthy et al., 2021
23	1:0.53	91	100	Sharma et al., 2021
13	1:0.18	62	85	Singh et al., 2021a, Singh et al., 2021b
111	1:0.42	94	60	Meher et al., 2022

Fig. 5

Demographics for select black fungus patients in India focussing on gender, diabetes mellitus, and corticosteroid treatment history.

Proposed pathway for incidence of black fungus in COVID-19 patients

COVID-19 patients already have a suppressed immune system (immunosuppression with fewer CD4+ T and CD8+ T cells, a condition called lymphopenia) (Sharma et al., 2021) and lower oxygen levels (a condition called hypoxia) (Singh et al., 2021a, Singh et al., 2021b), reducing one’s ability to fight infections. At the same time, high glucose levels (a condition called hyperglycemia) due to diabetes mellitus (new-onset or pre-existing) with or without diabetic ketoacidosis (a complication of diabetes mellitus) stimulates the proliferation of fungal spores by providing a fertile acid-rich or low pH media (as in case of diabetic ketoacidosis) (Afroze et al., 2017, Singh et al., 2021a, Singh et al., 2021b). Hyperglycemia also reduces the iron binding capacity leading to increased amount of free serum iron, an ideal environment for the growth of the opportunistic fungal spores (Ibrahim et al., 2008). A similar phenomenon is also observed in COVID-19 patients, whereby increased secretion of cytokines lowers the iron transport rate surpassing its production and increasing the susceptibility to black fungus (Singh et al., 2021a, Singh et al., 2021b).

The risk of contracting black fungus as a secondary infection in diabetic individuals is exacerbated by the intake of corticosteroids, an anti-inflammatory drug used for treating acute respiratory distress syndrome and hyper-inflammation triggered by the novel SARS-CoV-2 (Fig. 6 ) (Alessi et al., 2020, Deng et al., 2021, van Paassen et al., 2020). For instance, in a cohort study conducted in Bangalore, India, significant association (p = 0.0013) was found between the occurrence of black fungus in COVID-19 patients with diabetes and on corticosteroid treatment (Moorthy et al., 2021).

Fig. 6

Risks associated with corticosteroid treatment regime in COVID-19 positive diabetic patients; other factors exacerbating black fungus outbreak.

Prolonged use of corticosteroids predisposes diabetes patients to the fungal infection by facilitating uncontrolled hyperglycemia, further weakening their immune system (Geerlings and Hoepelman, 1999). Corticosteroids elevate blood sugar levels to uncontrolled levels mainly by augmenting glucose production in liver, reducing its update by muscle and adipose tissues, and increasing insulin resistance (Alessi et al., 2020, Sosale et al., 2021). Uncontrolled hyperglycemia coupled with old age, hypertension, severe obesity (BMI = 40 kg/m2), and presence of cardiovascular diseases also contribute to immunosuppression thereby increasing the risk of infections and even mortality in COVID-19 patients (Muniyappa and Gubbi, 2020). In an effort for minimizing the risks of contracting secondary infection, the National Institute of Health recommends using corticosteroids only for patients on ventilator or those requiring supplemental oxygen and not for cases with milder infection (National Institutes of Health (NIH), 2021). However, efforts for regulating the optimum dose of corticosteroids and duration of the therapy are still underway.

Besides the corticosteroid treatment regime, prolonged hospital stays have also been found to be responsible for the occurrence of mucormycosis in COVID-19 patients (Patel et al., 2020, Singh et al., 2021a, Singh et al., 2021b). A significant correlation (p = 0.0001) was found between the duration of stay and the survival rate, suggesting longer stay at hospital is associated with higher risk of contracting the infection and subsequent mortality (Patel et al., 2020). Longer durations are often associated with greater usage of hospital supplies, which has been found to be responsible for exposure to environmental contaminants. For instance, hospital linens have been identified as a potential carrier for fungal pathogens (Duffy et al., 2014). Also, contaminated medications and packed food have been correlated with enhanced mucormycosis infection risks (Benedict et al., 2016).

Conclusions

A review of 3354 cases shows that the spread of black fungus can be attributed to a multitude of factors working together. History of corticosteroid treatment and uncontrolled diabetes (new-onset or pre-existing) along with weekend immunity in COVID-19 patients were found to be the most widely cited factors for black fungus outbreak in India. However, we found significant gaps in the understanding of the risk factors leading to the infection and press on the need for future investigations to focus on other less studied factors. For instance, although prevalence of diabetes was among the common risk factors across studies, its absence in a considerable proportion of patients points towards the possibility that other factors may be responsible for increased risk of fungal infections. Therefore, a holistic approach is required to address all the potential factors and establish a protocol that could contain this deadly fungal infection.

Black fungus is a long known fungal infection, and its rising incidence in immunosuppressed individuals during COVID-19 outbreak can prove deadly. Therefore, it is pivotal that we as accept secondary fungal infections as a reality and not a myth, even if it is not fully understood if COVID-19 on its own increases the risk in the absence of diabetes or steroid use. At the same time, health authorities should step up measures to diagnose the disease so that the required information can be timely disseminated to public, and precautions can be put into practice. Meanwhile, maintaining physical hygiene in hospitals including the use medical grade supplies, checking for contaminated food and medicines, stemming the overuse of steroids, and cleaning oxygen masks after regular intervals can be some of the preventive measures to curb the spread of mucormycosis while patient is undergoing COVID-19 treatment.

CRediT authorship contribution statement

Archana Sharma: Writing – original draft. Megha Bedi: Data curation, Formal analysis, Methodology, Writing – review & editing. Prachi Patel: Investigation. Amarpreet Singh Arora: Conceptualization, Writing – original draft.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.