COVID-19, mucormycosis, and the cow: Damned lies!

Mucormycosis, a deep-seated mycosis associated with high mortality, affects individuals with compromised immunity [1]. While an uncommon invasive infection, an epidemic of mucormycosis occurred following the coronavirus disease 2019 (COVID-19) pandemic worldwide, especially in India [2,3]. The first case of COVID-19-associated mucormycosis (CAM) was reported in an autopsy series from the UK [4], followed by rhino-orbital mucormycosis (ROM) in a diabetic patient from the United States [5]. More cases were reported from India during the first wave of the COVID-19 pandemic (peaking in September–October 2020) [2]. Indeed, a multicenter study from India noted a doubling of mucormycosis cases following the first wave of COVID-19 than before the pandemic [6]. However, the scale of this outbreak was small, and the discussion of the potential causes of the outbreak remained limited to the few clinicians handling CAM [7].

A few months later, following the second wave of COVID-19 (attributed to the δ variant of the novel coronavirus [SARS-CoV-2], peaking in April–May 2021), a large number of CAM cases were reported [8], gaining attention from the national and international scientific community [[9], [10], [11]]. The devastating epidemic affected nearly 50,000 people and claimed thousands of lives [12]. Perplexed by the abruptness and the unprecedented scale of the CAM epidemic, experts and the lay public discussed various contributing factors [[13], [14], [15], [16]]. The proposed risk factors included well-established causes like uncontrolled diabetes mellitus, glucocorticoid therapy and novel ones (zinc supplementation during COVID-19, contaminated masks, oxygen cylinders or nebulizers, and environmental pollution due to the burning of cattle dung) [17]. Several risk factors were scientifically investigated [8,[18], [19], [20], [21], [22]], but some were unreasonably publicized, with little scientific proof [23]. Herein, we discuss how the misinformation on cattle dung burning as a reason for CAM started, spread and what is known thus far about the CAM epidemic.

1. How did the misinformation begin?

Mucormycosis, now widely addressed by the general public as ‘black fungus,’ was mentioned in a viral social media post claiming ‘Indian scientists link cow urine to 9000 cases of mucormycosis.’ [24]. Replete with grammatical and factual errors [24], the morphed article led to a widespread debate on the topic and marked the beginning of the misinformation extravaganza [23,25,26]. Further, some media reports from India found a few individuals from a population of 1.4 billion who suggested using cow dung or cow urine to prevent COVID-19 [27]. The same news reports were repeatedly discussed on social media [16,28]. Altruistic physicians and experts discouraged such unscientific practices and proposed that application of cow dung could pose several health hazards, including mucormycosis. The Indian doctors were amongst the first to issue condemnation messages discouraging such non-scientific practices [29]. Interestingly, camel urine use for COVID-19 was discussed in some West Asian countries and received support from a few Indians for its purported medicinal value [30,31]. While camel and cow urine remain unproven regarding their medicinal effects, cow dung was widely discussed, to the extent of being labeled as rampant [32]. Indeed, news on camels would not have been as sensational in India as an article on cows.

2. Is there truth to the claim of CAM due to cow dung exposure? What does the scientific literature mention?

To our knowledge, no case of mucormycosis (neither in published literature nor news articles) has ever been associated with the burning of animal dung [33]. None of the specialized centers or experts dealing with mucormycosis encountered cases of CAM following exposure to cow dung [6,34]. Skaria et al. suggested cattle dung burning as the prime factor leading to the CAM epidemic in India [35]. To investigate this novel hypothesis, we conducted an aero-mycological study to evaluate the role of cattle dung burning in mucormycosis [44]. Contrary to the hypothesis, the proportion of air samples growing Mucorales was similar before and after burning cow dung. Undried cattle dung grew Mucorales in six of the eight samples tested, and 83% of these cultures showed Lichtheimia corymbifera [34]. Thus, cutaneous mucormycosis could occur if susceptible individuals smear cow dung on themselves. However, neither cutaneous mucormycosis nor infection by Lichtheimia corymbifera was encountered excessively during the CAM outbreak in India [3,6,8]. Rather, Rhizopus arrhizus was the most commonly isolated agent (>60%) like that seen before the COVID-19 pandemic, and Lichtheimia infection remains rare [6,8,36].

If a disease outbreak occurs due to a specific practice (e.g., smearing of dung over the body), one would expect a disproportionate increase in cases of cutaneous mucormycosis [37,38], which did not happen. For instance, in HIV-infected intravenous drug users, mucormycosis was primarily renal (41%) or cerebral (39%) than ROM cases commonly encountered with conventional risk factors [39]. Contrarily, the case mix of invasive mucormycosis in India remained like that before the COVID-19 pandemic, indicating a systemic predisposition to mucormycosis than a local factor [6,8,36].

Further, in a recent case-control study, we compared 39 cases of pulmonary mucormycosis in diabetes mellitus with 199 controls with diabetes mellitus (119 from the community and 80 from the hospital) without pulmonary mucormycosis [40]. We elicited a detailed history of various environmental exposures, including farming practices, place of stay, cattle handling, use of cow-dung cakes as fuel, and several others. Cattle dung exposure was not significantly different between the mucormycosis cases and controls. Instead, we found male sex, COVID-19 infection, and residence at a ‘kutchha’ house as factors associated with pulmonary mucormycosis in individuals with diabetes mellitus [40]. Interestingly, another recent study found a genetic similarity between the clinical strains isolated from CAM patients and their indoor environment (patient’s residence [bedroom]) rather than the outdoor air samples [41].

Several authors and news articles mention cow dung as the primary source of mucormycosis by misquoting the information available on the CDC website, which lists animal dung as one of the several possible environmental sources of Mucorales. The more common sources include decaying organic matter in the soil, such as dried leaves and compost piles [42]. The ubiquitous presence of fungal spores is insufficient to result in disease and compromised host immunity or an altered net state of immunosuppression, which is probably the most critical factor underlying invasive mucormycosis. The rearing of cows, the use of cow-dung cakes as fuels, and several other cultural practices have been present in India for several centuries, and it is imprudent to proclaim that these practices led to an outbreak of nearly 50,000 cases over four months following the COVID-19 pandemic without any supporting data.

While the ubiquitous presence of Mucoralean spore in rural, indoor, and outdoor environments has been highlighted in India [[43], [44], [45], [46]], hospital reports are more alarming [47,48]. Healthcare-associated mucormycosis is a well-known entity described from several transplant centers catering to immunocompromised individuals [49]. Hospital linens have been shown to cause outbreaks of cutaneous mucormycosis [50]. In a study from a network of transplant centers in the United States, even freshly laundered linens were contaminated with Mucorales in 47% of hospitals [51]. Thus, Mucorales from various hospital sources in a general hospital in India could have contributed to mucormycosis in immunocompromised individuals, especially ongoing construction activity during COVID-19 [52]. Notably, a study from France observed a cluster of CAM cases in relation to hospital renovation near the ICU catering to critically ill COVID-19 subjects [53].

3. Why was CAM rampant in India and not elsewhere?

The widespread perception of CAM as an exclusively Indian problem was fuelled by misleading articles and news items, which led to the proposal of several ‘India-specific’ risk factors [35]. Unfortunately, it is a myth that CAM occurred only in India. In a nationwide survey from Germany, a few of their intensive care units reported nearly a 100-fold increase in mucormycosis following COVID-19 than before [54]. Another multisite ICU study from France reported 1% of mucormycosis in COVID-19 patients, an incidence rate like India [55]. The reported prevalence of COVID-19-associated pulmonary mucormycosis was similar in Chile and India [34,56]. The other countries that reported CAM include Pakistan, Iran, Egypt, Turkey, Egypt, Honduras, Mexico, Russia, Latin America, and several European countries (Romania, France, and others) [9,53,[57], [58], [59], [60], [61], [62], [63], [64], [65], [66]]. The occurrence of CAM in such high proportions (up to 1% of critically ill COVID-19 cases in France) in countries where cow dung is not used, points towards the need for a better explanation for CAM rather than India-specific factors [55,59].

While the absolute number of CAM cases was highest in India, there are several reasons for the high burden. Most prominently, the prevalence of mucormycosis was at least 70 times higher than global estimates even before the COVID-19 pandemic given the 1.4 billion people residing in India [67]. However, cattle dung and its burning have never been clinically associated with mucormycosis. Further, mucormycosis was highly prevalent in the urban areas where cow dung was not used. Rather, unknown genetic factors might be responsible for the high burden of mucormycosis in India. Secondly, India can be considered the ‘diabetes capital’ of the world, and uncontrolled diabetes mellitus is the most common predisposing factor associated with mucormycosis in India [68]. Third, a significant contribution by several unproven therapies to treat COVID-19 cannot be excluded [19,20,22]. The largest case-control study on CAM strongly suggested inappropriate glucocorticoid therapy and zinc supplementation associated with mucormycosis in COVID-19 patients [8]. Not surprisingly, COVID-19 and its treatment precipitated a massive outbreak in India, much more than elsewhere. Of note, even during the peak of the CAM outbreak, COVID ICUs in India practicing guideline-concordant glucocorticoid therapy and optimizing glycemic control could avoid cases of mucormycosis [69].

4. The elephant in the room: SARS-CoV-2 as a risk factor for CAM

While several environmental or host factors were proposed and discussed during the CAM outbreak in India, the unevaluated and most crucial factor is likely coronavirus. In one of the earliest multicenter studies from India, nearly 33% of CAM subjects had COVID-19 as the only risk factor (and no conventional risk factors, diabetes mellitus, or organ transplantation). Importantly, 20% of these subjects did not even receive glucocorticoids for COVID-19, suggesting the role of SARS-CoV-2 infection in predisposing to CAM [6]. Additionally, in our recent study of PM among diabetes mellitus, the mean glycated hemoglobin among those with COVID-19 infection (10.5%) was significantly lower than those developing PM without COVID-19 (12.4%) [40]. Thus, even among subjects with diabetes mellitus, COVID-19 infection likely precipitated mucormycosis among those with relatively better glycemic control.

Only a few studies conducted during the outbreak have indirectly studied the possible role of COVID-19 infection. COVID-19 infection has been associated with increased levels of serum glucose-regulated peptide (GRP-78), a heat shock protein, that has been implicated in the pathogenesis of rhino-orbital mucormycosis. We also demonstrated a significantly higher serum level of serum GRP-78 in CAM subjects than in COVID-19 without mucormycosis [70]. Neutrophils and innate immunity are also crucial in protecting against Mucorales infection and may be compromised by uncontrolled diabetes, glucocorticoids, and possibly COVID-19 [71]. More recent studies have also suggested decreased phagocytic activity of circulating monocytes and altered cytokine profile in CAM [72,73]. However, more research and animal models are required to decipher the pathophysiology of CAM and mucormycosis (Fig. 1 ).

Fig. 1.

Schematic representation of the known and unevaluated factors predisposing to mucormycosis following COVID-19 infection. On the left half of the figure (green shade) are associations that have reasonable evidence (≥2 case-control studies). In contrast, the right half of the image depicts factors that remain largely unexplored (primarily related to COVID-19 and host susceptibility). ∗The list is not exhaustive and does not include several factors such as cloth masks [18], elevated C-reactive protein [8], and serum GRP-78 that have only been studied in a single or small case-control study with limitations [70]. The hypothesis with little scientific basis or not adequately studied (contaminated oxygen cylinders) or disproven ones (cattle dung burning and others) [35] are also not shown in the figure.

5. Conclusions

In conclusion, there are no reported cases or scientific basis to attribute the CAM outbreak in India to the burning of cattle dung. Instead, there are observational and experimental data against this hypothesis, and continuing such misinformation is unwarranted. While a few studies have evaluated the immune alterations induced by SARS-CoV-2, more research is required. The unbiased evaluation of how COVID-19 predisposed to mucormycosis could have yielded valuable information into the pathogenesis of mucormycosis and the subsequent development of therapeutic targets. Unfortunately, misinformation and myths that spread during the COVID-19 pandemic did not spare the CAM outbreak [74]. A hypothesis should be generated based on astute observation and interpretation of facts rather than on personal biases and prejudices [16]. Considerable time, effort, and resources are expended in dispelling myths, taking us farther from science and the truth.

Declaration of interests

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.