Changing Trend of Risk Factors of Mucormycosis Including Diabetes, Acidosis, and Serum Iron in the Second Wave of COVID-19

There is documented evidence of increasing cases of invasive mucormycosis in India since the past 3 decades, with the highest of 50 cases per year [1]. However, an official estimate of these cases in May 2021 was 11,700 [11]. Due to this unprecedented spike, mucormycosis could be called a public health concern as of now. In the present study a higher incidence in men (64.71%) than women (35.29%) has been found similar to the other post covid studies [7]. The youngest patient was 30 years old and the eldest was 86 years. The absence of pediatric mucor cases could have been because COVID-19 did not affect children as severely as adults [12]. Mean or average age of our study (53.96 years) was similar in that of other post covid studies (49 years, 51.7 years and 55 years) [4, 5, 7].

There was a significant association found between the presence of co-morbidities (other than diabetes mellitus) & addictions and the nasal involvement of the disease. However, other structures involvement including the brain, eye, and orbit did not show such significant association.

There were no patients with pulmonary involvement or with disseminated disease in present work unlike others [5].

Many studies have established a strong association of diabetes mellitus with mucormycosis [2, 3, 6]. A random blood glucose level over 200 was seen in 47.06% of our participants; however symptoms of hyperglycemia could not be ascertained in many of them. This could be attributed to the attention paid to symptoms of mucormycosis more than hyperglycemia or the intrinsic stress of mucormycosis could also result in elevated levels of random blood sugar. However, 66.67% of participants had HbA1c levels over 6.5 mg/dL, and were considered diabetic [8], of whom 79.4% had uncontrolled diabetes which constituted 52.94% of all study participants (Fig. 1c). The percentage of diabetic patients ranged from 31.7 to 85.71% of the post COVID 19 mucormycosis ones in other works [4, 5, 7].

Of the 33.33% participants who were non diabetic and pre diabetic, 41.17% had elevated levels of random blood glucose on multiple occasions. It is hypothesized that sustained hyperglycemia possibly of even a considerable short phase, while COVID-19 stress may play a role in the causation of the mucormycosis infection. The frequency of patients having diabetes and uncontrolled diabetes was relatively lower than the known literature i.e., 94% and 67%, respectively [2]. This might indicate the increasing role of risk factors other than or coexisting diabetes and uncontrolled diabetes in etiopathogenesis of mucormycosis in this second wave COVID-19. Also, in non-diabetic patients of mucormycosis there are known causes of immunosuppression, including corticosteroid use, hematological and other malignancies, organ transplantation and prolonged neutropenia etc. But in this work the possible risk factor—corticosteroid use—as well as the others was also not found consistently in them. This also may indicate role of lesser known or unknown risk factors.

A history of severe COVID-19 and diabetic ketoacidosis are documented to have a role in pathogenesis of mucormycosis [2, 13, 14]. However, only 5.88% of subjects were found to have a past history of severe COVID-19 in the present study. This is in contrast to the 45% of subjects in other studies, especially in pulmonary or disseminated disease (80%) [15]. Almost one fifth of the patients did not have a known history of COVID-19 but this absence of history could not be confirmed by serology testing for COVID-19 antibodies or CT scan of thorax, therefore any inference is indeterminate. Almost one fourth patients had only mild COVID-19, similarly, only two participants displayed acidosis at the time of admission out of which only one had diabetes. Among the participants whose arterial blood gas analysis was conducted, 59.09% suffered from alkalosis instead of the expected acidosis [3] (Fig. 1b). Another study also has mentioned the absence of the diabetic ketoacidosis in their subjects [4]. Exact cause of the alkalosis could not be determined as majority of the patients were referred from other hospitals and the non-receipt of amphotericin B could not be ascertained before admission. Also, no significant associations were found in other parameters of ABG that is pH, bicarbonate ions and PCO2 with radiological involvement of mucormycosis.

Hemochromatosis or iron overload is also a traditional risk factor for mucormycosis as iron acts as a growth factor for the fungus [1]. Discordant to this only 1.96% of participants were found to have elevated serum iron levels (Fig. 2a). Another work has found elevated serum iron in people with COVID-19 and ketoacidosis [15]. Serum ferritin values have been found elevated in two studies [5, 7], and yet another mentions variable result [4]. However, 37.25% of the participants had serum iron values below normal range (Fig. 2a). Also, no significant association of serum iron levels and extent of radiological involvement by the fungus were found. It is known that even in the patients expected to have elevated available serum iron, such as those with diabetic ketoacidosis, most iron remains bound to carrier molecules, and free serum iron would still be present in submicromolar concentrations that induce the high-affinity rather than the low-affinity uptake system, for example iron regulated high-affinity ferric reductase activity [14]. This might explain the occurrence of mucormycosis in these patients in spite of having low serum iron.

A significant association was found between serum creatinine levels and orbital involvement of the disease. Noteworthy was the presence of elevated blood urea in 76.47% of subjects (Fig. 2b), the frequency of which was higher than the presence of raised blood glucose, serum iron, and acidosis. Such high frequency of uremia could be attributed to preexisting diabetes mellitus, previous administration of amphotericin, and dehydration [16, 17]. Some patients displayed clinical features of dehydration at the time of admission, though it was not assessed critically. About 12% of the patients had both raised serum urea and serum creatinine, however only one patient had creatinine levels high enough to contra-indicate administration of amphotericin, therefore 50 out of the 51 participants received amphotericin at the time of admission. Another work found raised blood urea and blood creatinine levels [7].

The use of glucocorticoids and ventilator-based oxygen supply has also been associated with mucormycosis [3, 6]. 62.75% of the participants stated to have received steroid therapy, and 25.49% of participants stated to have received oxygen supply during their treatment of COVID-19 (Fig. 1a), however since the patients did not provide medical records as proof, recall bias cannot be ruled out which is a limitation to our study.

When long and chronic COVID syndrome relation with mucormycosis was studied, a significant association was found in the duration between the initiation of treatment of COVID-19 and the appearance of the first symptom suggestive of mucor infection and nasal involvement of mucormycosis. Highest burden of cases was observed in the time period between 3 and 8 weeks (long COVID syndrome) and the period between first day to three weeks after the start of treatment for COVID-19 infection which was 37.25% each.

Three deaths occurred during the period of the study. No significantly common clinical and/or laboratory findings were found in these subjects. The first patient succumbed to respiratory failure with renal failure few days after surgery. This patient was getting injectable lipophilic amphotericin intermittently when his creatinine was low. Other two patients had extensive rhino-nasal-orbital-cerebral mucormycosis; extensive intracerebral involvement was the cause of death in these cases.

There were seven cases of mixed infections of mucormycosis with aspergillosis (five cases), candidiasis (one case), and actinomycetes (one case), respectively.

Present study is one of the first few works providing clinical and investigational findings of mucormycosis cases in the second wave of COVID-19 with their associations in a considerable number of subjects from a single tertiary care center; which is the strength of this study.

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