The coronavirus disease 2019 (COVID-19) pandemic has not only caused a global health crisis through its direct respiratory effects but has also led to an alarming rise in secondary opportunistic infections. Among these, mucormycosis has emerged as a particularly devastating fungal disease, predominantly affecting individuals with compromised immunity. In India, a significant surge in COVID-19–associated mucormycosis (CAM) was reported during the second wave of the pandemic, resulting in high morbidity and mortality rates despite aggressive medical and surgical interventions [1–3].

Mucormycosis is an angioinvasive fungal infection caused by filamentous fungi belonging to the order Mucorales, most frequently Rhizopus arrhizus, Mucor spp., and Lichtheimia spp.[4, 5]. These fungi are ubiquitous in the environment, but disease manifestation typically occurs in individuals with predisposing factors such as uncontrolled diabetes mellitus, diabetic ketoacidosis, prolonged corticosteroid therapy, haematological malignancies, or organ transplantation [6, 7]. The pathogenesis involves rapid fungal proliferation, tissue necrosis, and vascular invasion, leading to widespread dissemination if left untreated [8].

The pathophysiological link between COVID-19 and mucormycosis appears to be multifactorial. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces immune dysregulation, including lymphopenia and reduced CD4+/CD8+ T-cell counts [9]. The frequent use of corticosteroids and other immunomodulatory agents in COVID-19 treatment further impairs host immunity while contributing to hyperglycaemia [10]. Elevated serum ferritin levels, reflecting a hyperinflammatory state, may enhance fungal proliferation through increased availability of free iron [11]. Together, these factors create a permissive biochemical and immunological environment for Mucorales infection.

Given the aggressive nature of CAM, early diagnosis and targeted therapy are essential to improving outcomes. Conventional diagnostic methods—direct microscopy, histopathology, and fungal culture—remain the cornerstone for laboratory confirmation [12]. Culture-based identification enables species-level differentiation, which is clinically relevant as antifungal susceptibility can vary among Mucorales species [13]. Furthermore, antifungal susceptibility testing (AFST) is critical in guiding appropriate therapy, as emerging resistance to triazoles has been documented in some regions [14]. Amphotericin B remains the drug of choice, with posaconazole and isavuconazole as important alternatives; however, therapeutic decisions must be informed by local susceptibility patterns [15,16].

Despite the clinical importance of culture and AFST in CAM management, there is limited systematic data from tertiary care centres, particularly in the Indian context during the COVID-19 era. Understanding the local epidemiology of Mucorales species and their susceptibility profiles can aid in tailoring empirical therapy, reducing mortality, and mitigating the emergence of drug resistance. This study was undertaken to isolate and identify fungal pathogens from clinically diagnosed CAM cases and to determine their antifungal susceptibility patterns in a tertiary care hospital setting.

Study Design and Setting

This prospective, observational study was conducted in Kakatiya Medical College, Hanumakonda, Telangana, in association with MGM Hopital, attached tertiary care teaching hospital. The study spanned a two-year period from January 2021 to December 2022, coinciding with the peak incidence of CAM cases during and after the second wave of the COVID-19 pandemic in India.

Study Population

The study population comprised patients of all ages and both sexes who presented to the hospital with clinical features suggestive of mucormycosis in the background of a recent or concurrent COVID-19 infection. COVID-19 status was confirmed in each case either by reverse transcription polymerase chain reaction (RT-PCR) assay or by rapid antigen testing. Inclusion criteria consisted of patients with a confirmed COVID-19 diagnosis within the preceding eight weeks, accompanied by clinical and radiological findings consistent with mucormycosis. Patients were excluded if they had proven fungal infections caused by organisms other than Mucorales, if samples were inadequate or inappropriately collected, or if they declined participation.

Ethical Considerations

Ethical clearance for the study was obtained from the Institutional Ethics Committee of Kakatiya Medical College/MGM Hospital, Hanumakonda. Written informed consent was obtained from each patient or their legally authorized representative prior to sample collection. All patient information was handled confidentially and used solely for the purposes of the study.

Clinical Specimen Collection

Specimens were collected aseptically from clinically suspected sites of infection. These included nasal crusts and tissues obtained during endoscopic sinus surgery, orbital tissue samples collected during debridement procedures, and necrotic material or aspirates from other affected regions. Samples were placed in sterile containers and promptly transported to the microbiology laboratory without exposure to formalin or fixatives to preserve viability for culture.

Direct Microscopy

For preliminary diagnosis, a portion of each specimen was subjected to direct microscopic examination using a 10–20% potassium hydroxide (KOH) mount to detect the characteristic broad, ribbon-like, aseptate hyphae of Mucorales. In selected cases, calcofluor white staining was employed to enhance visualization under a fluorescence microscope.

Histopathological Examination

Representative tissue fragments were fixed in 10% neutral buffered formalin, processed by routine histopathological techniques, and stained with hematoxylin and eosin (H&E) and periodic acid–Schiff (PAS). The demonstration of fungal hyphae invading blood vessels and adjacent tissues confirmed the diagnosis of mucormycosis on histology.

Fungal Culture

Each specimen was inoculated onto Sabouraud Dextrose Agar (SDA) supplemented with chloramphenicol (0.05 g/L) to suppress bacterial growth. Two sets of culture tubes were prepared: one incubated at 25 ± 2°C and the other at 37 ± 2°C. Cultures were examined daily for up to seven days, and fungal isolates were identified based on their macroscopic colony characteristics such as colour, texture, and growth rate.

Species Identification

Species-level identification was achieved through microscopic examination of lactophenol cotton blue (LPCB) mounts prepared from the cultured colonies. Diagnostic morphological features, including the presence or absence of rhizoids, sporangiophore branching patterns, and sporangial shape, were used for differentiation. Rhizopus arrhizus was recognized by unbranched sporangiophores arising opposite rhizoids, Mucor spp. by sporangiophores lacking rhizoids, and Lichtheimia spp. by branched sporangiophores arising between rhizoids with characteristic pyriform sporangia.

Antifungal Susceptibility Testing (AFST)

Antifungal susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) M38-A2 guidelines for filamentous fungi. The antifungal agents tested included amphotericin B, posaconazole, and isavuconazole. Standardized spore suspensions were prepared in sterile saline containing 0.05% Tween 20, and the inoculum was adjusted to 0.4–5 × 10⁴ CFU/mL. The broth microdilution method was carried out in RPMI-1640 medium buffered with MOPS, and microdilution plates were incubated at 35 ± 2°C. Minimum inhibitory concentrations (MICs) were determined after 24 and 48 hours as the lowest drug concentrations that produced complete growth inhibition.

Biochemical Parameters

To assess potential biochemical risk factors, serum samples from the study participants were analyzed for fasting and postprandial blood glucose, glycated hemoglobin (HbA1c), serum ferritin, and C-reactive protein (CRP). All biochemical tests were performed using fully automated clinical chemistry analyzers following standard operating procedures.

Data Collection and Statistical Analysis

Patient demographic details, comorbidities, history of corticosteroid use, microbiological and biochemical results, and clinical outcomes were recorded in a structured proforma. Data entry was carried out using Microsoft Excel, and statistical analysis was performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were expressed as means, standard deviations, and percentages. Associations between categorical variables were evaluated using the chi-square test, and a p-value of less than 0.05 was considered statistically significant.

1. Demographic and Clinical Profile

Across 200 consecutively enrolled patients (January 2021–December 2022), the mean age was 51.6 ± 12.4 years (range 18–82), with a male: female ratio of 1.8:1. Most patients clustered in the 41–60-year bracket (61%). The common presenting complaints were facial pain/swelling (73%), nasal obstruction/discharge (64%), and ocular findings—ptosis, proptosis, diplopia, or visual diminution (49%). Headache was reported by 42%, and 11% noted loosening of teeth or palatal involvement. Comorbidities were frequent: uncontrolled diabetes in 76%, hypertension in 34%, and chronic kidney disease in 9% (Table 1). A recent history of systemic corticosteroid therapy during COVID-19 illness was documented in 81%.

Table 1. Demographic and clinical characteristics (n = 200)

2. Direct Microscopy and Histopathology Overview

On 10–20% KOH mounts, broad, pauciseptate, ribbon-like hyphae with predominantly right-angle branching were visualized in 176/200 (88%) specimens. Calcofluor white (performed in 40 selected cases) improved hyphal delineation against necrotic backgrounds and blood clots. Histopathology confirmed mucormycosis in 170/200 (85%) cases, with typical angioinvasion and coagulative necrosis.

3. Fungal Culture and Species Distribution

Culture positivity on chloramphenicol-supplemented Sabouraud dextrose agar was 164/200 (82%). Rhizopus arrhizus was the predominant isolate (70.7%), followed by Mucor spp. (17.1%), Lichtheimia spp. (7.3%), R. microsporus (3.7%), and Syncephalastrum spp. (1.2%). Mixed Mucorales growth was uncommon (1.8%) (Table 2).

Table 2. Species distribution (n = 164 isolates)

4. Antifungal Susceptibility Patterns

Broth microdilution demonstrated low MICs to amphotericin B across species. Posaconazole showed generally favourable activity, while isavuconazole displayed reduced susceptibility in ~15% of isolates, particularly Mucor spp (Table 3).

Table 3. MIC ranges (µg/mL) for key agents (n = 164 isolates)

5. Biochemical Parameters

Hyperglycaemia was prominent: fasting glucose 182.4 ± 46.8 mg/dL, postprandial 246.3 ± 52.1 mg/dL, and HbA1c 9.1 ± 1.7%. Ferritin was elevated in 72% (mean 682.5 ± 210.6 ng/mL), and CRP was raised in 81% (mean 38.4 ± 10.2 mg/L).

7. Hematoxylin & Eosin (H&E) Staining Findings

On H&E, viable tissue at advancing margins demonstrated broad, pale eosinophilic, pauciseptate hyphae with irregular width and predominantly right-angle branching embedded within necrotic debris and fibrin. Angioinvasion was frequent, with luminal thrombosis, endothelial damage, and perivascular neutrophilic infiltrates. Central zones showed coagulative necrosis, haemorrhage, and ghost outlines of devitalized tissue. In orbital specimens, hyphae tracked along vascular and perineural planes, occasionally breaching bone trabeculae. The inflammatory response ranged from acute suppurative at early margins to mixed acute–chronic patterns in partially treated cases.

The COVID-19 pandemic, while primarily a viral respiratory disease crisis, rapidly evolved into a complex interplay of viral, bacterial, and fungal infections. Among these, CAM emerged as an especially lethal opportunistic infection, with India reporting the largest number of cases globally during the second wave in 2021 [1, 17]. The synergistic effect of SARS-CoV-2–induced immune dysregulation, widespread corticosteroid use, uncontrolled hyperglycaemia, and iron dysmetabolism created an unprecedented epidemiological scenario. The present prospective study at a tertiary care hospital in Hanumakonda provides an integrated view of microbiological identification, antifungal susceptibility, and host biochemical risk profiles in 200 patients with CAM over a two-year period (2021–2022).

Our cohort showed a male predominance (1.8:1) and a mean age in the early fifties, consistent with multiple Indian multicentric studies [2, 3]. This demographic alignment may reflect both the higher prevalence of diabetes in middle-aged Indian men and increased occupational/environmental exposure to fungal spores [7]. Nearly three-quarters of patients were diabetic, and over 80% had received systemic corticosteroids during COVID-19 management. These figures echo the findings of John et al. (2021) [11], who termed the combination of SARS-CoV-2, uncontrolled diabetes, and corticosteroid therapy the “perfect storm” for mucormycosis development.

The role of hyperglycaemia in mucormycosis pathogenesis is multifaceted: it reduces neutrophil chemotaxis and phagocytosis, impairs oxidative burst, and increases free iron levels through glycation of transferrin and ferritin [6, 8]. Our biochemical data, with a mean HbA1c of 9.1%, underscores that most infections developed in patients with chronically poor glycaemic control rather than transient COVID-related hyperglycaemia alone.

Elevated ferritin, seen in 72% of our patients, likely represents the convergence of two pathological states: COVID-19–induced hyperinflammation (cytokine storm) and diabetes-related iron dysregulation [18]. Experimental studies have demonstrated that iron overload markedly enhances Rhizopus virulence, as the fungus possesses high-affinity iron permeases and siderophore-mediated uptake systems [4]. This reinforces the potential value of iron-modulating therapies or cautious iron chelation in high-risk patients.

KOH wet mount remains a rapid and cost-effective diagnostic tool in resource-limited settings, detecting hyphae in 88% of our cases, a sensitivity comparable to other Indian series [19]. However, false negatives can occur due to sample necrosis or paucifungal tissue, emphasizing the value of histopathology. H&E in our study confirmed mucormycosis in 85% of cases, frequently revealing angioinvasion (85.9%), coagulative necrosis, and perivascular inflammation.

Histopathology not only confirms the diagnosis but also provides insights into disease aggressiveness. In our material, perineural spread (12.9%) and bony trabecular invasion (21.2%) were observed, both associated with worse clinical outcomes in prior studies [20, 21]. Perineural spread may explain some cases of orbital or intracranial extension despite apparently adequate surgical margins.

Culture positivity (82%) in our series was higher than some reports from the West, where prior antifungal exposure or delayed sampling often reduced recovery rates [22]. Rhizopus arrhizus was overwhelmingly predominant (70.7%), reflecting both its global ubiquity and its thermotolerant, angioinvasive characteristics [2, 23]. The presence of Mucor spp. and Lichtheimia spp., though less frequent, is clinically relevant, as subtle morphological differences can influence antifungal susceptibility [24]. Rare recovery of Syncephalastrum spp. underscores the need for careful morphological and, where available, molecular confirmation to avoid misidentification.

Our antifungal susceptibility testing confirmed amphotericin B as the most consistently active drug, with MICs within ranges widely reported for Mucorales [25]. Posaconazole exhibited variable MICs but remained active against most isolates, supporting its role as salvage therapy or step-down treatment. Isavuconazole demonstrated reduced susceptibility in approximately 15% of isolates, echoing earlier reports and raising concern for emerging azole tolerance in certain species, particularly Mucor spp [14, 26, 27].

The absence of standardized breakpoints for Mucorales in CLSI guidelines complicates categorical interpretation of MIC values [28]. Nonetheless, longitudinal surveillance remains crucial given increasing use of triazoles for prophylaxis in haematology–oncology patients and the potential for resistance selection.

The statistically significant association between poor glycaemic control and extensive disease (orbital/cerebral involvement) supports mechanistic studies showing that hyperglycaemia impairs both innate and adaptive immunity [4, 8]. Elevated ferritin correlated with multisite disease, consistent with the hypothesis that iron overload fuels fungal growth and tissue invasion [4]. CRP elevation in over 80% of patients reflects the inflammatory synergy between COVID-19 and mucormycosis, and could potentially serve as a marker for disease monitoring in high-risk patients.

From a biochemical–microbiological perspective, CAM emerges from the convergence of multiple interrelated factors. Immune suppression resulting from SARS-CoV-2 infection and corticosteroid therapy significantly weakens host defenses, while metabolic derangements associated with diabetes and COVID-19 precipitate persistent hyperglycaemia and ketoacidosis. Concurrently, iron dysregulation driven by inflammation-induced ferritin elevation and increased transferrin saturation enhances fungal growth potential. These vulnerabilities are further compounded by the high environmental spore load characteristic of India’s tropical climate, which increases the risk of inhalation exposure. Together, these conditions dismantle host immune barriers and generate a nutrient-rich microenvironment that facilitates the rapid proliferation and angioinvasive behaviour of Mucorales, as consistently observed in both histopathological and clinical settings [4-12].

Pre-pandemic mucormycosis in India already exhibited a high prevalence of diabetes as a predisposing factor [29], but CAM has amplified this risk profile through widespread corticosteroid use and COVID-related inflammation. The speed of onset—often within 2–4 weeks of COVID-19 diagnosis in our cohort—was also shorter than in pre-pandemic post-diabetic ketoacidosis cases, reflecting a more aggressive disease trajectory reported in other CAM studies [4-8].

Our findings reaffirm that early suspicion, rapid microscopy, and prompt initiation of amphotericin B are essential to reducing mortality in CAM. Where surgical debridement is feasible, histopathology should be performed on fresh margins to assess invasion patterns. Antifungal stewardship, with local susceptibility mapping, will be vital in preventing emergence of azole-resistant Mucorales. At the community level, targeted public health messages for glycaemic control during COVID-19 treatment and cautious steroid use could significantly reduce CAM incidence.

Limitations

The study was limited by the absence of molecular confirmation of isolates, which could detect cryptic species or mixed infections not distinguishable morphologically. Antifungal susceptibility testing was performed using CLSI broth microdilution, which, while standardized, lacks definitive interpretive breakpoints for Mucorales. Follow-up data on long-term outcomes were beyond the scope of this report but would add prognostic context.

This prospective study from a tertiary care centre in Hanumakonda underscores the significant burden and aggressive clinical course of COVID-19–associated mucormycosis (CAM) during the pandemic period of 2021–2022. Our findings reaffirm that Rhizopus arrhizus is the predominant etiological agent, with Mucor spp. and Lichtheimia spp. constituting important but less frequent pathogens. Amphotericin B continues to demonstrate the highest in vitro activity against Mucorales, whereas posaconazole and isavuconazole exhibit variable susceptibility profiles, highlighting the importance of local antifungal surveillance to guide therapy.

The study also emphasizes the critical role of host biochemical factors—particularly uncontrolled diabetes, persistent hyperglycaemia, elevated HbA1c, and iron dysregulation evidenced by high serum ferritin—in predisposing individuals to CAM and influencing disease severity. Histopathological examination, especially with hematoxylin and eosin staining, proved invaluable in confirming diagnosis, delineating tissue invasion patterns, and correlating with clinical progression.

The convergence of immunosuppression from COVID-19 and corticosteroid therapy, metabolic imbalance, iron overload, and high environmental spore exposure creates an ideal microenvironment for Mucorales proliferation and angioinvasion. Early recognition of high-risk patients, prompt mycological diagnosis, and immediate initiation of appropriate antifungal therapy, combined with surgical debridement when indicated, are essential to improve outcomes.

Our data advocate for integrated clinical, microbiological, and biochemical monitoring in suspected CAM cases, rational use of corticosteroids during COVID-19 treatment, and stringent glycaemic control in both COVID-19 and post-COVID patients. Sustained public health awareness and hospital-based infection surveillance are crucial to mitigate future outbreaks of this devastating opportunistic infection.

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