Mucormycosis is an aggressive, angioinvasive fungal infection caused by fungi belonging predominantly to the order Mucorales. Although uncommon in immunocompetent individuals, it is associated with substantial morbidity and mortality among patients with uncontrolled diabetes mellitus, diabetic ketoacidosis, neutropenia, haematological malignancies, organ transplantation, prolonged corticosteroid exposure and other immunocompromising conditions. During the second wave of the COVID-19 pandemic, India experienced an unprecedented increase in COVID-19-associated mucormycosis, with rhino-orbital and rhino-orbito-cerebral disease constituting the predominant clinical presentations. A systematic review by Singh et al. reported that most initially published cases originated in India and that diabetes mellitus and corticosteroid exposure were the principal associated factors [1]. The pathogenesis of post-COVID-19 mucormycosis is multifactorial. COVID-19-associated immune dysregulation, lymphopenia, endothelial injury and tissue hypoxia may facilitate fungal invasion. These effects may be compounded by uncontrolled hyperglycaemia, corticosteroid-induced immunosuppression, increased availability of free iron, prolonged hospitalization, mechanical ventilation and broad-spectrum antimicrobial therapy. The fungus characteristically invades blood-vessel walls, resulting in thrombosis, tissue ischaemia, infarction and extensive necrosis. Clinically, patients may present with facial pain or swelling, nasal obstruction, blackish nasal discharge, headache, proptosis, ophthalmoplegia, loss of vision, palatal ulceration or neurological manifestations. Histopathological examination has an essential role in establishing tissue invasion and differentiating mucormycosis from colonisation and other invasive fungal infections. The characteristic morphology consists of broad, irregular, ribbon-like, pauci-septate or aseptate hyphae with predominantly right-angled branching. Haematoxylin and eosin staining may demonstrate fungal hyphae within areas of necrosis, while periodic acid-Schiff and Grocott-Gomori methenamine silver stains improve fungal visualisation. Important histopathological findings include angioinvasion, vascular thrombosis, perineural invasion, bone invasion, coagulative necrosis, acute suppurative inflammation, granulomatous inflammation and mixed fungal infection. Jain et al. demonstrated that the extent of tissue necrosis, fungal load, angioinvasion and involvement of adjacent structures could provide useful information about disease severity [2]. Mani et al. also documented neutrophilic inflammation, angioinvasion and variable inflammatory responses in COVID-19-associated rhino-orbito-cerebral mucormycosis [3]. Subsequent histopathological studies confirmed considerable variation in fungal density, tissue response and vascular invasion among post-COVID-19 patients [4,5]. Systematic assessment of this spectrum, together with clinical presentation and predisposing factors, may improve diagnostic accuracy, facilitate early multidisciplinary management and help identify pathological features associated with advanced disease. AIM To evaluate the histopathological spectrum and associated clinicopathological characteristics of mucormycosis in post-COVID-19 patients. OBJECTIVES 1. To describe the demographic profile, clinical presentation, anatomical distribution and predisposing factors among post-COVID-19 patients with histopathologically confirmed mucormycosis. 2. To determine the frequency and distribution of fungal morphology, tissue necrosis, inflammatory response, angioinvasion, thrombosis, perineural invasion and bone invasion in tissue specimens. 3. To assess the association of major histopathological findings with clinical extent, underlying risk factors, microbiological findings and patient outcomes

Source of Data The study data were obtained from the records of the Departments of Pathology, Otorhinolaryngology, Ophthalmology, Oral and Maxillofacial Surgery, General Medicine and Microbiolog. The sources included histopathology request forms, biopsy registers, pathology reports, paraffin blocks, stained slides, microbiology records, operation notes, radiological reports, inpatient case records, COVID-19 laboratory reports, treatment records and discharge or mortality summaries. Study Design This was a hospital-based, retrospective, observational clinicopathological study. Study Location The study was conducted in the Department of Pathology in collaboration with the Departments of Otorhinolaryngology, Ophthalmology, Oral and Maxillofacial Surgery, General Medicine and Microbiology. Study Duration Cases diagnosed during the period of 12 months were included. Retrieval of records, review of histopathological material, data entry and statistical analysis were undertaken. Study Population The study population comprised post-COVID-19 patients of all eligible age groups who had undergone biopsy, surgical debridement, maxillectomy, orbital exenteration or another tissue-sampling procedure for clinically suspected mucormycosis and in whom tissue examination demonstrated fungal morphology consistent with mucormycosis. A post-COVID-19 patient was operationally defined as a patient with documented previous SARS-CoV-2 infection established by reverse-transcription polymerase chain reaction, rapid antigen testing or another institutionally accepted diagnostic method, who subsequently developed mucormycosis during active infection or within 12 weeks after COVID-19 diagnosis or recovery. Sample Size A total of 200 eligible patients with histopathologically confirmed post-COVID-19 mucormycosis were included. As all eligible cases available during the defined study period were studied, a census or complete-enumeration sampling method was adopted. No separate sampling or participant allocation was performed. When multiple specimens from the same patient were available, the patient was counted only once. However, all available specimens were reviewed to document the complete histopathological spectrum, and the specimen demonstrating the most extensive tissue invasion was used for patient-level statistical analysis. Inclusion Criteria Patients were included when they fulfilled all the following criteria: 1. Documented current or previous SARS-CoV-2 infection. 2. Clinical or radiological suspicion of mucormycosis during or after COVID-19. 3. Availability of biopsy, debridement or resection tissue for histopathological examination. 4. Demonstration of broad, irregular, pauci-septate or aseptate fungal hyphae with morphology consistent with Mucorales and evidence of tissue invasion. 5. Availability of sufficient clinical and histopathological information for analysis. 6. Cases diagnosed within the predefined study period. Exclusion Criteria The following cases were excluded: 1. Suspected mucormycosis without histopathological evidence of tissue invasion. 2. Fungal colonisation confined to surface debris without invasion of viable or necrotic tissue. 3. Cases showing only another fungal infection without morphological evidence of mucormycosis. 4. Patients without documented evidence of COVID-19. 5. Patients in whom mucormycosis had been diagnosed before COVID-19 infection. 6. Cytology-only specimens or specimens that were inadequate for definitive histopathological diagnosis. 7. Autolysed, poorly preserved or improperly labelled specimens. 8. Duplicate specimens or repeat admissions of the same patient; these were consolidated into a single patient record. 9. Cases with substantially incomplete clinical records that prevented clinicopathological assessment. Procedure and Methodology After obtaining approval from the Institutional Ethics Committee, the histopathology database and departmental registers were searched using terms such as “mucormycosis,” “zygomycosis,” “invasive fungal infection,” “fungal sinusitis” and “post-COVID mucormycosis.” Potential cases were cross-checked with hospital identification numbers and COVID-19 records. For every eligible patient, demographic characteristics, presenting symptoms, anatomical site, COVID-19 history, comorbidities, treatment exposure, laboratory findings, radiological extent, surgical procedures and outcomes were recorded. Diabetes mellitus, diabetic ketoacidosis, hypertension, chronic kidney disease, malignancy and other immunocompromising conditions were documented. Details of systemic corticosteroid therapy, oxygen supplementation, mechanical ventilation, antiviral treatment and broad-spectrum antimicrobial exposure during COVID-19 management were also collected wherever available. The anatomical extent of disease was classified as: • Isolated sinonasal mucormycosis • Rhino-orbital mucormycosis • Rhino-orbito-cerebral mucormycosis • Oral or maxillary mucormycosis • Pulmonary mucormycosis • Gastrointestinal mucormycosis • Cutaneous mucormycosis • Disseminated or other-site mucormycosis All available slides were independently reviewed by two pathologists who were unaware of the final clinical outcome at the time of review. Disagreements were resolved by joint examination using a multiheaded microscope or consensus review. The following histopathological variables were assessed: • Type and adequacy of tissue • Presence and morphology of fungal hyphae • Fungal density or load • Distribution of fungal elements • Percentage and pattern of tissue necrosis • Acute neutrophilic or suppurative inflammation • Chronic inflammatory response • Granulomatous inflammation and giant-cell reaction • Angioinvasion • Vascular thrombosis and infarction • Perineural invasion • Soft-tissue, skeletal-muscle, mucosal or submucosal invasion • Bone and bone-marrow invasion • Fat necrosis • Presence of bacterial colonies • Coexisting fungal infection, particularly aspergillosis Fungal load was semiquantitatively graded as mild, moderate or severe according to the density and distribution of fungal hyphae in the examined sections. Necrosis was categorised as focal or extensive using a predefined departmental protocol. Special attention was given to the presence of fungal hyphae within vascular walls or lumina because this represented angioinvasion. Clinical, radiological, microbiological and histopathological findings were correlated. Outcomes were classified as recovery or improvement, persistent or progressive disease, recurrence, loss to follow-up or in-hospital death, depending on the available records. Sample Processing Tissue specimens had been received in appropriately labelled containers containing 10% neutral-buffered formalin. Gross examination had documented the type, number, size, colour, consistency and appearance of the tissue fragments, including necrotic, haemorrhagic, ulcerated or bony areas. Representative sections had been taken from viable-necrotic interfaces, mucosa, soft tissue, blood vessels and bone wherever available. After adequate fixation, soft-tissue specimens had undergone routine dehydration, clearing, paraffin embedding and sectioning at approximately 3-5 µm. Bony specimens had been decalcified using the routinely approved decalcifying solution before tissue processing. Sections had initially been stained with haematoxylin and eosin. Periodic acid-Schiff and Grocott-Gomori methenamine silver stains had been performed or were performed on retrieved blocks whenever fungal morphology was inconspicuous, mixed fungal infection was suspected or confirmation was required. The stains were interpreted as follows: • Haematoxylin and eosin: tissue architecture, necrosis, inflammation, vascular invasion and visible fungal profiles. • Periodic acid-Schiff: fungal walls appeared magenta. • Grocott-Gomori methenamine silver: fungal hyphae appeared dark brown to black against a pale background. Mucorales were identified morphologically by their broad, irregular, ribbon-like, pauci-septate or aseptate hyphae with predominantly wide or right-angled branching. Aspergillus was suspected when narrow, regularly septate hyphae with relatively uniform acute-angle branching were present. Mixed infection was recorded when both distinct morphological patterns were demonstrated. Direct potassium hydroxide mount, fungal culture and organism identification were retrieved from microbiology records wherever performed. Negative culture did not exclude mucormycosis when characteristic fungal hyphae with tissue invasion were demonstrated histopathologically. Data Collection Data were collected using a predesigned structured case-record form. Each patient was assigned a unique study identification number, and identifying information was removed from the analytical dataset. The following groups of variables were collected: • Demographic: age, sex, residence and occupation. • COVID-19-related: date, diagnostic method, severity, hospitalisation, intensive-care admission, oxygen requirement and treatment received. • Risk factors: diabetes, glycaemic status, ketoacidosis, corticosteroid exposure, renal disease, malignancy and immunosuppression. • Clinical: presenting symptoms, duration, anatomical site and extent of disease. • Laboratory: blood glucose, glycated haemoglobin, complete blood count, renal parameters, inflammatory markers and microbiological findings. • Radiological: sinus, orbital, cerebral, pulmonary or other organ involvement. • Histopathological: fungal morphology, fungal load, necrosis, inflammation, angioinvasion, thrombosis, perineural invasion, bone invasion and mixed infection. • Management and outcome: surgery, number of debridements, antifungal treatment, clinical improvement, recurrence and mortality. Two investigators independently checked the completed dataset against the original records. Missing information was coded as “not available” and was not treated as an absence of the characteristic. Statistical Methods Data were entered into Microsoft Excel and analysed using IBM SPSS Statistics version 28.0. Statistical significance was set at α=0.05, and all tests were two-sided. Continuous variables were assessed for distribution using histograms, Q-Q plots and the Shapiro-Wilk test. Normally distributed variables were summarised as mean and standard deviation with 95% confidence intervals. Skewed variables were presented as median and interquartile range. Categorical variables were expressed as frequencies and percentages with appropriate 95% confidence intervals. Associations between categorical variables, such as angioinvasion, extensive necrosis, bone invasion, diabetes, corticosteroid exposure, clinical extent and outcome, were analysed using the Pearson chi-square test or Fisher’s exact test. Effect sizes were reported as odds ratios with 95% confidence intervals. Independent-samples t tests or one-way analysis of variance were used to compare normally distributed continuous variables. Mann-Whitney U or Kruskal-Wallis tests were employed for non-normally distributed data. When serial or paired measurements were available, paired t tests or Wilcoxon signed-rank tests were used as appropriate. Variables associated with extensive disease or adverse outcome at p<0.20 in univariable analysis and clinically important factors were considered for multivariable binary logistic-regression analysis. Adjusted odds ratios with 95% confidence intervals were reported. Multicollinearity, interaction and model fit were evaluated before interpreting the final model. Cases with missing values were excluded analysis-wise, and the denominator used for each analysis was reported. Ethical Considerations Approval was obtained from the Institutional Ethics Committee before commencement of the study. As this was a retrospective record-based investigation involving archived specimens, a waiver of individual informed consent was obtained where permitted by the committee. Patient confidentiality was maintained throughout the study.

Table 1: Overall clinicopathological characteristics of post-COVID-19 mucormycosis (N=200) Parameter Mean (SD) or n (%) 95% CI Test of significance P value Age, years 51.84 (12.73) 50.06-53.62 One-sample t=2.04† 0.043* Interval between COVID-19 and mucormycosis, days 24.68 (11.42) 23.09-26.27 One-sample t=-6.59‡ <0.001* Male sex 137 (68.5%) 61.8%-74.5% Proportion z=5.23§ <0.001* Diabetes mellitus 144 (72.0%) 65.4%-77.8% Proportion z=6.22§ <0.001* Systemic corticosteroid exposure 129 (64.5%) 57.7%-70.8% Proportion z=4.10§ <0.001* Rhino-orbital or rhino-orbito-cerebral disease 101 (50.5%) 43.6%-57.4% Proportion z=0.14§ 0.888 Microbiological confirmation 104 (52.0%) 45.1%-58.8% Proportion z=0.57§ 0.572 Broad, pauci-septate fungal hyphae 176 (88.0%) 82.8%-91.8% Proportion z=10.75§ <0.001* Extensive tissue necrosis 107 (53.5%) 46.6%-60.3% Proportion z=0.99§ 0.322 Angioinvasion 107 (53.5%) 46.6%-60.3% Proportion z=0.99§ 0.322 Bone invasion 79 (39.5%) 33.0%-46.4% Proportion z=-2.97§ 0.003* Favourable outcome 152 (76.0%) 69.6%-81.4% Proportion z=7.35§ <0.001* Adverse outcome¶ 48 (24.0%) 18.6%-30.4% Proportion z=-7.35§ <0.001* †Tested against a reference mean age of 50 years. ‡Tested against a reference post-COVID interval of 30 days. §One-sample proportion test against a hypothesised proportion of 50%. ¶Adverse outcome included persistent or progressive disease, recurrence or in-hospital mortality. *Statistically significant at p<0.05. Table 1 presents the overall clinicopathological characteristics of 200 patients with post-COVID-19 mucormycosis. The mean age was 51.84 (12.73) years (95% CI: 50.06-53.62), which was significantly higher than the reference age of 50 years (t=2.04, p=0.043). Mucormycosis developed after a mean interval of 24.68 (11.42) days following COVID-19, significantly shorter than the reference interval of 30 days (t=-6.59, p<0.001). There was a significant male predominance, with 137 (68.5%) patients being male (95% CI: 61.8%-74.5%; z=5.23, p<0.001). Diabetes mellitus was present in 144 (72.0%) patients, while 129 (64.5%) had received systemic corticosteroids; both proportions were significantly above 50% (p<0.001). Rhino-orbital or rhino-orbito-cerebral disease was identified in 101 (50.5%) patients, and microbiological confirmation was obtained in 104 (52.0%); neither proportion differed significantly from 50% (p=0.888 and p=0.572, respectively). Histopathological examination showed characteristic broad, pauci-septate fungal hyphae in 176 (88.0%) cases, representing a significant predominance (z=10.75, p<0.001). Extensive tissue necrosis and angioinvasion were each observed in 107 (53.5%) cases, although these proportions were not significantly different from 50% (p=0.322). Bone invasion was found in 79 (39.5%) patients (95% CI: 33.0%-46.4%; p=0.003). A favourable outcome was recorded in 152 (76.0%) patients, whereas 48 (24.0%) experienced an adverse outcome. The predominance of favourable outcomes was statistically significant (z=7.35, p<0.001). Table 2: Demographic profile, clinical presentation, anatomical distribution and predisposing factors (N=200) Characteristic n (%) or Mean (SD) 95% CI Test of significance P value Demographic characteristics Age, years 51.84 (12.73) 50.06-53.62 One-sample t=2.04† 0.043* 18-30 years 19 (9.5%) 6.2%-14.4% 31-45 years 74 (37.0%) 30.6%-43.9% χ²=37.88‡ <0.001* 46-60 years 71 (35.5%) 29.2%-42.3% >60 years 36 (18.0%) 13.3%-23.9% Male 137 (68.5%) 61.8%-74.5% χ²=27.38 <0.001* Female 63 (31.5%) 25.5%-38.2% Clinical presentation§ Facial pain or swelling 163 (81.5%) 75.5%-86.3% z=8.91¶ <0.001* Nasal obstruction/discharge 142 (71.0%) 64.4%-76.8% z=5.94¶ <0.001* Headache 118 (59.0%) 52.1%-65.6% z=2.55¶ 0.011* Orbital swelling or proptosis 87 (43.5%) 36.8%-50.4% z=-1.84¶ 0.066 Visual impairment 66 (33.0%) 26.9%-39.8% z=-4.81¶ <0.001* Palatal ulceration/necrosis 31 (15.5%) 11.1%-21.2% z=-9.76¶ <0.001* Anatomical distribution Isolated sinonasal 67 (33.5%) 27.3%-40.3% Rhino-orbital 58 (29.0%) 23.2%-35.6% χ²=91.78‡ <0.001* Rhino-orbito-cerebral 43 (21.5%) 16.4%-27.7% Oral/maxillary 18 (9.0%) 5.8%-13.8% Pulmonary 8 (4.0%) 2.0%-7.7% Other/disseminated sites 6 (3.0%) 1.4%-6.4% Predisposing factors§ Diabetes mellitus 144 (72.0%) 65.4%-77.8% z=6.22¶ <0.001* Systemic corticosteroid exposure 129 (64.5%) 57.7%-70.8% z=4.10¶ <0.001* Poor glycaemic control, HbA1c ≥8% 91 (45.5%) 38.7%-52.4% z=-1.27¶ 0.203 Oxygen supplementation 87 (43.5%) 36.8%-50.4% z=-1.84¶ 0.066 Hypertension 54 (27.0%) 21.3%-33.5% z=-6.51¶ <0.001* Diabetic ketoacidosis 29 (14.5%) 10.3%-20.0% z=-10.04¶ <0.001* Chronic kidney disease 17 (8.5%) 5.4%-13.2% z=-11.74¶ <0.001* †Tested against a reference mean age of 50 years. ‡Chi-square goodness-of-fit test across all categories. §Categories were not mutually exclusive; therefore, their percentages did not total 100%. ¶One-sample proportion test against 50%. *Statistically significant at p<0.05. Table 2 describes the demographic profile, clinical manifestations, anatomical distribution and predisposing factors. The largest proportion of patients belonged to the 31-45-year age group (37.0%), followed by 46-60 years (35.5%), >60 years (18.0%) and 18-30 years (9.5%). The differences in age-group distribution were statistically significant (χ²=37.88, p<0.001). Males accounted for 68.5% of the study population compared with 31.5% females, demonstrating a significant male predominance (χ²=27.38, p<0.001). Facial pain or swelling was the most frequent clinical presentation, occurring in 163 (81.5%) patients, followed by nasal obstruction or discharge in 142 (71.0%) and headache in 118 (59.0%). Each of these symptoms occurred significantly more frequently than the hypothesised proportion of 50% (p<0.001, p<0.001 and p=0.011, respectively). Orbital swelling or proptosis was observed in 87 (43.5%) patients and did not differ significantly from 50% (p=0.066). Visual impairment was reported in 66 (33.0%) patients, while palatal ulceration or necrosis was present in 31 (15.5%); both occurred significantly less frequently than 50% (p<0.001). Isolated sinonasal mucormycosis was the most common anatomical presentation, affecting 67 (33.5%) patients. This was followed by rhino-orbital disease in 58 (29.0%), rhino-orbito-cerebral disease in 43 (21.5%), oral or maxillary disease in 18 (9.0%), pulmonary involvement in 8 (4.0%) and other or disseminated involvement in 6 (3.0%). The anatomical distribution differed significantly across these categories (χ²=91.78, p<0.001), indicating a marked predominance of sinonasal and rhino-orbital disease. Diabetes mellitus was the most frequent predisposing factor, identified in 144 (72.0%) patients, followed by systemic corticosteroid exposure in 129 (64.5%); both were significantly more prevalent than 50% (p<0.001). Poor glycaemic control with HbA1c ≥8% was documented in 91 (45.5%) patients, while 87 (43.5%) had received oxygen supplementation; neither proportion differed significantly from 50% (p=0.203 and p=0.066). Hypertension was present in 54 (27.0%), diabetic ketoacidosis in 29 (14.5%) and chronic kidney disease in 17 (8.5%) patients. These factors occurred significantly less frequently than the 50% reference proportion (all p<0.001). Table 3: Histopathological spectrum of mucormycosis in tissue specimens (N=200) Histopathological characteristic n (%) 95% CI Test of significance P value Predominant fungal morphology Broad, irregular, pauci-septate hyphae 176 (88.0%) 82.8%-91.8% χ²=115.52† <0.001* Predominantly fragmented/degenerate hyphae 24 (12.0%) 8.2%-17.2% Fungal load Mild 49 (24.5%) 19.1%-30.9% Moderate 93 (46.5%) 39.7%-53.4% χ²=15.11† <0.001* Severe 58 (29.0%) 23.2%-35.6% Extent of tissue necrosis Extensive necrosis 107 (53.5%) 46.6%-60.3% Focal necrosis 61 (30.5%) 24.5%-37.2% χ²=42.91† <0.001* No appreciable necrosis 32 (16.0%) 11.6%-21.7% Predominant inflammatory response Acute neutrophilic/suppurative 116 (58.0%) 51.1%-64.6% Mixed acute and chronic 47 (23.5%) 18.2%-29.8% χ²=57.91† <0.001* Granulomatous/giant-cell response 37 (18.5%) 13.7%-24.5% Tissue-invasive characteristics‡ Angioinvasion 107 (53.5%) 46.6%-60.3% z=0.99§ 0.322 Vascular thrombosis 96 (48.0%) 41.2%-54.9% z=-0.57§ 0.572 Perineural invasion 59 (29.5%) 23.6%-36.2% z=-5.80§ <0.001* Bone or bone-marrow invasion 79 (39.5%) 33.0%-46.4% z=-2.97§ 0.003* Soft-tissue or skeletal-muscle invasion 129 (64.5%) 57.7%-70.8% z=4.10§ <0.001* Mixed mucormycosis and aspergillosis 29 (14.5%) 10.3%-20.0% z=-10.04§ <0.001* Bacterial colonies/superadded infection 37 (18.5%) 13.7%-24.5% z=-8.91§ <0.001* †Chi-square goodness-of-fit test across mutually exclusive categories. ‡Histopathological characteristics were not mutually exclusive. §One-sample proportion test against 50%. *Statistically significant at p<0.05.’ Table 3 demonstrates the histopathological spectrum of mucormycosis. Broad, irregular and pauci-septate fungal hyphae, which represent the characteristic morphology of Mucorales, were identified in 176 (88.0%) specimens. Predominantly fragmented or degenerate hyphae were found in the remaining 24 (12.0%). The difference between these morphological patterns was statistically significant (χ²=115.52, p<0.001). A moderate fungal load was most common and was observed in 93 (46.5%) cases, followed by a severe fungal load in 58 (29.0%) and a mild fungal load in 49 (24.5%). The distribution of fungal load differed significantly across the three categories (χ²=15.11, p<0.001). Extensive tissue necrosis was present in 107 (53.5%) specimens, focal necrosis in 61 (30.5%) and no appreciable necrosis in 32 (16.0%). This distribution was also statistically significant (χ²=42.91, p<0.001), demonstrating that some degree of necrosis was present in most specimens. Acute neutrophilic or suppurative inflammation was the predominant inflammatory response, occurring in 116 (58.0%) cases. A mixed acute and chronic inflammatory response was observed in 47 (23.5%), while granulomatous or giant-cell inflammation was present in 37 (18.5%). The inflammatory patterns were distributed unequally (χ²=57.91, p<0.001), with acute suppurative inflammation being the dominant response. Among the invasive characteristics, angioinvasion was present in 107 (53.5%) specimens and vascular thrombosis in 96 (48.0%). Neither differed significantly from the 50% reference proportion (p=0.322 and p=0.572, respectively). Perineural invasion was identified in 59 (29.5%) cases and bone or bone-marrow invasion in 79 (39.5%), with both proportions significantly below 50% (p<0.001 and p=0.003, respectively). Soft-tissue or skeletal-muscle invasion was observed in 129 (64.5%) specimens and was significantly more frequent than 50% (z=4.10, p<0.001). Mixed mucormycosis and aspergillosis was identified in 29 (14.5%) cases, while bacterial colonies or superadded infection were present in 37 (18.5%); both were significantly less frequent than the reference proportion (p<0.001). Table 4: Association of major histopathological findings with clinical extent, risk factors, microbiological findings and outcomes (N=200) Table 4A. Association with advanced clinical disease Advanced disease was defined as rhino-orbital, rhino-orbito-cerebral, disseminated or other extrasinonasal involvement. Factor Advanced disease (n=105), n (%) Limited disease (n=95), n (%) Odds ratio (95% CI) Test of significance P value Angioinvasion present 76 (72.4%) 31 (32.6%) 5.41 (2.95-9.92) χ²=31.68 <0.001* Extensive tissue necrosis 83 (79.0%) 24 (25.3%) 5.48 (2.96-10.15) χ²=31.18 <0.001* Bone invasion present 61 (58.1%) 18 (18.9%) 5.53 (2.91-10.49) χ²=29.52 <0.001* Table 4A shows that major invasive histopathological findings were strongly associated with advanced clinical disease. Angioinvasion was present in 76 (72.4%) patients with advanced disease compared with 31 (32.6%) patients with limited disease. Patients with angioinvasion had 5.41 times higher odds of advanced disease (95% CI: 2.95-9.92; χ²=31.68, p<0.001). Extensive tissue necrosis was observed in 83 (79.0%) advanced cases compared with 24 (25.3%) limited cases and was associated with approximately 5.5-fold higher odds of advanced disease (OR=5.48; 95% CI: 2.96-10.15; χ²=31.18, p<0.001). Similarly, bone invasion was detected in 61 (58.1%) patients with advanced disease and 18 (18.9%) with limited disease. Bone invasion increased the odds of advanced clinical involvement by 5.53 times (95% CI: 2.91-10.49; χ²=29.52, p<0.001). Table 4B: Association of risk factors and microbiology with angioinvasion Factor Angioinvasion present (n=107), n (%) Angioinvasion absent (n=93), n (%) Odds ratio (95% CI) Test of significance P value Diabetes mellitus 91 (85.0%) 53 (57.0%) 4.29 (2.19-8.40) χ²=19.43 <0.001* Corticosteroid exposure 81 (75.7%) 48 (51.6%) 2.92 (1.61-5.29) χ²=12.55 <0.001* Poor glycaemic control, HbA1c ≥8% 61 (57.0%) 30 (32.3%) 2.79 (1.56-4.98) χ²=12.29 <0.001* Positive fungal culture/KOH 72 (67.3%) 32 (34.4%) 3.92 (2.18-7.06) χ²=21.55 <0.001* Table 4B presents the association of underlying risk factors and microbiological findings with angioinvasion. Diabetes mellitus was present in 91 (85.0%) patients with angioinvasion compared with 53 (57.0%) without angioinvasion. Diabetes was associated with 4.29-fold higher odds of angioinvasion (95% CI: 2.19-8.40; χ²=19.43, p<0.001). Corticosteroid exposure was reported in 81 (75.7%) patients with angioinvasion and 48 (51.6%) without it, producing an OR of 2.92 (95% CI: 1.61-5.29; χ²=12.55, p<0.001). Poor glycaemic control was also significantly associated with angioinvasion, occurring in 61 (57.0%) patients with angioinvasion compared with 30 (32.3%) without it (OR=2.79; 95% CI: 1.56-4.98; χ²=12.29, p<0.001). A positive fungal culture or KOH mount was recorded in 72 (67.3%) patients with angioinvasion and 32 (34.4%) without angioinvasion. Microbiological positivity was associated with 3.92-fold higher odds of angioinvasion (95% CI: 2.18-7.06; χ²=21.55, p<0.001). Table 4C: Association of histopathological findings with adverse outcome Histopathological finding Adverse outcome (n=48), n (%) Favourable outcome (n=152), n (%) Odds ratio (95% CI) Test of significance P value Angioinvasion 39 (81.3%) 68 (44.7%) 5.35 (2.42-11.82) χ²=19.55 <0.001* Extensive necrosis 42 (87.5%) 65 (42.8%) 9.37 (3.76-23.36) χ²=29.35 <0.001* Perineural invasion 24 (50.0%) 35 (23.0%) 3.34 (1.69-6.60) χ²=12.76 <0.001* Bone invasion 32 (66.7%) 47 (30.9%) 4.47 (2.24-8.92) χ²=19.51 <0.001* Mixed fungal infection 13 (27.1%) 16 (10.5%) 3.16 (1.39-7.17) χ²=8.07 0.005* Abbreviations: CI, confidence interval; KOH, potassium hydroxide mount. Favourable outcome: recovery or clinical improvement. Adverse outcome: persistent or progressive disease, recurrence or in-hospital mortality. *Statistically significant at p<0.05. Table 4C evaluates the relationship between histopathological findings and adverse patient outcomes. Angioinvasion was observed in 39 (81.3%) patients with an adverse outcome compared with 68 (44.7%) patients with a favourable outcome. Its presence was associated with 5.35-fold higher odds of an adverse outcome (95% CI: 2.42-11.82; χ²=19.55, p<0.001). Extensive necrosis demonstrated the strongest association: it was found in 42 (87.5%) adverse-outcome cases compared with 65 (42.8%) favourable-outcome cases and increased the odds of an adverse outcome by 9.37 times (95% CI: 3.76-23.36; χ²=29.35, p<0.001). Perineural invasion was present in 24 (50.0%) patients with adverse outcomes and 35 (23.0%) with favourable outcomes, corresponding to an OR of 3.34 (95% CI: 1.69-6.60; χ²=12.76, p<0.001). Bone invasion occurred in 32 (66.7%) adverse-outcome cases compared with 47 (30.9%) favourable-outcome cases and was associated with 4.47-fold greater odds of an adverse outcome (95% CI: 2.24-8.92; χ²=19.51, p<0.001). Mixed fungal infection was detected in 13 (27.1%) patients with an adverse outcome and 16 (10.5%) with a favourable outcome. It was associated with approximately threefold higher odds of an adverse outcome (OR=3.16; 95% CI: 1.39-7.17; χ²=8.07, p=0.005).

The present clinicopathological study evaluated 200 patients with post-COVID-19 mucormycosis and demonstrated a characteristic combination of middle-age predominance, male preponderance, diabetes mellitus, corticosteroid exposure, rhinosino-orbital involvement and aggressive tissue-invasive histopathological features. The mean age was 51.84±12.73 years, 68.5% of the patients were male, 72.0% had diabetes mellitus and 64.5% had received systemic corticosteroids. Broad, irregular, pauci-septate fungal hyphae were identified in 88.0% of specimens, while extensive necrosis and angioinvasion were each present in 53.5%. Histological evidence of angioinvasion, extensive necrosis, perineural invasion, bone invasion and mixed fungal infection was significantly associated with advanced disease or adverse outcome. Demographic characteristics and interval after COVID-19 The mean age of 51.84 years observed in the present study was comparable with the demographic pattern reported in major Indian studies. Sen et al. (2021)[1], in the COSMIC study of 2,826 patients, reported that COVID-19-associated rhino-orbito-cerebral mucormycosis predominantly affected middle-aged adults and showed a strong male predominance. Patel et al. (2021)[2] similarly observed that CAM occurred primarily in middle-aged patients with underlying metabolic risk factors. The concentration of cases in the 31-45-year and 46-60-year groups in the present study suggests that economically and socially active adults constituted the principal affected population. Male patients constituted 68.5% of the present cohort. This finding agrees with Singh et al. (2021)[3], who found that 78.9% of the first 101 globally reported CAM cases occurred among men. Pal et al. (2021)[4] and Hoenigl et al. (2022)[5] also reported a clear male predominance. The reason may involve the higher prevalence of diabetes, greater occupational environmental exposure to fungal spores, differences in healthcare-seeking behaviour and sex-related biological or hormonal factors. However, male sex may also reflect the demographic profile of hospitalised COVID-19 patients rather than an independent biological susceptibility. Mucormycosis developed after a mean interval of 24.68±11.42 days following COVID-19. This interval supports the recognition of an early post-COVID susceptibility period during which hyperglycaemia, immune dysregulation and corticosteroid-associated suppression may persist. Bhanuprasad et al. (2021)[6] found that CAM frequently developed within the first few weeks after COVID-19 diagnosis. Ostovan et al. (2022)[7] reported a median interval of approximately 15 days between COVID-19 and the onset of mucormycosis manifestations. The slightly longer interval in the present study could be explained by differences in the definition of disease onset, delay in recognising early sinonasal symptoms or referral after progression to orbital or cerebral involvement. Predisposing factors Diabetes mellitus was the most frequent predisposing factor, affecting 72.0% of the patients. This finding agrees with the established epidemiology of mucormycosis in India even before the COVID-19 pandemic. Prakash and Chakrabarti (2019)[8] identified uncontrolled diabetes as the most important underlying condition for mucormycosis in India. Among patients with CAM, Singh et al. (2021)[3] reported diabetes in approximately 80% of cases, while the meta-analysis by Watanabe et al. (2022)[9], which included 2,312 proven cases, found diabetes in 82%. Thus, although the frequency in the present study was slightly lower, diabetes remained the dominant risk factor. Poor glycaemic control with HbA1c ≥8% was observed in 45.5%, and diabetic ketoacidosis was present in 14.5%. Mishra et al. (2021)[10] demonstrated that patients with CAM commonly had uncontrolled diabetes and markedly elevated HbA1c levels. Hyperglycaemia impairs neutrophil chemotaxis, phagocytosis and oxidative killing, while acidosis increases free serum iron and enhances fungal growth. Increased expression of glucose-regulated protein 78 under hyperglycaemic and acidic conditions may also facilitate endothelial invasion by Mucorales. The association between poor glycaemic control and angioinvasion in the present study (OR=2.79; 95% CI: 1.56-4.98; p<0.001) supports the biological importance of the metabolic environment in promoting tissue and vascular invasion. Systemic corticosteroid exposure was documented in 64.5% of patients and was associated with almost threefold higher odds of angioinvasion (OR=2.92; 95% CI: 1.61-5.29; p<0.001). Gupta et al. (2021)[11] similarly reported a high prevalence of diabetes and previous corticosteroid therapy in a multicentre Indian cohort. Watanabe et al. (2022)[9] found that 77% of patients with CAM had received systemic corticosteroids. The lower proportion in the present study may reflect differences in COVID-19 severity, steroid prescribing practices or completeness of treatment records. Corticosteroids probably increase susceptibility through suppression of innate immune responses and aggravation of pre-existing or newly diagnosed hyperglycaemia. Nevertheless, the findings should not be interpreted as evidence against appropriately indicated corticosteroid therapy in hypoxaemic COVID-19; rather, they reinforce the need for correct dosage, limited duration and close glucose monitoring. Oxygen supplementation was recorded in 43.5% of patients. Patel et al. (2021)[2] found that COVID-19-related hypoxaemia and inappropriate glucocorticoid use were independently associated with CAM. In comparison, Watanabe et al. (2022)[9] reported oxygen requirement in 57% of cases. Oxygen administration itself is unlikely to be a direct cause; it more probably indicates severe COVID-19, prolonged hospitalisation, immune disturbance and greater corticosteroid exposure. Hypertension, diabetic ketoacidosis and chronic kidney disease were less frequent than diabetes and corticosteroid exposure but could have increased the vulnerability of individual patients. Clinical presentation and anatomical distribution Facial pain or swelling was the most frequent manifestation, occurring in 81.5% of patients, followed by nasal obstruction or discharge in 71.0%, headache in 59.0%, orbital swelling or proptosis in 43.5%, visual impairment in 33.0% and palatal ulceration or necrosis in 15.5%. Similar manifestations were described by Sen et al. (2021)[1], who emphasised facial pain, periocular swelling, proptosis, ophthalmoplegia and visual loss as important clinical warning signs. In the meta-analysis by Watanabe et al. (2022)[9], headache occurred in 54%, periorbital swelling or pain in 53%, proptosis in 41% and nasal discharge or congestion in 36%. The greater frequency of facial and nasal manifestations in the present cohort might reflect the inclusion of a larger proportion of biopsy-confirmed sinonasal disease. Isolated sinonasal mucormycosis accounted for 33.5%, rhino-orbital disease for 29.0% and rhino-orbito-cerebral disease for 21.5%. Consequently, the sinonasal-orbital-cerebral pathway represented the predominant anatomical spectrum. Pulmonary and disseminated disease were relatively uncommon, affecting 4.0% and 3.0%, respectively. Pal et al. (2021)[4] found rhino-orbital disease to be the most common presentation, while Watanabe et al. (2022)[9] reported that approximately 97% of pooled CAM cases were rhino-orbital-cerebral and only 2.7% were pulmonary. Hoenigl et al. (2022)[5] likewise identified rhino-orbito-cerebral mucormycosis as the leading form but warned that pulmonary disease may be underdiagnosed because tissue confirmation is difficult in critically ill patients. The lower pulmonary frequency in the present histopathology-based cohort may therefore represent both a genuinely lower occurrence and diagnostic under-ascertainment. Histopathological spectrum Broad, irregular and pauci-septate hyphae were demonstrated in 88.0% of specimens, whereas 12.0% showed predominantly fragmented or degenerate forms. This morphology is characteristic of Mucorales and helps distinguish mucormycosis from aspergillosis, which usually demonstrates narrower, regularly septate, acute-angle branching hyphae. Ganesan and Sivanandam (2022)[12], in their study of 60 post-COVID-19 biopsy specimens, also described broad aseptate or pauci-septate fungal hyphae with tissue invasion as the defining histomorphological feature. Fragmentation and degeneration may result from tissue necrosis, prior antifungal treatment or processing artefacts and can make diagnosis more difficult. A moderate fungal load was most common at 46.5%, followed by severe load in 29.0% and mild load in 24.5%. Sree Lakshmi et al. (2023)[13] found variable fungal density in post-COVID-19 specimens, including a substantial number with severe fungal load. Jain et al. (2022)[14] demonstrated that grading fungal load, tissue invasion and necrosis could help assess histological severity. Variability in fungal load may depend on the timing and site of biopsy, antifungal exposure, immune response and adequacy of tissue sampling. A low fungal load does not necessarily exclude severe disease because extensive vascular occlusion and necrosis may remain after viable hyphae have decreased. Extensive tissue necrosis was observed in 53.5% and focal necrosis in 30.5%, showing that 84.0% of patients had some degree of necrosis. Acute neutrophilic or suppurative inflammation was the predominant reaction in 58.0%, whereas mixed acute-chronic and granulomatous responses were seen in 23.5% and 18.5%, respectively. Mani and Thirunavukkarasu (2022)[15] reported variable inflammatory responses in COVID-19-associated rhino-orbito-cerebral mucormycosis, including minimal inflammation, prominent neutrophilic infiltration, neutrophil extracellular traps and angioinvasion. Jain et al. (2022)[14] similarly documented necrosis, acute inflammation, granulomatous response and tissue invasion of varying severity. An acute suppurative response may reflect an active host reaction, while minimal inflammation in extensively necrotic tissue may indicate vascular compromise or impaired immunity. Angioinvasion was found in 53.5%, vascular thrombosis in 48.0%, perineural invasion in 29.5%, bone invasion in 39.5% and soft-tissue or skeletal-muscle invasion in 64.5%. Sree Lakshmi et al. (2023)[13] reported angioinvasion in 48 patients and perineural invasion in 32 patients in their post-COVID-19 series. Gupta et al. (2024)[16] also identified necrosis, vascular invasion and thrombosis as important histological characteristics associated with clinical severity and outcome. These findings reflect the pathobiology of mucormycosis: fungal hyphae invade vascular walls, producing thrombosis, ischaemia, infarction and tissue necrosis. Perineural spread and bone invasion represent further progression through deep anatomical compartments. Microbiological confirmation was obtained in 52.0% of the present cases. The moderate concordance between histopathology and microbiology is expected because culture sensitivity is limited by nonviable fungal elements, prior antifungal therapy, inadequate sampling and damage to fragile hyphae during tissue homogenisation. Histopathology remains particularly valuable because it establishes true tissue invasion, whereas culture identifies viable organisms and permits species-level diagnosis. The significant association between culture or KOH positivity and angioinvasion (OR=3.92; 95% CI: 2.18-7.06) may indicate that specimens with a greater viable fungal burden were more likely to be microbiologically positive. Mixed mucormycosis and aspergillosis was identified in 14.5% of cases. Ganesan and Sivanandam (2022)[12] and other pathological series have reported mixed invasive fungal infections in the post-COVID-19 setting. Mixed infection is clinically important because morphological overlap, extensive necrosis and fragmented hyphae may complicate diagnosis, while therapeutic decisions may require consideration of antifungal susceptibility. The presence of bacterial colonies or superadded bacterial infection in 18.5% further highlights the polymicrobial nature of necrotic sinonasal tissue. Histopathological findings and advanced disease Angioinvasion was observed in 72.4% of patients with advanced disease compared with 32.6% of those with limited disease and was associated with 5.41-fold higher odds of advanced involvement. Extensive necrosis was present in 79.0% of advanced cases and was associated with an OR of 5.48. Bone invasion similarly increased the odds of advanced disease by 5.53 times. These results agree with Jain et al. (2022)[14], who found that the degree of tissue invasion and histological severity increased with clinical disease extent. Radotra et al. (2022)[17] described extensive soft-tissue involvement, vascular invasion and perineural invasion as characteristic pathological features of CAM. These relationships are biologically plausible. Angioinvasion allows rapid haematogenous and contiguous progression by producing vascular occlusion and tissue infarction. Necrotic tissue has limited antifungal penetration and may therefore serve as a persistent reservoir unless adequately debrided. Bone invasion indicates deeper extension beyond the sinonasal mucosa and is expected to correlate with orbital, maxillary or cerebral spread. Histopathological predictors of outcome A favourable outcome was recorded in 76.0% of patients, while 24.0% experienced persistent or progressive disease, recurrence or in-hospital death. This adverse-outcome frequency was comparable with the 21.7% mortality reported by Gupta et al. (2021)[11] and slightly lower than the pooled CAM mortality of 29% reported by Watanabe et al. (2022)[9]. Sahu et al. (2023)[18] reported a six-week case-fatality of 14% in a multicentric Indian cohort but found a substantially higher risk of death in cerebral, gastrointestinal and disseminated disease. In contrast, Hoenigl et al. (2022)[5] reported 49% mortality across cases from 18 countries, partly because pulmonary, disseminated and cerebral cases were strongly represented. Extensive necrosis was the strongest histopathological correlate of adverse outcome in the present study (OR=9.37; 95% CI: 3.76-23.36), followed by angioinvasion (OR=5.35), bone invasion (OR=4.47), perineural invasion (OR=3.34) and mixed fungal infection (OR=3.16). These findings agree with the clinicopathological observations of Jain et al. (2022)[14], Mani and Thirunavukkarasu (2022)[15], and Gupta et al. (2024)[16],/ who identified extensive necrosis, vascular invasion and advanced tissue involvement as markers of severe disease. The particularly strong association between necrosis and adverse outcome may be explained by irreversible tissue destruction, reduced vascular delivery of antifungal agents and the need for repeated or extensive surgical debridement. Angioinvasion and thrombosis promote further necrosis, while perineural and bone invasion reflect extension into anatomical planes that are difficult to clear surgically. Mixed fungal infection may complicate diagnosis and therapeutic selection. Nevertheless, these are unadjusted associations and may be influenced by disease stage, treatment delay, anatomical site, antifungal availability, surgical adequacy and comorbidities. Multivariable analysis would be required to determine whether these histopathological findings independently predicted outcome.

Post-COVID-19 mucormycosis predominantly affected middle-aged men and was strongly associated with diabetes mellitus and systemic corticosteroid exposure. Sinonasal, rhino-orbital and rhino-orbito-cerebral disease constituted the principal anatomical spectrum, with facial pain or swelling, nasal symptoms and headache being the most frequent presentations. Histopathological examination commonly demonstrated broad, irregular, pauci-septate fungal hyphae accompanied by tissue necrosis, acute suppurative inflammation, angioinvasion, vascular thrombosis and soft-tissue invasion. Angioinvasion, extensive tissue necrosis and bone invasion were significantly associated with advanced clinical disease. Diabetes mellitus, corticosteroid exposure, poor glycaemic control and microbiological positivity were associated with increased angioinvasion. Extensive necrosis was the strongest correlate of adverse outcome, followed by angioinvasion, bone invasion, perineural invasion and mixed fungal infection. Histopathological examination therefore played an essential role not only in confirming mucormycosis but also in evaluating disease severity and identifying patients at increased risk of progression and poor outcome. Early tissue diagnosis, adequate sampling, strict glycaemic control, judicious corticosteroid use, prompt antifungal treatment and aggressive surgical debridement remain essential for improving outcomes. LIMITATIONS OF THE STUDY 1. The retrospective, observational study design depended on previously documented clinical and laboratory records, resulting in the possibility of incomplete information and information bias. 2. The study was conducted at a single tertiary-care hospital; therefore, referral bias may have increased the representation of severe and surgically managed cases and limited the generalisability of the findings. 3. Only patients with available tissue specimens and histopathological confirmation were included. Patients diagnosed exclusively through clinical, radiological or microbiological methods were not represented. 4. The study did not include a control group of COVID-19 patients without mucormycosis or non-COVID-19 patients with mucormycosis. Consequently, the independent contribution of COVID-19 could not be determined. 5. Histopathological features such as fungal load, extent of necrosis and intensity of inflammation were assessed semiquantitatively and could have been affected by interobserver variability. 6. Tissue specimens were obtained through different procedures and from different anatomical sites. Variations in specimen size, sampling depth, prior debridement and tissue preservation may have influenced the observed histopathological spectrum. 7. Prior antifungal therapy may have reduced fungal viability, altered fungal morphology and contributed to fragmented or degenerate hyphae and negative fungal cultures. 8. Microbiological confirmation was unavailable or negative in some cases, and molecular identification of Mucorales to the genus or species level was not routinely performed. 9. Information regarding the dose, duration and appropriateness of corticosteroid treatment was not uniformly available. Therefore, a dose-response relationship between corticosteroid exposure and disease severity could not be evaluated. 10. Glycaemic control was assessed mainly using available blood glucose and HbA1c measurements. Serial glucose variation and the duration of uncontrolled diabetes were not evaluated consistently. 11. Adverse outcome combined persistent disease, progression, recurrence and in-hospital mortality into a composite endpoint. These outcomes may have different determinants and clinical implications. 12. The follow-up period was limited and not uniform for all patients; consequently, late recurrence, long-term visual impairment, neurological disability and post-surgical morbidity may have been underestimated. 13. The reported associations were primarily unadjusted. Residual confounding by age, COVID-19 severity, treatment delay, anatomical extent, comorbidities, antifungal availability and surgical management could not be excluded. 14. As an observational study, it established associations but could not confirm causal relationships between diabetes, corticosteroid exposure, histopathological findings and patient outcomes.

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