Sunday, May 28, 2023
| Category | Controls, n = 3,911 | CAM, n = 1,733 | p value |
|---|---|---|---|
| Age, y, mean (SD) | 52.7 (13.5) | 52.6 (12.5) | 0.66 |
| Male sex | 2,738/3,911 (70.0) | 1,285/1,733 (74.1) | 0.002 |
| Rural residence, n = 3,924 | 309/2,615 (11.8) | 360/1,309 (27.5) | 0.0001 |
| Risk factors for mucormycosis | 0.0001 | ||
| None | 2,076/3,911 (53.1) | 316/1,733 (18.2) | |
| 1 risk factor | 1,743/3,911 (44.5) | 1,374/1,733 (79.3) | |
| >1 risk factors | 92/3,911 (2.4) | 43/1,733 (2.5) | |
| Details of potential risk factors for mucormycosis† | |||
| Diabetes mellitus | 1,763/3,911 (45.1) | 1,402/1,733 (80.9) | 0.0001 |
| Hyperglycemia at admission, n = 5,236 | 998/3,625 (27.5) | 758/1,611 (47.1) | 0.0001 |
| Plasma glucose at admission, mg/dL, mean (SD), n = 3,487 | 195 (94) | 235 (106) | 0.0001 |
| Glycated hemoglobin, mean (SD), n = 1,856 | 7.7 (2.5) | 10.1 (2.9) | 0.0001 |
| Duration of diabetes, y, mean (SD), n = 861 | 9.6 (9.5) | 8.4 (6.8) | 0.04 |
| Recent onset of diabetes mellitus | 319/1,763 (18.1) | 246/1,402 (17.5) | 0.66 |
| DKA at the time of admission for COVID-19 | 48/1,763 (2.7) | 73/1,402 (5.2) | 0.0003 |
| Renal transplant | 36/3,911 (0.9) | 31/1,733 (1.8) | 0.005 |
| Bone marrow transplant | 0/3,911 (0) | 1/1,733 (0.1) | 0.31 |
| Hematological malignancy | 36/3,911 (0.9) | 6/1,733 (0.3) | 0.02 |
| Immunosuppressive therapy | 76/3,911 (1.9) | 22/1,733 (1.3) | 0.07 |
| HIV | 7/3,911 (0.2) | 6/1,733 (0.3) | 0.23 |
| Others‡ | 2/3,911 (0.0) | 2/1,733 (0.1) | 0.23 |
| Comorbidities | |||
| Any comorbidity | 828/3,911 (21.5) | 265/1,733 (15.3) | 0.0001 |
| Coronary artery disease | 285/3,911 (7.3) | 126/1,733 (7.3) | 0.98 |
| Chronic kidney disease | 284/3,911 (7.3) | 98/1,733 (5.7) | 0.03 |
| Chronic heart failure | 59/3,911 (1.5) | 17/1,733 (1.0) | 0.11 |
| Chronic liver disease | 71/3,911 (1.8) | 13/1,733 (0.8) | 0.002 |
| Chronic respiratory disease | 104/3,911 (2.7) | 17/1,733 (1.0) | 0.0001 |
| Others§ | 151/3,911 (3.9) | 35/1,733 (2.0) | 0.0001 |
| Laboratory parameters during COVID-19 illness | |||
| Hemoglobin, g/dL, mean (SD), n = 4,506 | 12.2 (2.4) | 12.1 (2.2) | 0.11 |
| Total leukocyte count, cells/µL, mean (SD), n = 4,501 | 9,853 (6,844) | 11,396 (6,110) | 0.0001 |
| Median absolute lymphocyte count, cells/µL (IQR), n = 4,129 | 1,135 (720–1,706) | 1,275 (803–1,833) | 0.0001 |
| Median absolute neutrophil count, cells/µL (IQR), n = 4,071 | 6,177 (3,658–10,244) | 7,858 (4,943–11,867) | 0.0001 |
| Median NLR (IQR), n = 4,061 | 5.5 (2.7–11.4) | 5.7 (3.2–11.7) | 0.04 |
| Platelet count, × 103/µL, mean (SD), n = 4,454 | 222 (107) | 240 (105) | 0.0001 |
| Median C-reactive protein mg/dL (IQR), n = 3,972 | 26.7 (8.4–79.3) | 48.8 (20–102.5) | 0.0001 |
| Median serum ferritin, µg/L (IQR) n = 3,168 | 454 (189–977) | 580 (238–1,052) | 0.02 |
| Details of COVID-19 illness | |||
| Hypoxemia, n = 5,476 | 2,100/3,851 (54.5) | 751/1,625(46.2) | 0.0001 |
| ICU admission, n = 5,425 | 1,551/3,809 (40.7) | 331/1,616 (20.5) | 0.0001 |
| Mechanical ventilation, n = 5,376 | 1,126/3,765 (29.9) | 153/1,611 (9.5) | 0.0001 |
| Management during COVID-19 | |||
| Glucocorticoid therapy, n = 5,431 | 2,690/3,827 (70.3) | 1,200/1,604 (74.8) | 0.001 |
| Glucocorticoid use in the absence of hypoxemia, n = 5,021 | 789/3,532 (22.3) | 509/1,489 (34.2) | 0.0001 |
| Median cumulative dose of glucocorticoids in milligram equivalent of dexamethasone (IQR), n = 2,809 |
52.8 (30–84) | 62.6 (30.2–120) | 0.0001 |
| Median no. days on glucocorticoid treatment (IQR), n = 2,887 | 8 (5–12) | 10 (6.3–14) | 0.0001 |
| Zinc supplementation, n = 5,179 | 1,502/3,633 (41.3) | 741/1,546 (47.9) | 0.0001 |
| Remdesivir, n = 5,167 | 1,785/3,631 (49.2) | 317/1,536 (20.6) | 0.0001 |
| Tocilizumab, n = 5,167 | 72/3,631 (2.0) | 37/1,536 (2.4) | 0.41 |
| Baricitinib, n = 5,167 | 38/3,631 (1.0) | 13/1,536 (0.8) | 0.50 |
| Antibacterial therapy, n = 5,396 | 2,467/3,841 (64.2) | 952/1,555 (61.2) | 0.04 |
| Antifungal therapy before CAM, n = 5,039 | 174/3,513 (5.0) | 68/1,526 (4.5) | 0.45 |
Table 1. Baseline features of CAM case-patients and COVID-19 control-patients at admission for COVID-19, India, January–June 2021*
*Values are no. observed/total no. (%) unless otherwise indicated. CAM, COVID-19–associated mucormycosis; DKA, diabetic ketoacidosis; DM, diabetes mellitus; ICU, intensive care unit; IQR, interquartile range; NLR, neutrophil-to-lymphocyte ratio. †A single person might have had >1 risk factor; hence the numbers do not sum to 5,644. ‡Others include neutropenia (n = 3) and primary immunodeficiency (n = 1). §Others include neurologic, endocrinologic, and rheumatologic illnesses.
| Parameter | Adjusted OR (95% CI) | p value |
|---|---|---|
| Female sex | 0.92 (0.74–1.14) | 0.46 |
| Rural residence | 2.88 (2.12–3.79) | 0.0001 |
| Risk factor | ||
| No risk factor | Referent | |
| Diabetes mellitus | 6.72 (5.45–8.28) | 0.0001 |
| Renal transplantation | 7.58 (3.31–17.40) | 0.0001 |
| Others† | 1.20 (0.67–2.18) | 0.54 |
| Presence of any comorbidity | 0.50 (0.39–0.63) | 0.0001 |
| Hypoxia during COVID-19 | 0.26 (0.21–0.32) | 0.0001 |
| Diabetic ketoacidosis during COVID-19 | 4.41 (2.03–9.60) | 0.0001 |
| Cumulative glucocorticoid dose for COVID-19‡ | 1.006 (1.004–1.007) | 0.0001 |
| Zinc supplementation during COVID-19 | 2.76 (2.24–3.40) | 0.0001 |
| C-reactive protein at admission | 1.004 (1.002–1.006) | 0.0001 |
| Serum ferritin, µg/L | 1.00 (1.00–1.00) | 0.21 |
| Neutrophil-to-lymphocyte ratio | 1.0 (0.99–1.01) | 0.92 |
Table 2. Multivariate logistic regression analysis showing factors associated with CAM, India, January–June 2021*
*CAM, COVID-19–associated mucormycosis. †Includes malignancies, hematological malignancies, immunosuppressive therapy, HIV, and others. ‡In milligram equivalent of dexamethasone.
| Parameter | No. observed/total no. (%) |
|---|---|
| Site of mucormycosis† | |
| Rhino-orbito-cerebral | |
| Sinus | 1,526/1,733 (88.1) |
| Orbit | 789/1,733 (45.5) |
| Palate | 373/1,733 (21.5) |
| Jaw | 315/1,733 (18.2) |
| Brain | 261/1,733 (15.1) |
| Blackening of skin over face | 102/1,733 (5.9) |
| Cavernous sinus | 44/1,733 (2.5) |
| Skull base | 65/1,733 (3.8) |
| Pulmonary† | 122/1,733 (7.0) |
| Cutaneous or soft tissue | 5/1,733 (0.3) |
| Gastrointestinal | 2/1,733 (0.1) |
| Renal† | 2/1,733 (0.1) |
| Diagnosis of mucormycosis | |
| Microscopy alone | 352/1,733 (20.3) |
| Culture growth of Mucorales alone | 61/1,733 (3.5) |
| Histopathology alone | 177/1,733 (10.2) |
| ≥1 evidence (smear, culture, or histopathology) of mucormycosis | 1,143/1,733 (66.0) |
| Treatment practices | |
| Intended therapy could not be administered | 321/1,526 (21.0) |
| Missed doses due to drug non-availability | 248/1,457 (17.0) |
| Primary therapy | |
| Any formulation of amphotericin B‡ | 1,634/1,733 (94.3) |
| Primary combination therapy§ | |
| Any combination | 699/1,733 (41.6) |
| Amphotericin B and posaconazole | 541/699 (77.4) |
| Amphotericin B and isavuconazole | 121/699 (17.3) |
| Amphotericin B and isavuconazole or posaconazole | 37/699 (5.3) |
| Surgery | |
| Combined medical and surgical treatment | 1,449/1,773 (83.6) |
| Survival | |
| Death by 6 weeks | 442/1,546 (28.6) |
| Death by 12 weeks | 473/1,471 (32.2) |
Table 3. Diagnosis, treatment practices, and survival in patients with CAM, India, January–June 2021*
*CAM, COVID-19–associated mucormycosis †Total number does not sum to 1,733 since patients might have had involvement at >1 site. There were 18 cases of disseminated mucormycosis (17 had pulmonary in addition to rhino-orbital, while 1 person had rhino-orbito-cerebral and renal mucormycosis). ‡Of the 1,634 persons receiving amphotericin B, liposomal amphotericin B alone was used in 1,210 (74.1%) patients, amphotericin B deoxycholate in 143 (8.7%) patients, amphotericin B lipid emulsion in 21 (1.3%) patients, >1 formulation in 236 (14.4%) patients, and the information was not clear in 24 (1.5%) patients. §Primary therapy with a combination of amphotericin and isavuconazole or posaconazole within the first 14 days was used in 699/1,733 (41.6%) patients.
| Parameter | Adjusted odds ratio (95% CI) | p value |
|---|---|---|
| Age | 1.02 (1.01–1.04) | 0.0001 |
| Sex | 1.00 (0.74–1.34) | 0.99 |
| Risk factor | ||
| No risk factor | Referent | |
| Diabetes mellitus | 1.27 (0.93–1.74) | 0.13 |
| Renal transplantation | 2.66 (1.04–6.81) | 0.04 |
| Others† | 1.51 (0.55–4.18) | 0.42 |
| Presence of any comorbidity | 1.38 (0.97–1.97) | 0.08 |
| Hypoxemia during COVID-19 illness | 1.31 (0.93–1.83) | 0.12 |
| Site of mucormycosis | ||
| Rhino-orbital mucormycosis | Referent | |
| Rhino-orbital mucormycosis with brain involvement | 2.30 (1.66–3.19) | 0.0001 |
| Other sites‡ | 1.44 (0.90–2.32) | 0.13 |
| Primary combination medical therapy | 0.53 (0.37–0.77) | 0.001 |
| Combined medical and surgical treatment | 0.20 (0.14–0.27) | 0.0001 |
Table 4. Factors associated with death at 12 weeks in persons with CAM, India, January–June 2021*
*CAM, COVID-19–associated mucormycosis. †Includes hematological malignancies, immunosuppressive therapy, and HIV infection. ‡Includes pulmonary, gastrointestinal, disseminated, and renal mucormycosis.
Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™
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This activity is intended for infectious disease clinicians, internists, pulmonologists, diabetologists, and other clinicians caring for patients with COVID-19 who may be at increased risk for COVID-19-associated mucormycosis.
The goal of this activity is for learners to be better able to describe risk factors for and clinical outcomes of COVID-19-associated mucormycosis (CAM), including potential associations of COVID-19 treatment practices with the occurrence of CAM, and factors associated with mortality in CAM at 12 weeks, based on a nationwide case-control study (1,733 CAM cases and 3,911 age-matched COVID-19 controls) across 25 hospitals in India from January to June 2021.
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We performed a case–control study across 25 hospitals in India for the period of January–June 2021 to evaluate the reasons for an COVID-19–associated mucormycosis (CAM) outbreak. We investigated whether COVID-19 treatment practices (glucocorticoids, zinc, tocilizumab, and others) were associated with CAM. We included 1,733 cases of CAM and 3,911 age-matched COVID-19 controls. We found cumulative glucocorticoid dose (odds ratio [OR] 1.006, 95% CI 1.004–1.007) and zinc supplementation (OR 2.76, 95% CI 2.24–3.40), along with elevated C-reactive protein (OR 1.004, 95% CI 1.002–1.006), host factors (renal transplantation [OR 7.58, 95% CI 3.31–17.40], diabetes mellitus [OR 6.72, 95% CI 5.45–8.28], diabetic ketoacidosis during COVID-19 [OR 4.41, 95% CI 2.03–9.60]), and rural residence (OR 2.88, 95% CI 2.12–3.79), significantly associated with CAM. Mortality rate at 12 weeks was 32.2% (473/1,471). We emphasize the judicious use of COVID-19 therapies and optimal glycemic control to prevent CAM.
Mucormycosis is an invasive fungal infection associated with high death rates. Poorly controlled diabetes mellitus, organ transplantation, hematological malignancies, and immunosuppression are the known predisposing factors for mucormycosis[1]. During the second wave of the COVID-19 pandemic (April–June 2021), a large number of cases of COVID-19–associated mucormycosis (CAM) were reported globally, primarily in India[2–5]. The explanation for this outbreak of CAM in India remains unclear. Diabetes mellitus and glucocorticoids (used for treating COVID-19) have been identified as risk factors for CAM[2,6]. Other factors proposed in the pathogenesis of CAM include altered iron metabolism, the severity of COVID-19, and immune dysfunction resulting from COVID-19 (e.g., lymphopenia and others)[7,8].
A high burden of Mucorales (in the hospital and outdoor environments) has been reported in India during and even before the CAM epidemic[9,10]. We also found no difference in the Mucorales species causing mucormycosis before and during the COVID-19 pandemic[2,11]. The epidemiologic triad of agent, environmental, and host factors is helpful to explain the occurrence of a new illness or the recrudescence of an old disease[6,8,9]. Because the data indicate no change in the environment or the agent (Mucorales), we hypothesized that COVID-19, its treatment, and specific host factors contributed to the CAM outbreak.
We evaluated the risk factors and clinical outcomes of CAM in a nationwide study. The main objective of our study was to assess whether treatment practices in COVID-19 were associated with the occurrence of CAM. We also evaluate the factors associated with death from CAM at 12 weeks.
