S econdary infections are known to complicate the clinical course of coronavirus disease . Bacterial infections are the most common secondary infections, but increasing reports of systemic fungal infections are causing concern. In the early part of the COVID-19 pandemic, <1% of secondary infections reported in COVID-19 patients were fungal (1,2). Preexisting conditions, indiscriminate use of antimicrobial and glucocorticoid drugs, and lapses in infection control practices are putative factors contributing to the emergence of systemic fungal infections in severe COVID-19 cases (3). After incidence of candidemia and invasive aspergillosis in COVID-19 patients increased (4,5), awareness of possible fungal co-infections increased among clinicians and microbiologists. One study reported invasive fungal infections in ≈6% of hospitalized COVID-19 patients (6). Occasional reports of COVID-19-associated mucormycosis (CAM) from various centers (7,8) and a series of 18 cases from a city in South India increased our concerns about CAM (9). India has a high burden of mucormycosis among patients with uncontrolled diabetes mellitus, and many severe COVID-19 patients have diabetes (8,10). India also is one of the countries worst affected by the COVID-19 pandemic. Thus, we would expect India to have many CAM cases. We conducted a nationwide multicenter study to evaluate the epidemiology and outcomes of CAM and compare the results with cases of mucormycosis unrelated to COVID-19 (non-CAM). Methods Study Design and SettingWe conducted a retrospective observational study involving 16 healthcare centers across India (Figure 1).

Objectives: To describe the epidemiology, management and outcome of individuals with mucormycosis; and to evaluate the risk factors associated with mortality. Methods: We conducted a prospective observational study involving consecutive individuals with proven mucormycosis across 12 centres from India. The demographic profile, microbiology, predisposing factors, management and 90-day mortality were recorded; risk factors for mortality were analysed. Results: We included 465 patients. Rhino-orbital mucormycosis was the most common (315/465, 67.7%) presentation followed by pulmonary (62/465, 13.3%), cutaneous (49/465, 10.5%), and others. The predisposing factors included diabetes mellitus (342/465, 73.5%), malignancy (42/465, 9.0%), transplant (36/ 465, 7.7%), and others. Rhizopus species (231/290, 79.7%) were the most common followed by Apophysomyces variabilis (23/290, 7.9%), and several rare Mucorales. Surgical treatment was performed in 62.2% (289/465) of the participants. Amphotericin B was the primary therapy in 81.9% (381/465), and posaconazole was used as combination therapy in 53 (11.4%) individuals. Antifungal therapy was inappropriate in 7.6% (30/394) of the individuals. The 90-day mortality rate was 52% (242/465). On multivariate analysis, disseminated and rhino-orbital (with cerebral extension) mucormycosis, shorter duration of symptoms, shorter duration of antifungal therapy, and treatment with amphotericin B deoxycholate (versus liposomal) were independent risk factors of mortality. A combined medical and surgical management was associated with a better survival. Conclusions: Diabetes mellitus was the dominant predisposing factor in all forms of mucormycosis. Combined surgical and medical management was associated with better outcomes. Several gaps surfaced in the management of mucormycosis. The rarer Mucorales identified in the study warrant further evaluation. A.

Mucormycosis due to Mucorales is reported at large numbers in uncontrolled diabetics across India, but systematic multicenter epidemiological study has not been published yet. The present prospective study was conducted at four major tertiary care centers of India (two in north and two in south India) during 2013-2015 to compare the epidemiology, treatment strategies and outcome of mucormycosis between the two regions. Molecular techniques were employed to confirm the identity of the isolates or to identify the agent in biopsy samples. A total of 388 proven/probable mucormycosis cases were reported during the study period with overall mortality at 46.7%. Uncontrolled diabetes (n = 172, 56.8%) and trauma (n = 31, 10.2%) were the common risk factors. Overall, Rhizopus arrhizus (n = 124, 51.9%) was the predominant agent identified, followed by Rhizopus microsporus (n = 30, 12.6%), Apophysomyces variabilis (n = 22, 9.2%) and Rhizopus homothallicus (n = 6, 2.5%). On multivariate analysis, the mortality was significantly associated with gastrointestinal (OR: 18.70, P = .005) and pulmonary infections (OR: 3.03, P = .015). While comparing the two regions, majority (82.7%) cases were recorded from north India; uncontrolled diabetes (n = 157, P = .0001) and post-tubercular mucormycosis (n = 21, P = .006) were significantly associated with north Indian cases. No significant difference was noted among the species of Mucorales identified and treatment strategies between the two regions. The mortality rate was significantly higher in north Indian patients (50.5%) compared to 32.1% in south India (P = .016). The study highlights higher number of mucormycosis cases in uncontrolled diabetics of north India and emergence of R. microsporus and R. homothallicus across India causing the disease.

Ovarian follicular development was studied in 13 heifers by daily ultrasound examination during 2 complete and consecutive natural oestrous cycles. In 21 cycles (81%) 3 dominant follicles were identified, in 4 cycles (15%) 2 and in the remaining cycle 1 (4%). Consistently, the first dominant follicle was detected on average on Day 4, reached a maximum size on Day 6, went through a period of relative stability between Days 6 and 10, then began to decrease in size and was undetectable by Day 15. The second dominant follicle was detected by Day 12, reached maximum size on Day 16 (or 19 in the 4 cycles in which the 2nd dominant follicle was the ovulatory follicle) and was undetectable by Day 19. The 3rd (ovulatory) follicle was identified on average by Day 16 (range Days 10 to 19) and maximum size was reached on Day 21. The ovulatory follicles were larger (P less than 0.05) than the previous ones and the stage of the cycle at which maximum size was reached was significantly different for each dominant follicle (P less than 0.05). The analysis of the rates of growth and atresia suggest that the rate of growth is slowest during mid-cycle. The number of dominant follicles that developed in the ovary ipsilateral to the corpus luteum was greater (P less than 0.05) than in the contralateral ovary.

The study highlighted a high burden of candidemia in Indian ICUs, early onset after ICU admission, higher risk despite less severe physiology score at admission and a vast spectrum of agents causing the disease with predominance of C. tropicalis.