We included 217 consecutive patients with CAM during the study period. About half the cases were in the age group of 37–54 years (n = 109, 50%) while 22 (10%) were younger than 37 years and 86 (40%) were older than 55 years. Majority of patients were men (n = 177, 82%). Cases were managed by multiple consultants from different specialities across the three participating centres. Majority of the cases (n = 201, 93%) were referred to the participating centres for mucormycosis infection management after the primary COVID-19 infection was managed at the referring centre. The infecting organism was found to be Rhizopus in 144 cases, (66%) Mucor in 37 cases (17%), Syncephalastrum in 1 case. Mixed infection of Rhizopus with Aspergillus was detected in 10 (5%) cases while the species was not identified in 25 cases (12%).
Previous COVID-19 infection
The mean time between recovery from prior COVID-19 and onset of mucormycosis was 15.2 ± 9.1 days and ranged from 2 to 60 days. Recovery was as not as such defined and the date of discharge from the previous hospital, as obtained from the records was taken as presumed recovery. Records showed that nearly half the patients (n = 100, 46%) had severe COVID-19 in the past while another 83 (38%) had moderate COVID-19 and 21 (10%) had mild disease, while records were not available to classify COVID severity in 13 (6%) patients. During the study period, we treated nearly 1250 patients of severe COVID-19, of which 100 patients had mucormycosis. Most of the cases (95/100) of mucormycosis with severe COVID-19 were referred to the participating centres for mucormycosis tertiary care and management.
About half the patient’s required non-invasive ventilation (NIV) (n = 109, 50%), while a further 36 (17%) required mechanical ventilation and 37 (17%) needed supplemental oxygen alone while 35 (16%) did not need any oxygen. 14(7%) of the patients were on home-based care and not hospitalized for COVID-19 disease and yet developed CAM.
Predisposing factors for mucormycosis
Predisposing factors for mucormycosis seen in this cohort, along with prior COVID-19 is shown in Tables 1 and 2. Majority of patients were diabetic (n = 192, 88%) of which 27 (12%) were newly diagnosed. Overall, 83% received high-dose systemic steroids, 80% had uncontrolled diabetes and 12% had coexisting diabetic ketoacidosis. In addition to diabetes and high-dose steroids, patients had other comorbidities such as hypertension (n = 66, 30%), prior stroke (n = 4, 2%), chronic kidney disease (n = 4, 2%) and coronary artery disease (n = 9, 4%). Other immunosuppressive conditions included 3 post renal transplant recipients. Most patients classified as mild to moderate COVID-19 also received 1–2 mg/kg of methylprednisolone or its equivalent in the referring centres (Tables 1, 2). The mean blood sugar of patients admitted with mucormycosis was 273 ± 108 mg, the HbA1c was 9.4 ± 2.4 gm%, serum ferritin was 553 ± 400 ng/ml and C-Reactive protein was 53 ± 61 mg/dl. There were no patients without any known predisposing factor for mucormycosis.
Sites of mucormycosis
In our patient cohort, mucormycosis involved the nasal sinuses most commonly (n = 95, 44%) followed by rhino-orbital (ROM, n = 69, 32%), rhino-cerebral (RCM, n = 3), rhino-orbito-cerebral (ROCM, n = 15, 9%), pulmonary (n = 25, 12%), gastrointestinal (n = 6, 3%), isolated cerebral (n = 2) and disseminated mucormycosis (n = 2). In cases with rhino-orbital disease, the majority had bilateral involvement (n = 152, 70%). The maxillary sinus was the most commonly involved (n = 173, 80%) followed by the ethmoid (n = 165, 76%) and sphenoid sinuses (n = 162, 75%). One hundred and forty-seven patients (68%) showed involvement of all three sinuses. Intracranial extension was observed in 29 (13%) on imaging and an additional 8 patients (4%) had cranial nerve palsies. A comparison of predisposing factor and outcomes between mucormycosis at different sites is shown in Table 3. Those with involvement of the cerebral, GI or disseminated disease had significantly higher mortality, that occurred significantly sooner compared to mucormycosis involving the sinuses, orbit, or lungs. This subset was also marginally older, had a lower percentage of patients with high dose steroid administration and uncontrolled DM. The several sites of involvement and the operative findings have been shown in Fig. 1.
In those with sinus and orbital involvement (n = 179), the commonest symptoms were headache (n = 85, 47%), and pain in the facial region, jaw pain and retroorbital (n = 88, 49%) regions. Proptosis was the commonest symptom in those with orbital involvement (n = 68, 39%) while 53 (30%) presented with visual blurring or frank visual loss. In those with pulmonary involvement (n = 25), all had cough and dyspnea (100%) while 20 (80%) had chest pain and 11 (35%) had hemoptysis.
The commonest medical treatment offered to patients was a combination of Liposomal amphotericin—B and Posaconazole, in a sequential manner (n = 141, 65%) followed by a combination of Liposomal amphotericin-B and Isavuconazole sequentially (n = 21, 10%) and lyophilized amphotericin B with Posaconazole sequentially (n = 22, 10%). Liposomal amphotericin B, the mainstay of medical management, was administered for a median of 17 days (IQR 11–22 days, range 1–36 days). Retrobulbar amphotericin-B was used in only 4 eyes. Similarly, functional endoscopic sinus surgery (FESS) was the mainstay of surgical management and was done in all cases of ROCM. Table 4 shows a summary of all surgical procedures done as per the anatomical site involved. Orbital exenteration was performed in 21% of cases with orbital involvement, while two-thirds of cases with pulmonary involvement underwent lobectomy and all patients with GI involvement underwent a hemicolectomy.
Outcomes and survival
A total of 31 (14%) patients died due to mucormycosis during the 6 weeks follow-up. Of these, 8 (26%) had sinus involvement, 9 (29%) had ROCM, 6 (19%) had pulmonary involvement, 5 (16%) had GI involvement, 1 (3%) had cerebral, 2 (7%) had disseminated mucormycosis. The cumulative probability of death (Fig. 2) increased from 9.7% (95% CI 6.4–14.5%) at day 10–14.4% (95% CI 10.2–20.2%) on day 20 and marginally more to 15.3% (95% CI 10.8–21.3%) on day 30. The cumulative probability of death was significantly higher in those with cerebral, GI and disseminated disease (Fig. 3) (log-rank p < 0.001). A univariate and multivariable Cox proportional hazards modeling showed that patients with cerebral or GI or disseminated mucormycosis had a 9 times higher risk of death (p < 0.001) compared to other locations. Pulmonary mucormycosis also had more than twice the higher risk of death compared to sinus involvement alone, though this was not statistically significant. Patients who required mechanical ventilation during their COVID-19 management were also at a 55% higher risk of mortality, but this was only marginally significant (p = 0.07). In pulmonary mucormycosis, of the 16 who underwent lobectomy, only 1 died (6%) while 5 out of 9 (55%) who did not undergo the procedure died (p < 0.001). However, 5/6 (83%) with GI involvement underwent hemicolectomy and still died (Fig. 4).