key: cord-0694691-y09gf89h
authors: Dravid, Ameet; Kashiva, Reema; Khan, Zafer; Bande, Balasaheb; Memon, Danish; Kodre, Aparna; Mane, Milind; Pawar, Vishal; Patil, Dattatraya; Kalyani, Suraj; Raut, Prathamesh; Bapte, Madhura; Saldanha, Charlotte; Chandak, Dinesh; Patil, Teerthagouda; Reddy, Sateesh; Bhayani, Krushnadas; Suresh, Laxmi; Dillibabu, Vishnu; Srivastava, Shipra; Khandelwal, Shubham; More, Sailee; Shakeel, Atif; Pawar, Mohit; Nande, Pranava; Harshe, Amol; Kadam, Sagar; Hallikar, Sudhir; Kamal, Nudrat; Andrabi, Danish; Bodhale, Sachin; Raut, Akshay; Chandrashekhar, Sangeeta; Raman, Chandrashekhar; Mahajan, Uma; Joshi, Gaurav; Mane, Dilip
title: Epidemiology, clinical presentation and management of COVID‐19 associated mucormycosis: A single centre experience from Pune, Western India
date: 2022-03-10
journal: Mycoses
DOI: 10.1111/myc.13435
sha: 40a86891bc044e4b8797122b4a896dee2389daa0
doc_id: 694691
cord_uid: y09gf89h

BACKGROUND: The second COVID‐19 wave in India has been associated with an unprecedented increase in cases of COVID‐19 associated mucormycosis (CAM), mainly Rhino‐orbito‐cerebral mucormycosis (ROCM). METHODS: This retrospective cohort study was conducted at Noble hospital and Research Centre (NHRC), Pune, India, between 1 April, 2020, and 1 August, 2021, to identify CAM patients and assess their management outcomes. The primary endpoint was incidence of all‐cause mortality due to CAM. RESULTS: 59 patients were diagnosed with CAM. Median duration from the first positive COVID‐19 RT PCR test to diagnosis of CAM was 17 (IQR: 12,22) days. 90% patients were diabetic with 89% having uncontrolled sugar level (HbA1c >7%). All patients were prescribed steroids during treatment for COVID‐19. 56% patients were prescribed steroids for non‐hypoxemic, mild COVID‐19 (irrational steroid therapy), while in 9%, steroids were prescribed in inappropriately high dose. Patients were treated with a combination of surgical debridement (94%), intravenous liposomal Amphotericin B (91%) and concomitant oral Posaconazole (95.4%). 74.6% patients were discharged after clinical and radiologic recovery while 25.4% died. On relative risk analysis, COVID‐19 CT severity index ≥18 (p = .017), presence of orbital symptoms (p = .002), presence of diabetic ketoacidosis (p = .011) and cerebral involvement (p = .0004) were associated with increased risk of death. CONCLUSIONS: CAM is a rapidly progressive, angio‐invasive, opportunistic fungal infection, which is fatal if left untreated. Combination of surgical debridement and antifungal therapy leads to clinical and radiologic improvement in majority of cases.

In December 2019, Wuhan city in China, became the epicentre of an outbreak of viral pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This disease was designated coronavirus disease 2019 in February 2020. 1, 2 COVID-19 spread rapidly worldwide and India was no exception. By 1 August, 2021, there have been more than 300 million infections and 0.4 million deaths due to COVID-19 in India. 3 With COVID-19, the incidence of secondary bacterial or fungal infections is 8%, with aspergillosis and candida being the most common fungi reported. 4, 5 The second COVID-19 wave in India (March 2021 -May 2021), triggered by the Delta variant, has been associated with an unprecedented increase in the cases of COVID-19 associated mucormycosis (CAM). 6, 7 Globally, the prevalence of mucormycosis varies from 0.005 to 1.7 per million population, while its prevalence is nearly 80 times higher (0.14 per 1000) in India as per a recent estimate of year 2019-2020. [7] [8] [9] Thus, India already had the highest number of mucormycosis cases in the world and its incidence increased exponentially during the second COVID-19 wave. As of 1 August, 2021, 45,374 cases of CAM have been reported in India. 6 CAM is an uncommon, rapidly progressive, angio-invasive, commonly fatal, opportunistic fungal infection. 9 Unusual alignment of multiple risk factors could be associated with sudden spurt of CAM in India. 10 Dysregulated immune response in COVID-19 characterized by exuberant activation of innate immune system, elevation in systemic inflammatory markers (C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH) and D-dimer, Interleukin-6 (IL-6), soluble IL-2 receptor [IL-2R], IL-10, TNFα) and depleted adaptive immune response (decline in CD4+ T cell, CD8+ T cell, natural killer cell and decreased interferon Gamma (IFNγ) expression in CD4+ T cells) could be one of the factors predisposing individuals to CAM. 11 In these patients, the activation of antiviral immunity to SARS-CoV-2 may, paradoxically, potentiate an inflammatory phenotype and thus may favour secondary infections. SARS-CoV-2 has been shown to affect the beta cells of the pancreas, resulting in metabolic derangement, possibly causing diabetes mellitus. 12, 13 Uncontrolled DM is a risk factor for both, severe COVID-19 and mucormycosis. 12, 13 Steroids, namely Dexamethasone and Methylprednisolone have been extensively used to resolve hyperinflammation and inflammatory lung damage in severe COVID-19. [14] [15] [16] Use of steroids can cause hyperglycaemia, suppression of several polymorphonuclear (PMN) leucocyte functions, impairment of phagocytosis by resident macrophages, depletion of T cell immunity and increase risk of mucormycosis. 10 In addition, indiscriminate use of steroids in patients with mild or asymptomatic COVID-19 can be counter-productive and make the person susceptible to opportunistic fungi. 17 Use of immunomodulator therapy such as Tocilizumab (TCZ, IL-6 receptor inhibitor) in combination with steroids for cytokine release syndrome (CRS, cytokine storm) could further aggravate immunosuppression and facilitate breakthrough fungal infection. 18 Thus, the primary reason for this sudden increase in CAM in India appears to be germination of Mucorales spores in an ideal environment of low oxygen (hypoxia), high glucose (diabetes mellitus, new onset hyperglycaemia, impaired fasting glucose or steroid-induced hyperglycemia) and immune dysfunction (mediated by Delta variant of SARS-CoV-2, steroid therapy or background co-morbidities). Acidic environment (metabolic acidosis, diabetic ketoacidosis [DKA] ) and high iron levels (excess intracellular iron due to COVID-19 associated hyper-ferritinemia and acidosis facilitating free iron release for Mucorales germination) also seem to contribute to the increase in CAM. 10, 19 The most common form of mucormycosis seen in India during the COVID-19 pandemic was the Rhino-orbito-cerebral (ROCM) one but cases of pulmonary or disseminated mucormycosis have also been reported. 7, 20, 21 Suspected ROCM requires urgent intervention, because of the often rapidly progressive and destructive nature of the infection. Delayed initiation of therapy is associated with increased mortality. 22, 23 Despite treatment, case-fatality rates due to mucormycosis during the pre-COVID-19 pandemic era were already high, ranging from 32% to 70%, according to organ involvement. 22, 23 However, in SARS-CoV-2 infection, the mortality maybe even higher. Maximizing survival rates requires rapid diagnostic and therapeutic intervention, including immediate involvement of a multidisciplinary medical, surgical, radiological and laboratory-based team. Multiple case reports [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] and retrospective cohort studies 7, [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] 

Patients were eligible for inclusion in this analysis if they were admitted to NHRC between 1st April 2020 and 1st August 2021 and were diagnosed with CAM. COVID-19 was diagnosed in patients if they tested positive for SARS-CoV-2 RNA in respiratory specimens by reverse transcription PCR (RT-PCR) or a positive rapid antigen test. Mild COVID-19 was defined as individuals who have various signs and symptoms of COVID-19 but who do not have shortness of breath, dyspnea, or abnormal chest imaging. 47 Moderate disease was defined as patients who show evidence of lower respiratory disease during clinical assessment or imaging and who have oxygen saturation (SpO 2 ) 90 to ≤93% on room air. Severe COVID-19 was defined as SpO 2 <90% on room air, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO 2 /FiO 2 ) < 300 mm Hg, respiratory frequency >30 breaths/min or lung infiltrates >50%. 47 Critical COVID-19 was defined as presentation with respiratory failure (respiratory system failing in its gas exchange functions like oxygenation and carbon dioxide elimination leading to hypoxemia (arterial oxygen tension (PaO 2 ) lower than 60 mm Hg ) and hypercapnia (PaCO 2 higher than 50 mm Hg)), septic shock and multiple Data was obtained from electronic health record of each individual admitted with CAM by manual abstraction. It included dates of COVID-19 related hospitalization, demographics, comorbidities, severity of COVID-19 (CT severity index) and treatment received including steroids and immunomodulator therapy. The CT severity index is a scoring system used to assess lung involvement by COVID-19. An approximate estimation is done by visual scoring of each of the five lung lobes seen on a computerized tomography (CT) scan of chest. A score from 1 to 5 is given to each lobe depending on extent of involvement (maximum score-25). 48 Presenting symptoms of CAM, anatomic site of involvement, diagnostic modalities including microscopy, culture, or histopathology, laboratory investigation data (including inflammatory markers), imaging reports (High resolution computerized tomography scan of chest, paranasal sinuses and brain (HRCT chest, CT PNS and CT brain)), treatment details of anti-fungal drug therapy and surgical debridement, data on use of supplemental oxygen, mechanical ventilation and hospitalization outcomes were also recorded.

For all patients diagnosed with CAM, we also scrutinized inpatient case files until hospital discharge, death, or 1st September 2021the date on which the database was locked-whichever happened first. Systemic complications developing in CAM patients during hospital admission were also noted. All patients who died due to CAM were identified and a death audit to look for cause of death was undertaken. For patients who left the hospital against medical advice, we considered a worst-case scenario for mortality analysis and assumed the patients died. All patients who recovered, got discharged from NHRC and had outpatient follow-up at 15, 30 and 90 days after discharge were identified. Their outpatient follow-up visits were traced from electronic database to look for delayed complications.

Treatment protocol for management of CAM at NHRC has been developed after careful consideration of current global and national guidelines. 49,50 As per NHRC protocol, early, radical, surgical debridement of affected site in addition to combination systemic antifungal therapy was utilized for treatment of CAM.

Functional endoscopic paranasal sinus surgery (FESS) with debridement of necrosed and diseased sinus tissue and orbital decompression was the most common surgical procedure performed in patients with ROCM. All efforts were made to preserve the eye for as long as possible in view of role of eye to not only provide vision but also its removal causing significant psycho-social problems to patient. In patients with total blindness, proptosis, fixed pupil and eyeball, imaging evidence of orbital involvement (globe/muscles/fat) and/or intracranial spread (superior or inferior orbital fissure involvement), surgical exenteration of the eye was performed. 51 Partial or total maxillectomy was performed in patients with evidence of osteomyelitis of maxilla or alveolar arch.

Neurosurgery was performed in case of intracranial spread of disease with involvement of skull base or formation of basi-frontal lobe brain abscess.

Combination therapy of Liposomal Amphotericin B (LAmB) and Oral Triazole (predominantly oral Posaconazole) was the most common medical treatment offered to all patients with CAM. LAmB was administered concomitantly with oral Posaconazole. LAmB was initiated at the dose of 5 mg/kg. The dose was increased to 10 mg/kg in case of intracranial spread. 49, 50 In the scenario of shortage of LAmB due to surge in CAM cases or non-affordability of patient, other formulations of Amphotericin B (Amphotericin B lipid complex (5 mg/kg/day), Amphotericin B lipid emulsion (5 mg/kg/day) and Amphotericin B de-oxycholate (1 mg/kg/day) were used for patients. The duration of Amphotericin B treatment was decided depending on the site of involvement (3 weeks for only paranasal sinus involvement, 4 weeks for orbital, lung and disseminated mucormycosis and 6 weeks for central nervous system (CNS) mucormycosis).

Oral Posaconazole (delayed release tablets, 300 mg twice a day on Day 1 and then 300 mg once a day) was started during hospital admission and continued after discharge from NHRC for a period of 1 to 3 months depending on local control of disease. In patients with concomitant chronic kidney disease, intravenous Posaconazole or Isavuconazole followed by step-down to oral therapy was treatment of choice. Serum Posaconazole levels were performed to guide dosage during oral therapy.

Primary endpoint: 1) Deaths in the cohort due to CAM.

2) Number of patients who had a clinical and radiologic recovery and were discharged from hospital. 

Continuous variables were summarized using median and interquartile range (IQR), while categorical variables were summarized using frequency and percentages. Continuous variables were compared using a Mann Whitney U test. Categorical variables were compared using Chi-square test, Proportion test and Fishers' exact test. Baseline and time dependent risk factors significantly associated with death due to CAM were identified by Relative risk analysis. Baseline risk factors included for analysis were age (<60 years or ≥60 years), gender, severity of baseline COVID-19 disease (CT severity index ≥18 versus <18), presence of orbital or central nervous system (CNS) symptoms, presence of diabetic keto-acidosis, presence of intracranial spread (cerebral involvement) and baseline investigations like absolute lymphocyte count (<1000 versus ≥1000 cells/mm 3 ), C reactive protein (≥50 versus <50 mg/L), D-dimer (≥252 versus <252 mcg/ml) and

Ferritin (≥1000 versus <1000 mcg/L). Time dependent risk factors included duration of Amphotericin B therapy (≤3 weeks versus >3 weeks) and development of systemic complications during treatment like acute kidney injury, hepatitis, anemia, thrombocytopenia, osteomyelitis and CNS complications (stroke or cerebritis). The p value ≤0.05 was considered as statistically significant.

All data was analyzed by SPSS version 12.0. (8, 15) 12 (8, 14) 14 (8, 17) .152

Duration of hospitalization (days) 9 (6, 14) 8 (6, 13.5) 10 (7, 15) .149

Duration of ICU stay (days) 0 (0, 10) 0 (0, 0) 0 (0, 10)

.303

Duration of ventilation (days) 0 (0, 10) 0 (0, 0) 0 (0, 10 (3, 9) 6 (3, 10) 5 (3, 8) .488

Duration between 1st positive COVID-19 test and CAM diagnosis Median (IQR) 17 (12, 22) 17 (13, 23) 17 (10, 21) .676

Abbreviations: CAM, COVID-19 associated mucormycosis; IQR, interquartile range.

Bold values indicate increased risk of mortality due to Mucormycosis. 

Haemoglobin (g/dl) 13.4 (11.4, 14.5) 13.75 (12.05, 14.5) 12.5 (10.9, 13.9) .169

WBC (per microliter) 10,400 (7000, 14,400) 10,150 (7000, 13,500) 11,900 (7000, 15,400) .568

Absolute Neutrophil count (ANC) 8100 (5248, 11, 475) 7902 (5214, 11, 260) 9559 (5250, 13, 490) .447

Platelet count 227,000 (178,000, 308,000) 231,000 (189, 000, 308, 500) 198,000 (160,000, 308,000)

.186

Blood urea level (mg/dl) 32 (22, 54) 28 (20.5, 49) 41 (27, 92) .030

Serum Creatinine (mg/dL) 1. .008 NIV (days) Median (IQR) 2 (1, 2) 0 (0, 0) 2 (1, 2) .015

Invasive mechanical ventilation (IMV) (1.4252, 9.1899) .005

Deviation of angle of mouth 1.662 (0.5140, 5.3715 However, presence of diabetic ketoacidosis (10.9% versus 8.6%) and

prevalence of cerebral involvement (44% versus 23%) was higher in our cohort than the MucoCovi study. 7 Both the factors, presence of diabetic ketoacidosis (p = .011) and cerebral involvement (p = .0004)

were associated with increased mortality on Relative risk analysis.

In CAM patients with cerebral involvement, mortality rate was 50%, which is 5 times higher than among patients without cerebral involvement. Our findings are consistent with studies of mucormycosis in patients not having prior COVID-19 infection. 54, 55 In these studies, presence of disseminated infection was associated with increased mortality while complete surgical removal of infected tissue and treatment with Amphotericin B was associated with improved survival. 54, 55 Development of ROCM while the patient is still under active treatment for moderate or severe COVID-19 may pose significant challenges in the management-specifically termination of corticosteroids and surgery under general anaesthesia. This was reflected in the CT severity index ≥18 (depicting severe COVID pneumonia) being a significant risk factor for increased risk of death due to CAM (p = .017). Patients with ROCM also remain at risk for delayed complications and may need re-admission with further surgical and anti-fungal treatment to resolve them.

Our study has several limitations. First, this is only a descriptive cohort. As there is no control group (COVID-19 patients without mucormycosis), risk factors for mucormycosis cannot be evaluated.

Second, as it is not a randomized controlled trial, unmeasured confounding cannot be ruled out. Third, as for all retrospective studies, some individuals diagnosed with mucormycosis may be unreported leading to measurement bias and underestimation of mortality due to CAM. Fourth, we collected data from a single centre in India unlike other multicentre cohort studies. 7, 37, 39, 40, 42 Fifth, an overwhelmed health care system, inadequate workforce and lack of exhaustive reporting due to surge of cases during second COVID-19 wave could be responsible for underestimation of co-morbidities, presenting symptoms and complications amongst patients in our cohort. Sixth, inflammatory markers such as ferritin, CRP and D-dimer were not available for all patients in the cohort. Seventh, we did not look for environmental factors causing healthcare-associated mucormycosis such as contaminated ventilation systems, air conditioners and ongoing construction in our hospital. We did not estimate the burden of Mucorales spores in our hospital environment. We also did not investigate the link between risk factors like use of industrial oxygen, contaminated nebulizer fluids or inline humidifier tubing used in ventilator circuits and contaminated oxygen delivery systems with increased incidence of CAM in our cohort. 10 Eighth, other unexplored factors, including genetic predisposition were not identified.

Despite these limitations, this retrospective cohort study adds to the growing body of literature on epidemiology, clinical features, anatomic site of involvement, management strategies, outcomes and long-term complications due to COVID-19 associated mucormycosis (CAM). 

Balasaheb Bande: Conceptualization (equal)

Danish Memon: Conceptualization (equal)

Aparna Kodre: Conceptualization (equal)

Milind Mane: Conceptualization (equal)

Supervision (equal)

Vishal Pawar: Data curation (equal)

Supervision (equal)

Validation (equal)

Visualization (equal)

Dattatraya Patil: Data curation (equal)

Supervision (equal)

Suraj Kalyani: Data curation (equal)

Supervision (equal)

Prathamesh Raut: Data curation (equal)

Supervision (equal)

Validation (equal)

Madhura Bapte: Data curation (equal)

Validation (equal)

Charlotte Saldanha: Data curation (equal)

Resources (equal)

Validation (equal)

Dinesh Chandak: Data curation (equal)

Resources (equal)

Supervision (equal)

Teerthgouda Patil: Data curation (equal)

Sateesh Reddy: Data curation (equal)

Investigation (equal)

Resources (equal)

Supervision (equal)

Krushnadas Bhayani: Data curation (equal)

Investigation (equal)

Resources (equal)

Supervision (equal)

Validation (equal)

Laxmi Suresh: Data curation (equal)

Investigation (equal)

Resources (equal)

Supervision (equal)

Validation (equal)

Vishnu Dillibabu: Data curation (equal)

Investigation (equal)

Resources (equal)

Supervision (equal)

Shipra Srivastava: Data curation (equal)

Investigation (equal)

Resources (equal)

Supervision (equal)

Validation (equal)

Shubham Khandelwal: Data curation (equal); Investigation (equal)

Resources (equal)

Sailee More: Conceptualization (equal)

Data curation (equal)

Investigation (equal)

Supervision (equal)

Atif Shakeel: Data curation (equal)

Resources (equal)

Pranava Nande: Data curation (equal)

Investigation (equal)

Resources (equal)

Software (equal)

Supervision (equal)

Amol Harshe: Data curation (equal)

Sudhir Halikar: Conceptualization (equal)

Data curation (equal)

Investigation (equal)

Nudrat Kamal: Data curation (equal)

Investigation (equal)

Danish Andrabi: Conceptualization (equal)

Data curation (equal)

Investigation (equal)

Sachin Bodhale: Data curation (equal)

Akshay Raut: Conceptualization (equal)

Data curation (equal)

Investigation (equal)

Methodology (equal)

Chandrashekhar Raman: Data curation (equal)

Investigation (equal)

Uma Mahajan: Conceptualization (equal); Data curation (equal); Formal analysis (equal)

Resources (equal)

Software (equal)

Supervision (equal)

Validation (equal)

Gaurav Joshi: Conceptualization (equal); Data curation (equal); Formal analysis (equal)

Resources (equal)

Software (equal)

Supervision (equal)

Dileep Mane: Conceptualization (equal); Data curation (equal)

Supervision (equal)

Validation (equal); Writing -original draft (equal)

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The authors would like to thank Dr Prashant Potdar, Dr Romi Pophalikar, Dr Kritika Agarwal, Dr Asir Tamboli, Dr Debashis