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The coronavirus disease 2019 (COVID-19) pandemic has led to a concerning resurgence of mucormycosis. More than 47,000 cases of mucormycosis were reported in three months from India. We update our systematic review on COVID-19-associated mucormycosis (CAM) till June 21st, 2021, comparing cases reported from India and elsewhere. We included individual patient details of 275 cases of CAM, of which 233 were reported from India and 42 from the rest of the world. Diabetes mellitus was the most common underlying risk factor for CAM in India than in other countries. The fatality rate of cases reported from India (36.5%) was less than the globally reported cases (61.9%), probably due to the predominance of rhino-orbital mucormycosis. On a multivariate analysis, we found that pulmonary or disseminated mucormycosis cases and admission to the intensive care unit were associated with increased mortality, while combination medical therapy improved survival. The paucity of pulmonary and disseminated mucormycosis cases from India suggests that these cases were either not diagnosed or reported, further supported by a trend of search data from the Google search engine. In this review, we discuss the factors explaining the substantial rise in cases of CAM. We also propose a hypothetical model describing the epidemiologic triad of CAM.

Severe coronavirus disease (COVID-19) is currently managed with systemic glucocorticoids. Opportunistic fungal infections are of concern in such patients. While COVID-19 associated pulmonary aspergillosis is increasingly recognized, mucormycosis is rare. We describe a case of probable pulmonary mucormycosis in a 55-year-old man with diabetes, end-stage kidney disease, and COVID-19. The index case was diagnosed with pulmonary mucormycosis 21 days following admission for severe COVID-19. He received 5 g of liposomal amphotericin B and was discharged after 54 days from the hospital. We also performed a systematic review of the literature and identified seven additional cases of COVID-19 associated mucormycosis (CAM). Of the eight cases included in our review, diabetes mellitus was the most common risk factor. Three subjects had no risk factor other than glucocorticoids for COVID-19. Mucormycosis usually developed 10–14 days after hospitalization. All except the index case died. In two subjects, CAM was diagnosed postmortem. Mucormycosis is an uncommon but serious infection that complicates the course of severe COVID-19. Subjects with diabetes mellitus and multiple risk factors may be at a higher risk for developing mucormycosis. Concurrent glucocorticoid therapy probably heightens the risk of mucormycosis. A high index of suspicion and aggressive management is required to improve outcomes.

During September-December 2020, we conducted a multicenter retrospective study across India to evaluate epidemiology and outcomes among cases of coronavirus disease (COVID-19)-associated mucormycosis (CAM). Among 287 mucormycosis patients, 187 (65.2%) had CAM; CAM prevalence was 0.27% among hospitalized COVID-19 patients. We noted a 2.1-fold rise in mucormycosis during the study period compared with September-December 2019. Uncontrolled diabetes mellitus was the most common underlying disease among CAM and non-CAM patients. COVID-19 was the only underlying disease in 32.6% of CAM patients. COVID-19-related hypoxemia and improper glucocorticoid use independently were associated with CAM. The mucormycosis case-fatality rate at 12 weeks was 45.7% but was similar for CAM and non-CAM patients. Age, rhino-orbital-cerebral involvement, and intensive care unit admission were associated with increased mortality rates; sequential antifungal drug treatment improved mucormycosis survival. The COVID-19 pandemic has led to increases in mucormycosis in India, partly from inappropriate glucocorticoid use.

Chronic pulmonary aspergillosis has a 5-year mortality of 50–80% globally, and the optimal duration of treatment for chronic pulmonary aspergillosis remains unclear. We aimed to compare the effect of 6-months of oral itraconazole with 12-months of oral itraconazole on chronic pulmonary aspergillosis clinical outcomes. In this single-centre, open-label, randomised controlled trial conducted in one chest clinic in Chandigarh, India, we screened consecutive patients with chronic pulmonary aspergillosis who were naive to antifungal treatment and randomised eligible patients, using block randomisation, to receive a starting dose of 400 mg/day of oral itraconazole for either 6 months or 12 months. There was no masking of participants or investigators. We excluded patients who were unable to provide informed consent; had an intake of any antifungal drugs for more than 3 weeks in the preceding 6 months; had active Mycobacterium tuberculosis or non-tuberculous mycobacterial pulmonary disease; and had allergic, subacute, or invasive forms of aspergillosis. The primary outcome was the proportion of patients having relapse 2 years after treatment initiation. We performed an intention-to-treat analysis for all outcomes. The study is registered with ClinicalTrials.gov, NCT03920527. We recruited participants between Feb 14, 2019, and Aug 30, 2019, and the last follow-up was completed on Aug 31, 2021. We screened 250 patients, of which 164 were included in the trial. 81 patients were randomised to the 6-month group and 83 patients were randomised to the 12-month group. The study population was 78 (48%) women and 86 (52%) men, and the mean age of participants was 44·3 (SD 13·3) years. The proportion of patients experiencing relapse was significantly lower in the 12-month group, 31 (38%) had a relapse in the 6-month group compared with 8 (10%) in the 12-month group, with an absolute risk reduction of 0.29 [95% CI 0·16–0·40]. The mean time to first relapse was 23 months in the 12-month group, which is significantly longer than the mean of 18 months in the 6-month group (p<0.0001). There were 16 deaths in total, eight in each group. Ten (12%) of 81 patients in the 6-months group and 18 (22%) of 83 patients in the 12-months group had adverse effects, with none requiring treatment modification. Nausea and anorexia were the most common adverse events in both groups. Treatment of chronic pulmonary aspergillosis with 12 months of oral itraconazole was superior to 6 months of oral itraconazole in reducing relapses at 2 years. Itraconazole should be given for at least 12 months for treating chronic pulmonary aspergillosis. None. For the Hindi translation of the abstract see Supplementary Materials section.

The proportion of COVID-19 patients having active pulmonary tuberculosis, and its impact on COVID-19 related patient outcomes, is not clear. We conducted this systematic review to evaluate the proportion of patients with active pulmonary tuberculosis among COVID-19 patients, and to assess if comorbid pulmonary tuberculosis worsens clinical outcomes in these patients. We queried the PubMed and Embase databases for studies providing data on (a) proportion of COVID-19 patients with active pulmonary tuberculosis or (b) severe disease, hospitalization, or mortality among COVID-19 patients with and without active pulmonary tuberculosis. We calculated the proportion of tuberculosis patients, and the relative risk (RR) for each reported outcome of interest. We used random-effects models to summarize our data. We retrieved 3,375 citations, and included 43 studies, in our review. The pooled estimate for proportion of active pulmonary tuberculosis was 1.07% (95% CI 0.81%-1.36%). COVID-19 patients with tuberculosis had a higher risk of mortality (summary RR 1.93, 95% CI 1.56-2.39, from 17 studies) and for severe COVID-19 disease (summary RR 1.46, 95% CI 1.05-2.02, from 20 studies), but not for hospitalization (summary RR 1.86, 95% CI 0.91-3.81, from four studies), as compared to COVID-19 patients without tuberculosis. Active pulmonary tuberculosis is relatively common among COVID-19 patients and increases the risk of severe COVID-19 and COVID-19-related mortality.

COVID-19-associated pulmonary mucormycosis (CAPM) remains an underdiagnosed entity. Using a modified Delphi method, we have formulated a consensus statement for the diagnosis and management of CAPM. We selected 26 experts from various disciplines who are involved in managing CAPM. Three rounds of the Delphi process were held to reach consensus (≥70% agreement or disagreement) or dissensus. A consensus was achieved for 84 of the 89 statements. Pulmonary mucormycosis occurring within 3 months of COVID-19 diagnosis was labelled CAPM and classified further as proven, probable, and possible. We recommend flexible bronchoscopy to enable early diagnosis. The experts proposed definitions to categorise dual infections with aspergillosis and mucormycosis in patients with COVID-19. We recommend liposomal amphotericin B (5 mg/kg per day) and early surgery as central to the management of mucormycosis in patients with COVID-19. We recommend response assessment at 4–6 weeks using clinical and imaging parameters. Posaconazole or isavuconazole was recommended as maintenance therapy following initial response, but no consensus was reached for the duration of treatment. In patients with stable or progressive disease, the experts recommended salvage therapy with posaconazole or isavuconazole. CAPM is a rare but under-reported complication of COVID-19. Although we have proposed recommendations for defining, diagnosing, and managing CAPM, more extensive research is required.

ObjectiveThe proportion of COVID-19 patients having active pulmonary tuberculosis, and its impact on COVID-19 related patient outcomes, is not clear. We conducted this systematic review to evaluate the proportion of patients with active pulmonary tuberculosis among COVID-19 patients, and to assess if comorbid pulmonary tuberculosis worsens clinical outcomes in these patients.MethodsWe queried the PubMed and Embase databases for studies providing data on (a) proportion of COVID-19 patients with active pulmonary tuberculosis or (b) severe disease, hospitalization, or mortality among COVID-19 patients with and without active pulmonary tuberculosis. We calculated the proportion of tuberculosis patients, and the relative risk (RR) for each reported outcome of interest. We used random-effects models to summarize our data.ResultsWe retrieved 3,375 citations, and included 43 studies, in our review. The pooled estimate for proportion of active pulmonary tuberculosis was 1.07% (95% CI 0.81%-1.36%). COVID-19 patients with tuberculosis had a higher risk of mortality (summary RR 1.93, 95% CI 1.56-2.39, from 17 studies) and for severe COVID-19 disease (summary RR 1.46, 95% CI 1.05-2.02, from 20 studies), but not for hospitalization (summary RR 1.86, 95% CI 0.91-3.81, from four studies), as compared to COVID-19 patients without tuberculosis.ConclusionActive pulmonary tuberculosis is relatively common among COVID-19 patients and increases the risk of severe COVID-19 and COVID-19-related mortality.

Allergic bronchopulmonary aspergillosis (ABPA) is an inflammatory disease caused by immunologic reactions initiated against Aspergillus fumigatus colonizing the airways of patients with asthma and cystic fibrosis. The common manifestations include treatment-resistant asthma, transient and fleeting pulmonary opacities and bronchiectasis. It is believed that globally there are about five million cases of ABPA, with India alone accounting for about 1.4 million cases. The occurrence of ABPA among asthmatic patients in special clinics may be as high as 13 per cent. Thus, a high degree of suspicion for ABPA should be entertained while treating a patient with bronchial asthma, particularly in specialized clinics. Early diagnosis and appropriate treatment can delay (or even prevent) the onset of bronchiectasis, which suggests that all patients of bronchial asthma should be screened for ABPA, especially in chest clinics. The current review summarizes the recent advances in the pathogenesis, diagnosis and management of ABPA.

We compared diagnostic accuracy of pleural fluid Xpert MTB/RIF (Xpert) and Xpert MTB/RIF Ultra (Ultra) assays for diagnosing tuberculous pleural effusion (TPE), through systematic review and comparative meta-analysis. We searched PubMed and Embase databases for publications reporting diagnostic accuracy of Xpert or Ultra for TPE. We used bivariate random-effects modeling to summarize diagnostic accuracy information from individual studies using either mycobacterial culture or composite criteria as reference standard. We performed meta-regression through hierarchical summary receiver operating characteristic (HSROC) modeling to evaluate comparative performance of the two tests from studies reporting diagnostic accuracy of both in the same study population. We retrieved 1097 publications, and included 74 for review. Summary estimates for sensitivity and specificity for Xpert were 0.52 (95% CI 0.43-0.60, I.sup.2 82.1%) and 0.99 (95% CI 0.97-0.99, I.sup.2 85.1%), respectively, using culture-based reference standard; and 0.21 (95% CI 0.17-0.26, I.sup.2 81.5%) and 1.00 (95% CI 0.99-1.00, I.sup.2 37.6%), respectively, using composite reference standard. Summary estimates for sensitivity and specificity for Ultra were 0.68 (95% CI 0.55-0.79, I.sup.2 80.0%) and 0.97 (95% CI 0.97-0.99, I.sup.2 92.1%), respectively, using culture-based reference standard; and 0.47 (95% CI 0.40-0.55, I.sup.2 64.1%) and 0.98 (95% CI 0.95-0.99, I.sup.2 54.8%), respectively, using composite reference standard. HSROC meta-regression yielded relative diagnostic odds ratio of 1.28 (95% CI 0.65-2.50) and 1.80 (95% CI 0.41-7.84) respectively in favor of Ultra, using culture and composite criteria as reference standard. Ultra provides superior diagnostic accuracy over Xpert for diagnosing TPE, mainly because of its higher sensitivity.