Risk factors for pulmonary mucormycosis in subjects with diabetes mellitus-A case-control study.

BACKGROUND: Factors associated with pulmonary mucormycosis (PM) among subjects with diabetes mellitus (DM) remain unclear. Following the coronavirus disease (COVID-19)-associated mucormycosis outbreak in India, specific environmental exposures (especially cattle dung exposure) were proposed as possible aetiology. We hypothesized that environmental factors are associated with PM. We compared subjects with DM with (cases) and without PM (controls). METHODS: In this case-control study, for each PM case, we included five unmatched diabetic controls (hospital [n = 2], community [n = 3]) without PM. We collected information on demography, COVID-19 infection, glycated haemoglobin% (HbA1c), the type of house (pucca vs. kutcha) where the participants reside, and other environmental factors. The primary exposure tested was cattle dung exposure (CDE; using cattle dung cakes as fuel or cattle handling). We performed a multivariate logistic regression to explore factors associated with PM and report the association as an adjusted odds ratio (OR) with 95% confidence intervals (CI). RESULTS: We enrolled 39 PM cases and 199 controls (hospital [n = 80], community [n = 119]). CDE (OR 0.68, 95% CI [0.14-3.31]; p = 0.63) was not associated with increased PM in DM. We found male sex (OR 4.07, 95% CI [1.16-14.31]), higher HbA1c (OR 1.51, 95% CI [1.18-16.32]), COVID-19 (OR 28.25, 95% CI [7.02-113.6]) and residence at kutcha house (OR 4.84, 95% CI [1.33-17.52]) associated with PM. CONCLUSION: Cattle dung exposure was not associated with PM in subjects with DM. Instead, male sex, poor glycaemic control, COVID-19 and the type of housing were associated with pulmonary mucormycosis.

Treatment of pulmonary mucormycosis with adjunctive nebulized amphotericin B (MUCONAB trial): Results of an open-label randomized controlled trial.

BACKGROUND: The role of nebulized amphotericin B (NAB) in managing pulmonary mucormycosis (PM) is unknown. METHODS: In this open-label trial, we randomized PM subjects to receive either intravenous liposomal amphotericin B (control arm, 3-5 mg/kg/day) alone or along with nebulized amphotericin B deoxycholate (NAB, 10 mg twice a day, every alternate day). The primary outcomes were: (1) overall response ('success' [complete or partial response] or 'failure' [stable disease, progressive disease, or death]) at 6 weeks; and (2) the proportion of subjects with adverse events (AE). The key secondary outcome was 90-day mortality. We performed a modified intention-to-treat (mITT) analysis where we included only subjects receiving at least a single dose of NAB. RESULTS: Fifteen and 17 subjects were randomized to the control and NAB arms; two died before the first dose of NAB. Finally, we included 30 subjects (15 in each arm; mean age 49.8 years; 80% men) for the mITT analysis. Diabetes mellitus (n = 27; 16/27 were COVID-19-associated PM) was the most common predisposing factor. The overall treatment success was not significantly different between the control and the NAB arms (71.4% vs. 53.3%; p = .45). Twenty-nine subjects experienced any AE, but none discontinued treatment. The 90-day mortality was not significantly different between the control (28.6%) and NAB arm (53.3%; p = .26). CONCLUSION: Adjunctive NAB was safe but did not improve overall response at 6 weeks. A different dosing schedule or nebulized liposomal amphotericin B may still need evaluation. More research is needed to explore other treatment options for PM.

Comparison of master two-step exercise stress test versus six-min walk test in patients tested positive for SARS-CoV-2.

Background and Aim: There has been a lack of uniformity on how to triage coronavirus disease 2019 (COVID-19) patients visiting the emergency units of hospitals. Triage tools are themselves spreading the pandemic in hospital areas. The present study compared a master two-step (M2ST) exercise stress test versus a 6-min walk test (6MWT) in COVID-19-positive patients visiting the emergency unit of a hospital. Materials and Methods: Thirty-nine patients underwent 6MWT followed by M2ST, while another set of 38 patients underwent M2ST followed by 6MWT in this randomized, crossover, open-label, and noninferiority study. The exercise tests assessed the change from baseline in SpO2, heart rate (HR), respiratory rate, blood pressure, exertion, and dyspnea on the modified-Borg scale. Results: Noninferiority was established for SpO2 (P < 0.05), systolic blood pressure (SBP; P < 0.001), and diastolic blood pressure (DBP; P < 0.05), but not for HR (P = 0.3) and respiratory rate (P = 0.6). The difference between the pretest and posttest (delta change) values for the parameters SpO2, respiratory rate, HR, SBP, and DBP correlated significantly (P < 0.001) with Pearson correlation coefficient (r = 0.764, 0.783, 0.473, 0.838, and 0.783, respectively). The delta change values of modified-Borg scale for dyspnea (P = 0.291) and exertion (P = 0.208) were statistically insignificant between the two exercise tests. However, the correlation between the tests was statistically significant (P < 0.001). Conclusion: M2ST, a timesaving, cost-effective, and easy to perform exercise stress test, has been identified as a reliable alternative for 6MWT.

SARS-CoV-2 infection, pulse oximetry, and interpretive caveats.

Hypoxaemia in COVID-19 does not necessarily imply COVID pneumonia or post-COVID lung fibrosis, and the caveats of finger pulse oximetry should be remembered. Drug-induced methaemoglobinemia should be considered in individuals with unexplained cyanosis, refractory hypoxaemia, or the presence of a saturation gap. Here, we share our recent encounter of 'spurious hypoxia' in a patient with COVID-19 and methaemoglobinemia.

Serum glucose-regulated protein 78 (GRP78) levels in COVID-19-associated mucormycosis: results of a case–control study

Background In experimental models, the expression of glucose-regulated protein 78 (GRP78) in endothelial cells played a role in the pathogenesis of mucormycosis. However, the role of GRP78 in COVID-19-associated mucormycosis (CAM) has not been studied. We hypothesized that serum GRP78 levels are elevated in subjects with CAM. Objective To compare the serum GRP78 levels in subjects with CAM and COVID-19 controls without mucormycosis. Design And Setting We performed a hospital-based, case–control study between 1 April 2021 and 31 May 2021. Participants We enrolled 24 subjects each of CAM and COVID-19 subjects without mucormycosis. We also measured serum GRP78 levels in ten healthy controls. Exposure The primary exposure studied was serum GRP78 concentration, estimated using a commercially available ELISA kit in stored serum samples. Results We found the mean ± standard deviation (SD) serum GRP78 levels significantly higher (p = 0.0001) among the CAM (374.3 ± 127.3 pg/mL) than the COVID-19 (246.4 ± 67.0 pg/mL) controls. The proportion of subjects with an abnormal GRP78 level (> mean [184.8 pg/mL] plus two SD [23.2 pg/mL] of GRP78 from healthy participants) was 87.5% and 45.8% in the CAM group and COVID-19 controls, respectively. Serum GRP78 level was independently associated with CAM (odds ratio 1.011;95% confidence interval [1.002–1.019]) after adjusting for diabetes mellitus and hypoxemia during acute COVID-19. Conclusion Serum GRP78 levels were significantly higher in CAM than in COVID-19 controls. Further studies are required to the role of GRP78 in the pathogenesis of CAM. Supplementary Information The online version contains supplementary material available at 10.1007/s11046-022-00645-6.

Serum glucose-regulated protein 78 (GRP78) levels in COVID-19-associated mucormycosis: results of a case-control study.

BACKGROUND: In experimental models, the expression of glucose-regulated protein 78 (GRP78) in endothelial cells played a role in the pathogenesis of mucormycosis. However, the role of GRP78 in COVID-19-associated mucormycosis (CAM) has not been studied. We hypothesized that serum GRP78 levels are elevated in subjects with CAM. OBJECTIVE: To compare the serum GRP78 levels in subjects with CAM and COVID-19 controls without mucormycosis. DESIGN AND SETTING: We performed a hospital-based, case-control study between 1 April 2021 and 31 May 2021. PARTICIPANTS: We enrolled 24 subjects each of CAM and COVID-19 subjects without mucormycosis. We also measured serum GRP78 levels in ten healthy controls. EXPOSURE: The primary exposure studied was serum GRP78 concentration, estimated using a commercially available ELISA kit in stored serum samples. RESULTS: We found the mean ± standard deviation (SD) serum GRP78 levels significantly higher (p = 0.0001) among the CAM (374.3 ± 127.3 pg/mL) than the COVID-19 (246.4 ± 67.0 pg/mL) controls. The proportion of subjects with an abnormal GRP78 level (> mean [184.8 pg/mL] plus two SD [23.2 pg/mL] of GRP78 from healthy participants) was 87.5% and 45.8% in the CAM group and COVID-19 controls, respectively. Serum GRP78 level was independently associated with CAM (odds ratio 1.011; 95% confidence interval [1.002-1.019]) after adjusting for diabetes mellitus and hypoxemia during acute COVID-19. CONCLUSION: Serum GRP78 levels were significantly higher in CAM than in COVID-19 controls. Further studies are required to the role of GRP78 in the pathogenesis of CAM.

Could cattle dung burning have contributed to the epidemic of COVID-19-associated mucormycosis in India? Results of an experimental aero-mycological study.

BACKGROUND: Several hypotheses have been proposed for explaining the outbreak of coronavirus disease 2019 (COVID-19)-associated mucormycosis in India, including the burning of cattle dung cakes, though no study has yet been conducted to support this claim. METHODS: We conducted an aero-mycological study to evaluate whether Mucorales in the air increased during or after burning cattle dung cakes. We further compared the growth of Mucorales in the indoor air samples from houses with and without cattle. We also cultured fresh and dried cattle dung and soil samples for Mucorales. RESULTS: We noted no significant difference in the proportion of air samples growing Mucorales during (4/22 [18.2%]) and after (3/2 [13.6%]) cattle dung burning than that collected immediately before (4/22 [18.2%]). Mucorales were isolated in 15.4% of the indoor air samples obtained from different houses (both rural and urban); the proportion of samples growing Mucorales was not significantly different in households with and without cattle. We also observed growth of Mucorales in 6 of the 8 [75%] fresh and 3 of the 6 [50%] dried dung samples. The most common Mucorales isolated from soil and dung samples was Lichtheimia corymbifera, while Rhizopus arrhizus was the most common species isolated from indoor air samples. CONCLUSIONS: We found no significant increase in the proportion of air samples growing Mucorales during or after burning cattle dung cake than that before. It seems unlikely that cattle dung burning contributes to the occurrence of mucormycosis.

Definition, diagnosis, and management of COVID-19-associated pulmonary mucormycosis: Delphi consensus statement from the Fungal Infection Study Forum and Academy of Pulmonary Sciences, India.

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.

Corticosteroids for Non-severe COVID-19: Primum Non Nocere.

Muthu V, Sehgal IS, Dhooria S, Prasad KT, Aggarwal AN, Agarwal R. Corticosteroids for Non-severe COVID-19: Primum Non Nocere. Indian J Crit Care Med 2022;26(3):403-404.

Pulmonary Artery Pseudoaneurysm in COVID-19-Associated Pulmonary Mucormycosis: Case Series and Systematic Review of the Literature.

Literature on COVID-19-associated pulmonary mucormycosis (CAPM) is sparse. Pulmonary artery pseudoaneurysm (PAP) is an uncommon complication of pulmonary mucormycosis (PM), and rarely reported in CAPM. Herein, we report five cases of CAPM with PAP managed at our center and perform a systematic review of the literature. We diagnosed PM in those with clinico-radiological suspicion and confirmed it by microbiology or histopathology. We encountered five cases of CAPM with PAP (size ranged from 1 × 0.8 cm to ~ 4.9 × 4.8 cm). All subjects had diabetes and were aged 55-62 years (75% men). In two cases, COVID-19 and mucormycosis were diagnosed simultaneously, while in three others, COVID-19 preceded PM. One subject who underwent surgery survived, while all others died (80% mortality). From our systematic review, we identified one additional case of CAPM with PAP in a transplant recipient. CAPM with PAP is rare with high mortality. Early diagnosis and multimodality management are imperative to improve outcomes.

Serum iron indices in COVID-19-associated mucormycosis: A case-control study.

BACKGROUND: Whether dysregulated iron metabolism is associated with COVID-19-associated mucormycosis (CAM) remains unknown. Herein, we compare the serum iron indices in COVID-19 subjects with and without mucormycosis. METHODS: We conducted a case-control study enrolling COVID-19 participants with and without mucormycosis. We compared the baseline serum iron indices (iron, ferritin, total iron-binding capacity [TIBC], unsaturated iron-binding capacity and percentage transferrin saturation) between CAM cases and COVID-19 controls. Additionally, we performed a multivariate logistic regression analysis to assess whether any iron indices are associated with CAM. RESULTS: We enrolled 28 CAM cases (mean age 53.6 years old; 78.6% men) and 26 controls (mean age 57.2 years old; 73.1% men). Rhino-orbital (±cerebral) mucormycosis (85.7%) was the most clinical presentation. Diabetes mellitus was more frequent in the cases than controls (75% vs. 42.3%; p = .015). Hypoxaemia during COVID-19 illness was more common in controls than cases. The mean serum iron values (33 vs. 45 µg/dl, p = .03) and TIBC (166.6 vs. 201.6 µg/dl, p = .003) were significantly lower in CAM cases than controls. On multivariate analysis, we found a lower TIBC (odds ratio [OR] 0.97; 95% confidence interval [CI], 0.95-0.99) and diabetes mellitus (OR 5.23; 95% CI, 1.21-22.68) to be independently associated with CAM after adjusting for serum iron, ferritin and glucocorticoid therapy. The case fatality rate of CAM was 73.9%. The iron indices were not significantly different between CAM survivors and non-survivors. CONCLUSIONS: The CAM is associated with lower TIBC levels than COVID-19 subjects without mucormycosis, suggesting dysregulated iron metabolism in its pathogenesis. Further studies are required to confirm our preliminary observations.

Active pulmonary tuberculosis and coronavirus disease 2019: A systematic review and meta-analysis.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Active pulmonary tuberculosis is relatively common among COVID-19 patients and increases the risk of severe COVID-19 and COVID-19-related mortality.