A multicentre, double-blind, placebo-controlled randomized trial of Mycobacterium w in critically ill patients with COVID-19 (ARMY-2).

BACKGROUND: Mycobacterium w (Mw), an immunomodulator, resulted in better clinical status in severe coronavirus infectious disease 19 (COVID-19) but no survival benefit in a previous study. Herein, we investigate whether Mw could improve clinical outcomes and survival in COVID-19. MATERIALS AND METHODS: In a multicentric, randomized, double-blind, parallel-group, placebo-controlled trial, we randomized hospitalized subjects with severe COVID-19 to receive either 0.3 mL/day of Mw intradermally or a matching placebo for three consecutive days. The primary outcome was 28-day mortality. The co-primary outcome was the distribution of clinical status assessed on a seven-point ordinal scale ranging from discharged (category 1) to death (category 7) on study days 14, 21, and 28. The key secondary outcomes were the change in sequential organ failure assessment (SOFA) score on days 7 and 14 compared to the baseline, treatment-emergent adverse events, and others. RESULTS: We included 273 subjects (136 Mw, 137 placebo). The use of Mw did not improve 28-day survival (Mw vs. placebo, 18 [13.2%] vs. 12 [8.8%], P = 0.259) or the clinical status on days 14 (odds ratio [OR], 1.33; 95% confidence intervals [CI], 0.79-2.3), 21 (OR, 1.49; 95% CI, 0.83-2.7) or 28 (OR, 1.49; 95% CI, 0.79-2.8) between the two study arms. There was no difference in the delta SOFA score or other secondary outcomes between the two groups. We observed higher injection site reactions with Mw. CONCLUSION: Mw did not reduce 28-day mortality or improve clinical status on days 14, 21 and 28 compared to placebo in patients with severe COVID-19. [Trial identifier: CTRI/2020/04/024846].

Bronchiectasis Severity Index and FACED scores in patients with allergic bronchopulmonary aspergillosis complicating asthma: do they correlate with immunological severity or high-attenuation mucus?

BACKGROUND: The utility of two disease-severity indices, namely bronchiectasis severity index (BSI) and FACED score in allergic bronchopulmonary aspergillosis (ABPA) remains unknown. OBJECTIVE: To correlate the BSI and FACED scores with immunological parameters (serum IgE [total and A. fumigatus-specific], A. fumigatus-specific IgG, blood eosinophil count), and high-attenuation mucus on chest computed tomography in ABPA. The secondary objectives were to evaluate the correlation between BSI and FACED scores and correlate the BSI/FACED scores with the bronchiectasis health questionnaire (BHQ) and Saint George's Respiratory Questionnaire (SGRQ). METHODS: We included treatment-naïve ABPA subjects with bronchiectasis in a prospective observational study. We computed the BSI and FACED scores for each subject before initiating treatment. The subjects also completed two quality-of-life questionnaires (BHQ and SGRQ). RESULTS: We included 91 subjects. The mean (standard deviation) BSI and FACED scores were 3.43 (3.39) and 1.43 (1.27). We found no correlation between BSI or FACED with any immunological parameter or high-attenuation mucus. There was a strong correlation between BSI and FACED scores (r = 0.76, p < 0.001). We found a weak correlation between BSI and BHQ/SGRQ and FACED and SGRQ. CONCLUSION: We found no correlation between BSI and FACED with immunological parameters in ABPA. However, we found a significant correlation between BSI and FACED and a weak correlation between SGRQ and BHQ. ABPA likely requires a separate disease-severity scoring system.

Chronic Pulmonary Aspergillosis as a Considerable Complication in Post-Tuberculosis Lung Disease.

Post-tuberculosis lung disease (PTLD) has only recently been put in the spotlight as a medical entity. Recent data suggest that up to 50% of tuberculosis (TB) patients are left with PTLD-related impairment after completion of TB treatment. The presence of residual cavities in the lung is the largest risk factor for the development of chronic pulmonary aspergillosis (CPA) globally. Diagnosis of CPA is based on four criteria including a typical radiological pattern, evidence of Aspergillus species, exclusion of alternative diagnosis, and a chronic course of disease. In this manuscript, we provide a narrative review on CPA as a serious complication for patients with PTLD.

Clinical Manifestation and Treatment of Allergic Bronchopulmonary Aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to airway colonization by Aspergillus fumigatus in patients with asthma and cystic fibrosis. The pathophysiology of ABPA involves a complex interplay between the fungus and the host immune response, which causes persistent inflammation and tissue damage. Patients present with chronic cough, wheezing, and dyspnea due to uncontrolled asthma. Characteristic symptoms include the expectoration of brownish mucus plugs. Radiographic findings often reveal fleeting pulmonary infiltrates, bronchiectasis, and mucus impaction. However, the definitive diagnosis of ABPA requires a combination of clinical, radiological, and immunological findings. The management of ABPA aims to reduce symptoms, prevent disease progression, and minimize the future risk of exacerbations. The treatment approach involves systemic glucocorticoids or antifungal agents to suppress the inflammatory response or fungal growth and prevent exacerbations. Biological agents may be used in patients with severe disease or glucocorticoid dependence. This review provides an overview of the clinical manifestations and current treatment options for ABPA.

Prevalence of Aspergillus sensitization and Allergic Bronchopulmonary Aspergillosis in bronchial asthma: A systematic review of Indian studies.

Background: The prevalence of allergic bronchopulmonary aspergillosis (ABPA) in Indian asthmatic patients remains unknown. We systematically reviewed the literature for estimating the prevalence of Aspergillus sensitization (AS) and ABPA in Indian subjects with bronchial asthma. Methods: We searched the PubMed and Embase databases for studies from India reporting the prevalence of AS or ABPA in at least 50 asthmatics. The primary outcome of our study was to assess the prevalence of ABPA. The secondary outcomes were to evaluate the prevalence of AS in asthma and ABPA in Aspergillus-sensitized asthma. We pooled the prevalence estimates using a random effects model and examined the factors influencing the prevalence using multivariate meta-regression. Results: Of the 8,383 records retrieved, 34 studies with 14,580 asthmatics met the inclusion criteria. All the studies were from tertiary centers. The pooled prevalence of ABPA in asthmatics (26 studies; 5,554 asthmatics) was 16.2% [95% confidence interval (CI), 12.5-20.4]. The pooled prevalence of AS in asthma (29 studies; 13,405 asthmatics) was 30.9% (95% CI, 25.3-36.6), while the prevalence of ABPA in AS (20 studies; 1,493 asthmatics) was 48.2% (95% CI, 39.6-56.8). Meta-regression identified studies published after 2009 (OR 1.14; 95% CI, 1.02-1.28) and studies with severe asthmatics (OR 1.12; 95% CI, 1.00-1.26) as the only factors associated with higher ABPA prevalence. Conclusions: There is a high prevalence of ABPA in Indian asthmatic subjects at tertiary centers, underscoring the need for screening all asthmatic subjects in special asthma and chest clinics for ABPA.

Doffing Corridor: Establishing Expedited High-Volume Doffing With Exposure Reduction to Contaminated Personal Protective Equipment (PPE) in a COVID-19 Hospital in India.

Background Considering the virulent nature of the COVID-19, the safety of healthcare workers (HCW) became a challenge for hospital administrators. Wearing a personal protective equipment (PPE) kit, called donning, which can be easily done by the help of another staff. But correctly removing the infectious PPE kit (doffing) was a challenge. The increased number of HCWs for COVID-19 patient care raised the opportunity to develop an innovative method for the smooth doffing of PPEs. Objective We aimed to design and establish an innovative PPE doffing corridor in a tertiary care COVID-19 hospital during the pandemic in India with a heavy doffing rate and minimize the COVID-19 virus spread among healthcare workers. Methodology A prospective, observational cohort study at the COVID-19 hospital, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, was conducted from July 19, 2020, to March 30, 2021. The time taken for PPE doffing process of HCWs was observed and compared between the doffing room and doffing corridor. The data was collected by a public health nursing officer using Epicollect5 mobile software and Google forms. The following parameters, like grade of satisfaction, time and volume of doffing, the errors in the steps of doffing, rate of infection, were compared between the doffing corridor and the doffing room. The statistical analysis was done by the use of SPSS software. Result 'Doffing corridor' decreased the overall doffing time by 50% compared to the initial doffing room. The doffing corridor solved the purpose of accommodating more HCWs for PPE doffing and an overall saving of 50% time. Fifty-one percent of HCWs rated the satisfaction rate as Good in the grading scale. The errors in the steps of doffing that occurred in the doffing process were comparatively lesser in the doffing corridor. The HCWs who doffed in the doffing corridor were three times less likely to get self-infection than the conventional doffing room. Conclusion Since COVID-19 was a new pandemic, the healthcare organizations focused on innovations to combat the spread of virus. One of these was an innovative doffing corridor to expedite the doffing process and decrease the exposure time to the contaminated items. The doffing corridor process can be considered at a high-interest rate to any hospital dealing with infectious disease, with high working satisfaction, less exposure to the contagion, and less risk of infection.

Ultra-Low Dose CT Chest in Acute COVID-19 Pneumonia: A Pilot Study from India.

The rapid increase in the number of CT acquisitions during the COVID-19 pandemic raised concerns about increased radiation exposure to patients and the resultant radiation-induced health risks. It prompted researchers to explore newer CT techniques like ultra-low dose CT (ULDCT), which could improve patient safety. Our aim was to study the utility of ultra-low dose CT (ULDCT) chest in the evaluation of acute COVID-19 pneumonia with standard-dose CT (SDCT) chest as a reference standard. This was a prospective study approved by the institutional review board. 60 RT-PCR positive COVID-19 patients with valid indication for CT chest underwent SDCT and ULDCT. ULDCT and SDCT were compared in terms of objective (noise and signal-to-noise ratio) and subjective (noise, sharpness, artifacts and diagnostic confidence) image quality, various imaging patterns of COVID-19, CT severity score and effective radiation dose. The sensitivity, specificity, positive and negative predictive value, and diagnostic accuracy of ULDCT for detecting lung lesions were calculated by taking SDCT as a reference standard. The mean age of subjects was 47.2 ± 10.7 years, with 66.67% being men. 90% of ULDCT scans showed no/minimal noise and sharp images, while 93.33% had image quality of high diagnostic confidence. The major imaging findings detected by SDCT were GGOs (90%), consolidation (76.67%), septal thickening (60%), linear opacities (33.33%), crazy-paving pattern (33.33%), nodules (30%), pleural thickening (30%), lymphadenopathy (30%) and pleural effusion (23.33%). Sensitivity, specificity and diagnostic accuracy of ULDCT for detecting most of the imaging patterns were 100% (p < 0.001); except for GGOs (sensitivity: 92.59%, specificity: 100%, diagnostic accuracy: 93.33%), consolidation (sensitivity: 100%, specificity: 71.43%, diagnostic accuracy: 93.33%) and linear opacity (sensitivity: 90.00%, specificity: 100%, diagnostic accuracy: 96.67%). CT severity score (range: 15-25) showed 100% concordance on SDCT and ULDCT, while effective radiation dose was 4.93 ± 1.11 mSv and 0.26 ± 0.024 mSv, respectively. A dose reduction of 94.38 ± 1.7% was achieved with ULDCT. Compared to SDCT, ULDCT chest yielded images of reasonable and comparable diagnostic quality with the advantage of significantly reduced radiation dose; thus, it can be a good alternative to SDCT in the evaluation of COVID-19 pneumonia.

Identification of distinct immunophenotypes in chronic pulmonary aspergillosis using cluster analysis.

BACKGROUND: Whether chronic pulmonary aspergillosis (CPA) has different immunophenotypes remains unknown. OBJECTIVE: To identify different CPA immunophenotypes using cluster analysis. METHODS: We used a subject-centred multivariate clustering approach without prior assumptions to identify CPA phenotypes. We retrospectively included the data of treatment-naïve subjects with CPA and excluded subjects with asthma and allergic bronchopulmonary aspergillosis (ABPA). We performed a scalable two-step cluster analysis using the log-likelihood distance measures to identify CPA phenotypes based on the blood immunological profile (total IgE, eosinophil count and Aspergillus-specific IgE and IgG). RESULTS: We included 351 CPA subjects and found two clusters. Cluster 2 (n = 118) had significantly higher serum total IgE, peripheral blood eosinophil count, and serum A. fumigatus-specific IgE and IgG than cluster 1 (n = 233). Cluster 2 subjects had a lower FEV1:FVC ratio on spirometry and were more likely to have a fungal ball (88 [74.6%] vs. 145 (62.2%), p = .023) on the CT thorax than cluster 1. After treatment discontinuation, cluster 2 had a longer median (interquartile range) time to relapse than cluster 1 (11.5 [7.3-27.4] vs. 4 [1.1-8.9] months, p = .005). CONCLUSION: We identified two distinct CPA phenotypes, type-2 dominant and non-type-2, with different clinical and radiological findings and treatment outcomes. Future studies should confirm our findings and investigate different treatment strategies based on CPA phenotypes.

Factors Associated With Non-invasive Oxygen Therapy Failure in COVID-19 Pneumonia: A Single Center, Retrospective Study in a Tertiary Hospital in North India.

BACKGROUND: Non-invasive oxygen therapy (NIT) consists of high-flow nasal oxygen (HFNO) and continuous positive airway pressure (CPAP). NIT is routinely being used for the management of acute respiratory failure secondary to coronavirus disease-2019 (COVID-19) with variable outcomes. However, previously published studies show that NIT failure might delay endotracheal intubation and invasive mechanical ventilation and results in worse outcomes in patients with hypoxemic respiratory failure. Early prediction of failure of NIT, will help in early decision-making in initiating invasive mechanical ventilation. We retrospectively studied the predictors for NIT failure in patients with moderate to severe COVID-19. METHODS: Adult patients (>18 years) admitted to the intensive care unit (ICU) with moderate to severe COVID-19 ARDS and received NIT [HFNO and CPAP non-invasive ventilation (NIV)] were included in this study. Baseline clinical and laboratory data were collected retrospectively from the electronic hospital information system. NIT failure was defined as the need for invasive mechanical ventilation after the initiation of NIT in the ICU. Univariate and multivariate logistic regression analyses were used to find out the possible predictors of NIT failure. RESULTS: Out of 254 patients admitted to ICU, 127 patients were initiated NIT at admission to ICU. During the course of the ICU stay, 33 (26%) patients subsequently required invasive mechanical ventilation (NIT failure). Respiratory rate-oxygenation index (ROX index) of <2.97 at two hours and <3.63 at six hours of ICU admission predicted NIT failure in our cohort of patients with a high positive predictive value. CONCLUSION: Patient selection is crucial for successful NIT in COVID-19. Application of ROX index measured in the first six hours of ICU admission helps in the identification of patients at risk of NIT failure with moderate to severe COVID-19 ARDS.

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.

Efficacy of 12-months oral itraconazole versus 6-months oral itraconazole to prevent relapses of chronic pulmonary aspergillosis: an open-label, randomised controlled trial in India.

BACKGROUND: 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. METHODS: 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. FINDINGS: We recruited participants between July 1, 2019, and 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. INTERPRETATION: 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. FUNDING: None. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.

Allergic Bronchopulmonary Aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a complex allergic disorder caused by immune reactions against Aspergillus fumigatus. ABPA most commonly complicates the course of patients with poorly controlled asthma. Patients commonly present with uncontrolled asthma, fleeting pulmonary opacities, and bronchiectasis. Pathogenetically, ABPA is characterized by the persistence of A. fumigatus in the airways and an exaggerated type-2 immune response. The interest in ABPA stems from the fact that bronchiectasis in ABPA can be prevented if the disorder is diagnosed timely and treated appropriately. Herein, we summarize the current concepts in the epidemiology, pathogenesis, diagnosis, and treatment of ABPA.

Autoimmune pulmonary alveolar proteinosis and sarcoidosis in the same patient: Case report and systematic review.

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder characterized by surfactant accumulation in the alveolar spaces while sarcoidosis is a multisystem granulomatous disease of unknown etiology. The occurrence of PAP and sarcoidosis in the same patient is rare. A 37-year-old woman presented with cough and breathlessness and was diagnosed to have autoimmune PAP. She responded well to subcutaneous injections of recombinant granulocyte macrophage colony stimulating factor. Three years later, she developed fever, chest pain, cough, and facial palsy. The evaluation revealed a diagnosis of sarcoidosis that responded to immunosuppressive treatment. We discuss the link between PAP and sarcoidosis and review the literature on this association.