Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses.

BACKGROUND: The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. METHODS: An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. RESULTS: We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. CONCLUSION: We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.

Burden, clinical features, and outcomes of post-tuberculosis chronic obstructive lung diseases.

PURPOSE OF REVIEW: Post-tuberculosis lung disease (PTLD) is an increasingly recognized and debilitating consequence of pulmonary tuberculosis (PTB). In this review, we provide a comprehensive overview of PTLD with airflow obstruction (PTLD-AFO), focusing on its burden, pathophysiology, clinical manifestations, diagnostic methods, and management strategies. RECENT FINDINGS: The relationship between PTLD and airflow obstruction is complex and multifactorial. Approximately 60% of the patients with PTLD have some spirometric abnormality. Obstruction is documented in 18-22% of PTLD patients. The host susceptibility and host response to mycobacterium drive the pathogenic mechanism of PTLD. A balance between inflammatory, anti-inflammatory, and fibrotic pathways decides whether an individual with PTB would have PTLD after microbiological cure. An obstructive abnormality in PTLD-AFO is primarily due to destruction of bronchial walls, aberrant healing, and reduction of mucosal glands. The most common finding on computed tomography (CT) of thorax in patients with PTLD-AFO is bronchiectasis and cavitation. Therefore, the 'Cole's vicious vortex' described in bronchiectasis applies to PTLD. A multidisciplinary approach is required for diagnosis and treatment. The disability-adjusted life-years (DALYs) attributed to PTLD represent about 50% of the total estimated burden of DALYs due to tuberculosis (TB). Patients with PTLD require comprehensive care that includes psychosocial support, pulmonary rehabilitation, and vaccination against respiratory pathogens. In the absence of trials evaluating different treatments for PTLD-AFO, therapy is primarily symptomatic. SUMMARY: PTLD with airflow obstruction has considerable burden and causes a significant morbidity and mortality. However, many aspects of PTLD-AFO still need to be answered. Studies are required to evaluate different phenotypes, especially concerning Aspergillus -related complications. The treatment should be personalized based on the predominant phenotype of airflow obstruction. Extensive studies to understand the exact burden, pathogenesis, and treatment of PTBLD-AFO are needed.

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.

Diagnostic Yield and Safety of the 19-Gauge versus 22-Gauge Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration Needle in Subjects with Sarcoidosis (GUESS).

INTRODUCTION: Observational data suggest that the 19-gauge (G) needle for endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) offers a higher diagnostic yield than the 22-G needle in sarcoidosis. No randomized trial has compared the yield of the two needles. METHODS: We randomized consecutive subjects with suspected sarcoidosis and enlarged thoracic lymph nodes to undergo EBUS-TBNA with either the 19-G or the 22-G needle. We compared the study groups for diagnostic sensitivity (primary outcome) assessed by the yield of granulomas in subjects finally diagnosed with sarcoidosis. We also compared the sample adequacy, difficulty performing the needle puncture assessed on a visual analog scale (VAS), the subject's cough intensity on an operator-rated VAS, and procedure-related complications (secondary outcomes). RESULTS: We randomized 150 (mean age, 43.0 years; 55% women) subjects and diagnosed sarcoidosis in 116 subjects. The diagnostic sensitivity of the 19-G needle (45/60, 75.0%) was not higher (p = 0.52) than the 22-G needle (39/56, 69.6%). We obtained adequate aspirates in 90.0% and 85.7% of subjects in the respective groups (p = 0.48). The operators had greater difficulty puncturing lymph nodes with the 19-G needle (p = 0.03), while the operator-assessed cough intensity was similar in the groups (p = 0.41). Transient hypoxemia was the only complication encountered during EBUS-TBNA (two subjects in either group). CONCLUSION: We did not find the 19-G needle superior to the 22-G in diagnostic sensitivity, specimen adequacy, or safety of EBUS-TBNA in sarcoidosis. Puncturing the lymph nodes was more difficult with the 19-G needle.

Sensitivity and specificity of LDBio Aspergillus ICT lateral flow assay for diagnosing allergic bronchopulmonary aspergillosis in adult asthmatics.

BACKGROUND: Aspergillus fumigatus-specific IgG estimation is crucial for diagnosing allergic bronchopulmonary aspergillosis (ABPA). A point-of-care LDBio immunochromatographic lateral flow assay (LFA) had 0%-90% sensitivity to detect IgG/IgM antibodies against A. fumigatus. OBJECTIVE: To assess the accuracy of LDBio-LFA in diagnosing ABPA, using the modified ISHAM-ABPA working group criteria as the reference standard. The secondary objective was to compare the diagnostic performance between LDBio-LFA and A. fumigatus-specific IgG (cut-offs, 27 and 40 mgA/L), using a multidisciplinary team (blinded to A. fumigatus-IgG and LDBio-LFA results) diagnosis of ABPA as the reference standard. METHODS: We prospectively enrolled adult subjects with asthma and ABPA. We performed the LDBio-LFA per the manufacturer's recommendations. We used the commercially available automated fluorescent enzyme immunoassay for measuring serum A. fumigatus-specific IgG. We used the same serum sample to perform both index tests. The tests were performed by technicians blinded to the results of other tests and clinical diagnoses. RESULTS: We included 123 asthmatic and 166 ABPA subjects, with a mean ± SD age of 37.4 ± 14.4 years. Bronchiectasis and high-attenuation mucus were seen in 93.6% (146/156) and 24.3% (38/156) of the ABPA subjects. The sensitivity and specificity of LDBio-LFA in diagnosing ABPA were 84.9% and 82.9%, respectively. The sensitivity of serum A. fumigatus-specific IgG ≥27 mgA/L was 13% better than LDBio-LFA, with no difference in specificity. There was no significant difference in sensitivity and specificity between LDBio-LFA and serum A. fumigatus-IgG ≥40 mgA/L. CONCLUSION: LDBio-LFA is a valuable test for diagnosing ABPA. However, a negative test should be confirmed using an enzyme immunoassay.

Innate and adaptive immune responses in subjects with CPA secondary to post-pulmonary tuberculosis lung abnormalities.

BACKGROUND: Post-tuberculosis lung abnormality (PTLA) is the most common risk factor for chronic pulmonary aspergillosis (CPA), and 14%-25% of the subjects with PTLA develop CPA. The pathogenesis and the host immune response in subjects with PTLA who develop CPA need to be better understood. METHODS: We prospectively compared the innate and adaptive immune responses mounted by patients of PTLA with or without CPA (controls). We studied the neutrophil oxidative burst (by dihydrorhodamine 123 test), classic (serum C3 and C4 levels) and alternative (mannose-binding lectin [MBL] protein levels) complement pathway, serum immunoglobulins (IgG, IgM and IgA), B and T lymphocytes and their subsets in subjects with PTLA with or without CPA. RESULTS: We included 111 subjects (58 CPA and 53 controls) in the current study. The mean ± SD age of the study population was 42.6 ± 15.7 years. The cases and controls were matched for age, gender distribution and body weight. Subjects with CPA had impaired neutrophil oxidative burst, lower memory T lymphocytes and impaired Th-1 immune response (lower Th-1 lymphocytes) than controls. We found no significant difference between the two groups in the serum complement levels, MBL levels, B-cell subsets and other T lymphocyte subsets. CONCLUSION: Subjects with CPA secondary to PTLA have impaired neutrophil oxidative burst and a lower Th-1 response than controls.

Incidence and prevalence of chronic pulmonary aspergillosis in patients with post-tuberculosis lung abnormality: Results from a community survey in North India.

BACKGROUND: Post-tuberculosis lung abnormality (PTLA) is the most common risk factor for developing chronic pulmonary aspergillosis (CPA). However, the prevalence and incidence of CPA in PTLA patients in India remain unknown. OBJECTIVES: We aimed to ascertain the incidence and prevalence of CPA in subjects with PTLA. METHODS: We identified a cohort of pulmonary tuberculosis who completed anti-tuberculosis therapy (ATT) before November 2019 from the records of the 12 tuberculosis treatment centers attached to the national program. We recorded the clinical and demographic details. We performed computed tomography (CT) of the chest and estimated serum A. fumigatus-specific IgG. We categorised subjects as PTLA with or without CPA using a composite of clinical, radiological, and microbiological features. We resurveyed the subjects at 6 months (or earlier) for the presence of new symptoms. We calculated the prevalence and the incidence rate (per 100-person years) of CPA. RESULTS: We included 117 subjects with PTLA, with a median of 3 years after ATT completion. Eleven subjects had CPA in the initial survey, and one additional case developed CPA during the second survey. The prevalence of CPA in PTLA subjects was 10.3% (12/117). The total observation period was 286.7 person-years. The median (interquartile range) time to develop CPA after ATT completion was 12.5 (5-36.7) months. We found the CPA incidence rate (95% confidence interval) of 4.2 (1.8-6.5) per 100-person years. CONCLUSION: Chronic pulmonary aspergillosis complicates 10% of PTLA subjects after successful outcomes with ATT. Four new CPA cases may develop per 100-persons years of observation after ATT completion. We suggest screening patients with PTLA who develop new symptoms for CPA.

High-dose (40†mg) versus low-dose (20†mg) prednisolone for treating sarcoidosis: a randomised trial (SARCORT trial).

BACKGROUND: Current guidelines recommend 20-40 mg·day-1 of oral prednisolone for treating pulmonary sarcoidosis. Whether the higher dose (40 mg·day-1) can improve outcomes remains unknown. METHODS: We conducted an investigator-initiated, single-centre, open-label, parallel-group, randomised controlled trial (ClinicalTrials.gov identifier NCT03265405). Consecutive subjects with pulmonary sarcoidosis were randomised (1:1) to receive either high-dose (40 mg·day-1 initial dose) or low-dose (20 mg·day-1 initial dose) oral prednisolone, tapered over 6 months. The primary outcome was the frequency of relapse or treatment failure at 18 months from randomisation. Key secondary outcomes included the time to relapse or treatment failure, overall response, change in forced vital capacity (FVC, in litres) at 6 and 18 months, treatment-related adverse effects and health-related quality of life (HRQoL) scores using the Sarcoidosis Health Questionnaire and Fatigue Assessment Scale. FINDINGS: We included 86 subjects (43 in each group). 42 and 43 subjects completed treatment in the high-dose and low-dose groups, respectively, while 37 (86.0%) and 41 (95.3%), respectively, completed the 18-month follow-up. 20 (46.5%) subjects had relapse or treatment failure in the high-dose group and 19 (44.2%) in the low-dose group (p=0.75). The mean time to relapse/treatment failure was similar between the groups (high-dose 307 days versus low-dose 269 days, p=0.27). The overall response, the changes in FVC at 6 and 18 months and the incidence of adverse effects were also similar. Changes in HRQoL scores did not differ between the study groups. INTERPRETATION: High-dose prednisolone was not superior to a lower dose in improving outcomes or the HRQoL in sarcoidosis and was associated with similar adverse effects.

Progressive pulmonary fibrosis: an expert group consensus statement.

This expert group consensus statement emphasises the need for standardising the definition of progressive fibrosing interstitial lung diseases (F-ILDs), with an accurate initial diagnosis being of paramount importance in ensuring appropriate initial management. Equally, case-by-case decisions on monitoring and management are essential, given the varying presentations of F-ILDs and the varying rates of progression. The value of diagnostic tests in risk stratification at presentation and, separately, the importance of a logical monitoring strategy, tailored to manage the risk of progression, are also stressed. The term "progressive pulmonary fibrosis" (PPF) exactly describes the entity that clinicians often face in practice. The importance of using antifibrotic therapy early in PPF (once initial management has failed to prevent progression) is increasingly supported by evidence. Artificial intelligence software for high-resolution computed tomography analysis, although an exciting tool for the future, awaits validation. Guidance is provided on pulmonary rehabilitation, oxygen and the use of non-invasive ventilation focused specifically on the needs of ILD patients with progressive disease. PPF should be differentiated from acute deterioration due to drug-induced lung toxicity or other forms of acute exacerbations. Referral criteria for a lung transplant are discussed and applied to patient needs in severe diseases where transplantation is not realistic, either due to access limitations or transplantation contraindications. In conclusion, expert group consensus guidance is provided on the diagnosis, treatment and monitoring of F-ILDs with specific focus on the recognition of PPF and the management of pulmonary fibrosis progressing despite initial management.

Silica-associated lung disease in developing countries.

PURPOSE OF REVIEW: There is a considerable burden of silica-associated lung diseases in the developing world. This review summarizes the epidemiology of these diseases, especially silicosis and silico-tuberculosis, mitigative efforts and treatment, especially in the context of developing countries. RECENT FINDINGS: In 2017, the highest incidence of silicosis was in China, India and Brazil among the developing countries. The prevalence of silicosis amongst exposed workers may vary from 4 to 55%; there is a risk of underestimation because of the 'healthy worker effect'. The permissible exposure limit for respirable silica adopted by governments in developing countries remains higher than the proposed 0.025 mg/m3. Silica exposure in informal or unorganized industries is challenging, as it falls outside statutory controls. Recent efforts on regulation and compensation by various governments in developing countries are encouraging but need proper implementation on the ground. Biomarkers such as club cell protein 16 and imaging methods such as computed tomography may offer earlier and easier detection of silicosis. Advanced silicosis remains incurable; novel treatments such as antifibrotics agents may be potentially effective. SUMMARY: Silica-associated lung diseases are prevalent in developing countries. Efforts directed at preventing or minimizing exposure to respirable crystalline silica are required for mitigation.

Nebulized amphotericin B for preventing exacerbations in allergic bronchopulmonary aspergillosis: A systematic review and meta-analysis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is complicated by exacerbations in more than one-third of the subjects. Whether nebulized amphotericin B (NAB) therapy prevents ABPA exacerbations remains unclear. OBJECTIVES: The primary objective of this systematic review and meta-analysis was to determine the frequency of subjects remaining exacerbation-free, one year after initiating NAB. The key secondary objectives were the time to first exacerbation and the safety of NAB therapy. METHODS: We searched the PubMed and Embase databases for studies evaluating ≥5 subjects of ABPA managed with NAB. We report the pooled proportion of ABPA subjects remaining exacerbation free after one year. For the randomized controlled trials (RCTs), we estimate the pooled risk difference (RD) of exacerbation-free status at one year with NAB versus the control arm. RESULTS: We included five studies for our analysis; three were observational (n = 28) and two RCTs (n = 160). The pooled proportion (95% confidence interval [CI]) of subjects remaining exacerbation free with NAB at one year was 76% (62-88). The pooled RD (95% CI) of an exacerbation-free status at one year was 0.33 (-0.12 to 0.78) and was not significantly different between the NAB and control arms. The time to first exacerbation was longer with NAB than with the standard therapy. No serious adverse events were reported with NAB. CONCLUSION: NAB does not improve exacerbation-free status at one year; however, weak evidence suggests it delays ABPA exacerbations. More research using different dosing regimens is required.

The minimal important difference of St.George's respiratory questionnaire in subjects with chronic pulmonary aspergillosis.

The estimates of the minimal important difference (MID) for the Saint George's respiratory questionnaire (SGRQ) score in CPA remain unknown. We performed a retrospective analysis on treatment-naïve CPA subjects (n = 148) treated with six-month oral itraconazole therapy and completed SGRQ at baseline and six months. The study's objective was to estimate the MID for SGRQ. We used an anchor-based method to determine the MID and found the MID for SGRQ of 7.3.

The estimates of the minimal important difference (MID) for the Saint George's respiratory questionnaire (SGRQ) score in CPA remain unknown. Using an anchor-based method, we found theMID for SGRQ of 7 in CPA.

Efficacy and safety of doxycycline versus iodopovidone for pleurodesis through an intercostal tube in malignant pleural effusions: a randomized trial.

PURPOSE: The search for an inexpensive agent for chemical pleurodesis in malignant pleural effusion (MPE) continues. We aimed to compare the efficacy and safety of iodopovidone versus doxycycline for pleurodesis in MPE. METHODS: We randomized consecutive subjects with recurrent symptomatic MPE (1:1) to undergo pleurodesis with either doxycycline or iodopovidone administered through an intercostal tube. The primary outcome was the success rate of pleurodesis at 30 days. The secondary outcomes were the time to pleurodesis, chest pain (assessed using visual analog scale [VAS]) after pleurodesis, and complications (hypotension, acute respiratory failure, empyema). RESULTS: We randomized 52 and 58 subjects to receive either doxycycline or iodopovidone. The mean (standard deviation [SD]) age of the study population (51% women) was 54.1 (13.6) years. Lung cancer (≥ 60%) was the most common underlying cause of MPE. We observed a similar frequency of success in the doxycycline vs. the iodopovidone group (complete response: 43 (82.7%) vs. 46 (79.3%) subjects; partial response: 7 (13.5%) vs. 10 (17.2%) subjects; p = 0.3). The mean (SD) time to pleurodesis was 1.5 (1.9) days and 1.9 (5.4) days in the doxycycline and iodopovidone groups, respectively. While the VAS for chest pain was significantly higher with iodopovidone (mean [SD] VAS: doxycycline, 31.9 [20.9]; iodopovidone, 41.3 [21.8]; p = 0.017), it did not reach the minimal clinically important difference. The complication rates were similar between the two groups. CONCLUSION: Iodopovidone was not superior to doxycycline for pleurodesis in MPE. TRIAL REGISTRATION NUMBER/DATE: clinicaltrials.gov (NCT02583282) / October 22, 2015.

Risk factors for clinically significant diffuse parenchymal lung abnormalities persisting after severe COVID-19 pneumonia.

Background & objectives: The risk factors for clinically significant diffuse parenchymal lung abnormalities (CS-DPLA) persisting after severe coronavirus disease 2019 (COVID-19) pneumonia remain unclear. The present study was conducted to assess whether COVID-19 severity and other parameters are associated with CS-DPLA. Methods: The study participants included patients who recovered after acute severe COVID-19 and presented with CS-DPLA at two or six month follow up and control group (without CS-DPLA). Adults volunteers without any acute illness, chronic respiratory illness and without a history of severe COVID-19 were included as healthy controls for the biomarker study. The CS-DPLA was identified as a multidimensional entity involving clinical, radiological and physiological pulmonary abnormalities. The primary exposure was the neutrophil-lymphocyte ratio (NLR). Recorded confounders included age, sex, peak lactate dehydrogenase (LDH), advanced respiratory support (ARS), length of hospital stay (LOS) and others; associations were analyzed using logistic regression. The baseline serum levels of surfactant protein D, cancer antigen 15-3 and transforming growth factor-ß (TGF-ß) were also compared among cases, controls and healthy volunteers. Results: We identified 91/160 (56.9%) and 42/144 (29.2%) participants with CS-DPLA at two and six months, respectively. Univariate analyses revealed associations of NLR, peak LDH, ARS and LOS with CS-DPLA at two months and of NLR and LOS at six months. The NLR was not independently associated with CS-DPLA at either visit. Only LOS independently predicted CS-DPLA at two months [adjusted odds ratios (aOR) (95% confidence interval [CI]), 1.16 (1.07-1.25); P<0.001] and six months [aOR (95% CI) and 1.07 (1.01-1.12); P=0.01]. Participants with CS-DPLA at six months had higher baseline serum TGF-ß levels than healthy volunteers. Interpretation and conclusions: Longer hospital stay was observed to be the only independent predictor of CS-DPLA six months after severe COVID-19. Serum TGF-ß should be evaluated further as a biomarker.

Drug-induced sleep endoscopy-continuous positive airway pressure (DISE-CPAP), a newer modality to choose the right candidates for CPAP.

BACKGROUND: Continuous positive airway pressure (CPAP) therapy is recommended for moderate-to-severe obstructive sleep apnea (OSA). We aimed to investigate whether or not combining drug-induced sleep endoscopy (DISE) with CPAP titration may inform more appropriate pressure settings. MATERIALS AND METHODS: A sleep CPAP titration study and DISE-CPAP treatment were performed on consecutive subjects with moderate-to-severe OSA under controlled sedation using bispectral monitoring. Video recordings of dynamic changes in UA with CPAP pressure ranges of 5 to 25 cm were assessed in accordance with the VOTE classification. The 95th percentile (95th PC) pressure of the CPAP titration trial was compared to optimal pressure for alleviating UA blockage. RESULTS: We included 30 subjects (mean age 37.5, 17% women). All showed UA collapse at more than one level, with more than 80% of them collapsing completely at the levels of the velum and oropharynx. At the velum, 90% of subjects experienced improvement with CPAP. At the oropharynx, 75% of subjects experienced improvement with CPAP. The mean pressure and standard deviation (SD) of the 95th PC of the CPAP titration was 14.3 (3.5) cmH2O, while the pressure required to partially or fully open the airway (best possible pressure) was 16.1 (3.9) cmH2O; mean (SD) difference, 1.9 (2.2); P ≤ 0.001. The limits of agreement between the CPAP 95th pressure and the ideal pressure were - 6.32 to + 2.52. CONCLUSIONS: The palate and lateral pharynx were more affected by CPAP than the hypopharynx. Most of the time, the mean 95th PC CPAP titration pressure was lower than the mean optimal pressure needed to alleviate the collapse.

Isolated tracheobronchial mucormycosis: Report of a case and systematic review of literature.

BACKGROUND: Isolated tracheobronchial mucormycosis (ITBM) is an uncommonly reported entity. Herein, we report a case of ITBM following coronavirus disease 2019 (COVID-19) and perform a systematic review of the literature. CASE DESCRIPTION AND SYSTEMATIC REVIEW: A 45-year-old gentleman with poorly controlled diabetes mellitus presented with cough, streaky haemoptysis, and hoarseness of voice 2 weeks after mild COVID-19 illness. Computed tomography and flexible bronchoscopy suggested the presence of a tracheal mass, which was spontaneously expectorated. Histopathological examination of the mass confirmed invasive ITBM. The patient had complete clinical and radiological resolution with glycaemic control, posaconazole, and inhaled amphotericin B (8 weeks). Our systematic review of the literature identified 25 additional cases of isolated airway invasive mucormycosis. The median age of the 26 subjects (58.3% men) was 46 years. Diabetes mellitus (79.2%) was the most common risk factor. Uncommon conditions such as anastomosis site mucormycosis (in two lung transplant recipients), post-viral illness (post-COVID-19 [n = 3], and influenza [n = 1]), and post-intubation mucormycosis (n = 1) were noted in a few. Three patients died before treatment initiation. Systemic antifungals were used in most patients (commonly amphotericin B). Inhalation (5/26; 19.2%) or bronchoscopic instillation (1/26; 3.8%) of amphotericin B and surgery (6/26; 23.1%) were performed in some patients. The case-fatality rate was 50%, primarily attributed to massive haemoptysis. CONCLUSION: Isolated tracheobronchial mucormycosis is a rare disease. Bronchoscopy helps in early diagnosis. Management with antifungals and control of risk factors is required since surgery may not be feasible.

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.

Efficacy of generic forms of itraconazole capsule in treating subjects with chronic pulmonary aspergillosis.

BACKGROUND: Itraconazole capsules have variable and unpredictable bioavailability. OBJECTIVE: Whether the generic brands are as effective as the innovator itraconazole in treating subjects with chronic pulmonary aspergillosis (CPA) remains unclear. METHODS: In this retrospective study, we treated CPA subjects with 6-month itraconazole capsule and measured itraconazole levels at 2 weeks, 3 months and 6 months. Our primary outcome was to compare the proportion of subjects achieving therapeutic drug levels (≥0.5 mg/L) with the generic and the innovator itraconazole after 2 weeks. We performed a multivariate logistic regression analysis to ascertain whether trough itraconazole levels affected treatment outcomes. We categorised treatment response as favourable or unfavourable based on improvement (or worsening) in clinical symptoms, microbiology and imaging. We also performed morphometric analysis of different brands of itraconazole by video-dermoscopy. RESULTS: We included 193 (generic brands [n = 94] and innovator itraconazole [n = 99]) CPA subjects. A higher proportion of subjects achieved therapeutic levels at 2 weeks with the innovator than with the generic brands (72/99 [73%] vs. 27/94 [29%], p < .0001). The median trough level at 2 weeks was higher with the innovator than the generic brands (0.8 vs. 0 mg/L). The mean trough itraconazole levels achieved (average of three values measured over 6 months) independently predicted a favourable treatment response after adjusting for age, gender and CPA severity. On morphometric analysis, the generic brands had variable pellet numbers and sizes, and dummy pellets. CONCLUSION: At 2 weeks, a significantly higher proportion of CPA subjects achieved therapeutic drug levels with the innovator than the generic itraconazole. The mean serum itraconazole levels independently predicted a favourable treatment response in CPA.

Long-term follow-up of allergic bronchopulmonary aspergillosis treated with glucocorticoids: A study of 182 subjects.

BACKGROUND: The long-term outcomes of allergic bronchopulmonary aspergillosis (ABPA) are poorly characterised. METHODS: We retrospectively included treatment-naïve subjects of acute stage ABPA-complicating asthma from three randomised trials. All the subjects received oral prednisolone for 4 months and were monitored every 6 weeks for 6 months and then every 6 months. Our primary objective was to estimate the incidence rate and the frequency of subjects experiencing ABPA exacerbation. The key secondary objectives were to evaluate the factors predicting ABPA exacerbation and the changes in serum total IgE seen during treatment. RESULTS: We included 182 subjects. Eighty-one (44.5%) patients experienced 120 exacerbations during 512 patient-years of follow-up. The incidence rate of ABPA exacerbations was 234/1000 patient-years. Most (73/81, 90.1%) subjects experienced ABPA exacerbation within three years of stopping therapy. On multivariate logistic regression analysis, peripheral blood eosinophil count ≥1000 cells/µL (adjusted odds ratio [aOR] 2.43; 95% confidence interval (CI), 1.26-4.67), the extent of bronchiectasis (aOR 1.10; 95% CI, 1.03-1.18), age (aOR 0.97; 95% CI, 0.94-0.99), and female sex (aOR 2.16; 95% CI, 1.10-4.24) independently predicted ABPA exacerbation after adjusting for serum total IgE and high-attenuation mucus. The best cut-off for serum total IgE after 6 weeks for identifying treatment response and ABPA exacerbations was a 20% decline and a 50% increase, respectively. CONCLUSIONS: ABPA exacerbations were common within 3 years of stopping treatment. Age, female sex, peripheral blood eosinophilia and the extent of bronchiectasis predicted ABPA exacerbations. The optimal serum total IgE cut-off for defining ABPA response and exacerbations is a 20% decline and a 50% increase, respectively.

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.