Baqir, Misbah

Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal lung disease most commonly encountered in older individuals. Several decades of research have contributed to a better understanding of its pathogenesis, though only two drugs thus far have shown treatment efficacy, i.e., by slowing the decline of lung function. The pathogenesis of IPF remains incompletely understood and involves multiple complex interactions and mechanisms working in tandem or separately to result in unchecked deposition of extracellular matrix components and collagen characteristic of the disease. These mechanisms include aberrant response to injury in the alveolar epithelium, inappropriate communication between epithelial cells and mesenchymal cells, imbalances between oxidative injury and tissue repair, recruitment of inflammatory pathways that induce fibrosis, and cell senescence leading to sustained activation and proliferation of fibroblasts and myofibroblasts. Targeted approaches to each of these mechanistic pathways have led to recent clinical studies evaluating the safety and efficacy of several agents. This review highlights selected concepts in the pathogenesis of IPF as a rationale for understanding current or future therapeutic approaches, followed by a review of several selected agents and their recent or active clinical studies. Current novel therapies include approaches to attenuating or modifying specific cellular or signaling processes in the fibrotic pathway, modifying inflammatory and metabolic derangements, and minimizing inappropriate cell senescence.

Abstract Objective ANCA-negative granulomatosis with polyangiitis (GPA) remains a diagnosis of exclusion. Clinical differences between patients with ANCA-negative vs ANCA-positive GPA have not been analysed in sizable case-control studies, and the effects of ANCA-seroconversion from negative to positive are not well documented. Methods A single-centre, sex and age matched case-control study evaluated ANCA-negative vs ANCA-positive GPA from 1 January 1996 to 31 December 2015. Patients who experienced seroconversion were the subject of a case-crossover study. Clinical data and outcomes were retrieved from electronic medical records. Results ANCA-negative GPA was identified in 110 patients; 65% were female; median age was 55 (IQR 39–65) years at time of diagnosis. Disease severity was milder in ANCA-negative GPA (BVAS/WG = 2 vs 6, P < 0.001). Mucous membranous/eye manifestations were more frequent in ANCA-negative GPA. General symptoms, pulmonary and renal involvement were more frequent in ANCA-positive GPA. Patients with ANCA-positive GPA relapsed more over 60 months (21.8% vs. 9.1%, P = 0.009) compared with ANCA-negative GPA and had shorter time to event (P = 0.043). Patients with general manifestations, BMI > 30kg/m2 and necrotizing granulomatous inflammation were more likely to relapse. The 16 patients who seroconverted into ANCA-positive during follow-up had higher mean BVAS/WG at time of diagnosis (P < 0.001) and increased incidence of relapses (P = 0.004) after seroconversion. Necrotizing granulomatous inflammation on biopsy in ANCA-negative GPA patients was identified as a risk factor for subsequent seroconversion to ANCA-positivity. Conclusion Patients with ANCA-negative GPA have milder disease and a lower frequency of relapse than those with ANCA-positive GPA. ANCA appearance portended higher disease severity and an increased frequency of relapses.

Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized disease that often results in heart failure and death. Traditionally, biological staging systems are used to stratify disease severity. Reduced aerobic capacity has recently been described as useful in identifying higher risk of cardiovascular events and death. Assessment of lung volume via simple spirometry might also hold prognostic relevance. We aimed to assess the combined prognostic value of spirometry, cardiopulmonary exercise testing (CPET) and biomarker staging in ATTR-CA patients in a multi-parametric approach. We retrospectively reviewed patient records with pulmonary function and CPET testing. Patients were followed until study endpoint (MACE: composite of heart-failure-related hospitalization and all-cause death) or censure (1 April 2022). In total, 82 patients were enrolled. Median follow-up was 9 months with 31 (38%) MACE. Impaired peak VO2 and forced vital capacity (FVC) were independent predictors of MACE-free survival, with peak VO2 < 50% and FVC < 70% defining the highest risk group (HR 26, 95% CI: 5–142, mean survival: 15 months) compared to patients with the lowest risk (peak VO2 ≥ 50% and FVC ≥ 70%). Combined peak VO2, FVC and ATTR biomarker staging significantly improved MACE prediction by 35% compared to ATTR staging alone, with 67% patients reassigned a higher risk category (p < 0.01). In conclusion, combining functional and biological markers might synergistically improve risk stratification in ATTR-CA. Integrating simple, non-invasive and easily applicable CPET and spirometry in the routine management of ATTR-CA patients might prove useful for improved risk prediction, optimized monitoring and timely introduction of newer-generation therapies.

Abstract Background/Objective A subset of patients with idiopathic inflammatory myopathy (IIM) develops highly fatal, rapidly progressive interstitial lung disease (RP-ILD). Treatment strategies consist of glucocorticoid and adjunctive immunosuppressive therapies. Plasma exchange (PE) is an alternative therapy, but its benefit is unclear. In this study, we aimed to determine whether PE benefited outcomes for patients with RP-ILD. Methods In this medical records review study, we compared baseline characteristics and clinical outcomes for 2 groups of patients with IIM-related RP-ILD: those who received and did not receive PE. Results Our cohort consisted of 15 patients, 9 of whom received PE. Baseline demographic characteristics and severity of lung, skin, and musculoskeletal disease between the 2 groups of patients were not significantly different. Five patients required mechanical ventilation (2, PE; 3, no PE). Plasma exchange was generally a third-line adjunctive treatment option. The PE group had a longer median (interquartile range) hospitalization (27.0 [23.0–36.0] days) than the non-PE group (12.0 [8.0–14.0] days) (p = 0.02). There was a potential benefit in 30-day mortality improvement in those receiving PE (0% vs 33%, p = 0.14), with a statistically significant improvement in 2 important composite end points including 30-day mortality or need for lung transplant (0% vs 50%, p = 0.04) and 1-year mortality or need for lung transplant or hospital readmission for RP-ILD in those receiving PE (22% vs 83%, p = 0.04). Conclusions Plasma exchange may be an underutilized, safe salvage therapy for patients with IIM-related RP-ILD when other immunosuppressive therapies fail.

We present a case of a woman who had progressive shortness of breath and wheezing with a mild restrictive pulmonary function pattern. She was initially diagnosed with eosinophilic granulomatosis with polyangiitis on the basis of peripheral eosinophilia, bronchoalveolar lavage eosinophilia (47%) and surgical lung biopsy findings. Six months following her diagnosis, the patient returned because of persistent symptoms, and a second review of the lung biopsy revealed thrombotic lesions in the pulmonary vessels with polarisable foreign body materials, associated giant cell reactions and numerous eosinophil infiltrates, consistent with intravenous drug abuse. Further investigation showed that she had a history of intravenous heroin overdose, and the diagnosis of excipient lung disease was made. This case highlights the importance of expert pathological, radiological and clinical review of complex presentations and the need for a thorough medication and drug use history review.

Recent advances in fibrotic hypersensitivity pneumonitis include improved diagnostic guidance, systematic assessments of immunosuppressive therapy, and the recent availability of antifibrotic therapy (nintedanib) for those with progressive disease. A standardized approach to diagnosis may lead to better inclusion criteria for future therapeutic protocols and delineation of disease or treatment response predictors for real-world management. This review will highlight current diagnostic and treatment challenges and remaining knowledge gaps or areas of uncertainty, with a practical overview of supporting evidence and its clinical implications. Exposure history, serologic testing for antigen sensitivity, bronchoalveolar lavage lymphocytosis, histopathology, and radiologic findings will be covered in the diagnosis section, with immunosuppression, antifibrotic therapy, lung transplantation, and disease prognosis in the treatment and management section.

Background: Amyloidosis can involve any compartment in the thorax. We aimed to explore the clinical and radiologic presentation, treatment, and clinical course of airway amyloidosis. Methods: A computer-assisted search was performed to identify patients who had biopsy-proven airway amyloidosis and were evaluated at Mayo Clinic in Rochester, MN, from January 1, 1997 through December 31, 2019. Demographic, clinical, and radiologic features along with clinical outcomes were analyzed. Results: We identified 43 patients who had airway amyloidosis. Median age was 60 years (range: 33 to 91 y), and 58% were female. Shortness of breath (63% of patients) and cough (44%) were the most common presenting symptoms. Most patients (82%) had localized amyloidosis with light chain being the most common amyloid type; 63% had tracheobronchial amyloidosis, and 23% had tracheal and upper airway involvement. On computed tomography of the chest, the most common findings were airway wall thickening with nodularity (60% of patients), airway calcification (53%), and airway occlusion without collapse (47%). On bronchoscopy (33 patients), the extent of amyloid involvement was most commonly submucosal (n=15) or nodular (n=8). External beam radiotherapy was the most common treatment modality. Among the 30 patients who had follow-up at our institution, the prognosis appeared to depend on the extent of the disease and whether patients had localized or systemic amyloidosis. Conclusion: Computed tomography of the chest, bronchoscopy, and biopsy are needed to establish the diagnosis of airway amyloidosis, and systemic amyloidosis should be ruled out. Treatment of amyloidosis requires a multidisciplinary approach.