Roden, Anja C.

Abstract Introduction E-cigarette use has risen dramatically in the past decade, accompanied by recognition of e-cigarette or vaping-use associated lung injury (EVALI). Although increasingly reported, the pathophysiology of EVALI remains poorly defined, and its clinical presentation and diagnostic evaluation are often nonspecific. Clinicians should maintain a high index of suspicion given its varied manifestations. We describe a young patient with EVALI complicated by histopathologic evidence of secondary pulmonary alveolar proteinosis (PAP), progressing to severe hypoxemic respiratory failure that ultimately required bilateral lung transplantation. Case Presentation A 28-year-old man with a nine-year history of vaping nicotine and THC-containing hash oil presented with chronic hypoxemic respiratory failure requiring BiPAP. One year earlier, he developed digital clubbing, followed by progressive cough and exertional dyspnea. Initial chest CT showed diffuse centrilobular ground-glass opacities without septal thickening, thought to represent hypersensitivity pneumonitis. Despite vaping cessation several months prior to presentation, his symptoms progressed rapidly, and he required high-flow supplemental oxygen (Fi02 80% at 50 L/min) within weeks of admission. Bronchoscopy with bronchoalveolar lavage and biopsy demonstrated focal organizing pneumonia, pigmented foamy macrophages, and eosinophilic acellular debris within alveoli, consistent with pulmonary alveolar proteinosis (PAP). Cultures and cytology were negative for infection or malignancy. Autoimmune serologies were unrevealing, and no alternative exposures were identified. Due to worsening hypoxemic respiratory failure and lack of response to vaping cessation, steroids, and nebulized sargramostim (recombinant human granulocyte-macrophage colony-stimulating factor), he underwent bilateral lung transplantation. Whole lung lavage was considered but not pursued due to concern for further deterioration. Explant pathology showed interstitial fibrosis with a nonspecific interstitial pneumonia pattern and extensive PAP-like reaction with cholesterol clefts and small airway injury. Discussion EVALI encompasses a broad spectrum of radiographic and histopathologic findings, but secondary pulmonary alveolar proteinosis (PAP) is rarely reported. Diagnostic criteria include e-cigarette use within 90 days and pulmonary infiltrates or ground-glass opacities, with exclusion of malignant, autoimmune, and infectious causes. Although most often associated with ground-glass opacities and organizing pneumonia with diffuse alveolar damage, the pathology of EVALI is variable and poorly understood, further complicated by heterogeneity in vaping exposures. This case highlights PAP as a potential manifestation of EVALI, raising the possibility that impaired alveolar macrophage function and surfactant clearance contribute to hypoxemia in severe disease. Clinicians should maintain a high index of suspicion for EVALI and be aware of its diverse histopathologic spectrum. Continued research is needed to clarify underlying mechanisms and guide management. This abstract is funded by: None

Context.— The Goldman criteria are widely used to categorize diagnostic discrepancies in autopsy reports for hospital quality assurance. Despite their adoption, little is known about how consistently they are applied across institutions. Objective.— To evaluate the interrater reliability among academic pathologists applying the Goldman criteria to classify missed diagnoses in autopsy cases. Design.— Thirty autopsy cases from 2 academic hospitals were reviewed by 5 experienced autopsy pathologists. Each reviewer independently assigned Goldman classification scores (class I–IV) to missed diagnoses based on the original 1983 definitions. Consensus was defined as at least 60% agreement (≥3 of 5 raters). Fleiss κ and Gwet AC1 were calculated to assess interrater reliability. Results.— A total of 196 missed diagnoses were identified by at least 1 rater. Only 26% (51 of 196) achieved a consensus Goldman classification, and just 4% (8 of 196) had unanimous classification agreement. Most diagnoses (65%; 127 of 196) were not identified by at least 3 raters. Among consensus classification ratings, 49% (25 of 51) were class IV. Fleiss κ was 0.176 (slight agreement) while Gwet AC1 was 0.390 (fair agreement). Collapsing major (classes I–II) and minor (classes III–IV) categories modestly improved agreement. Conclusions.— Interrater agreement in applying the Goldman criteria is only fair to moderate, suggesting significant subjectivity in their application. As the criteria are used for institutional comparison and quality metrics, efforts to standardize definitions and provide reviewer training are warranted to improve reproducibility and utility.

Context.— A clinic was created for patients to review their explanted organs with a pathologist. Objective.— To prospectively investigate the benefits of this type of clinic as perceived by both transplant patients and their pathologists. Design.— In this prospective study, patients participated in a videotaped viewing of heart and/or lung explants by the patient and their guest(s) and pathologist (December 2017–August 2022). Patients received a 3D-printed replica of their explant. After viewing the explanted organ, patients and their guests participated in an interview to assess their experiences. Video-reflexive ethnography was used by pathologists for data collection and practice improvement. Results.— Of 143 patients who viewed their explanted organ, 21 patients consented to having the organ-viewing session taped and to participate in a postviewing interview. The study group was comprised of 12 men; the median age was 57.5 years (range, 29–67 years). Five pathologists took part in reflexive sessions. The clinics were viewed positively by patients, providing an opportunity to better understand their disease. Pathologists had a similarly positive experience and gained important insights to patient journeys. Proposals for improvement were brought forward from both patients and pathologists. Conclusions.— Video-reflexive ethnography provided the opportunity for patients and pathologists to reflect on patient-pathology clinic appointments. This work serves as a template to build out pathology-based clinics.

AimsPolymyalgia rheumatica (PMR) is a chronic autoimmune disorder that mainly affects older adults. Pulmonary disease in PMR is rare but may be under‐recognized and pathological descriptions thereof are few. We aimed to characterize diffuse parenchymal lung disease (DPLD) in PMR.Methods and resultsInstitutional archives were searched for patients having PMR and DPLD with lung tissue sampling. After excluding cases with infection, concomitant rheumatoid arthritis, or smoking‐related DPLD only, 11 patients (9 women, median age 75 years) were enrolled. Clinical history and pathology slides were reviewed. One of the 11 patients (9%) had concomitant giant cell arteritis; the remaining patients had no other rheumatological diseases. All had been treated for PMR with immunosuppression, and most presented years later (median 6 years) with non‐specific respiratory symptoms. Radiographically, bilateral ground‐glass opacities and reticulation were typical and were usually lower lobe predominant. Histologically, fibrosis was seen in 8 of 11 (73%) patients and was unclassifiable in four; non‐specific interstitial pneumonia was encountered in three patients, and usual interstitial pneumonia was seen in only one case. Evidence of acute lung injury occurred in 9 (82%) patients, including three with acute lung injury only, usually manifesting as organizing pneumonia. Diffuse alveolar haemorrhage was seen in four cases (29%), including two patients with haemoptysis and capillaritis.ConclusionsOur data corroborate prior reports of clinically significant DPLD in some patients with PMR. Histopathological findings mirror other rheumatological disorders and include diffuse alveolar haemorrhage with capillaritis. Additional studies are warranted to clarify the association between PMR and DPLD.

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare diffuse parenchymal lung disease representing 3% of all interstitial lung diseases. PLCH occurs either as part of multi-system Langerhans cell histiocytosis (LCH) or an isolated disease of the lung. Isolated involvement of lungs is observed in approximately 50–70% of LCH cases and the age of onset peaks between 20 and 40 years without gender difference. Cigarette smoking is the only identified environmental risk factor. PLCH is characterized by Langerhans cell infiltrates that in general are in a bronchiolocentric distribution. Pulmonary lesions can occur after chronic systemic disease or are an initial sign of disease. The aims of this study are to (1) report five rare cases of PLCH in adults; (2) discuss the relationship of PLCH with interstitial lung fibrosis; (3) provide a concise review of PLCH epidemiology, pathophysiology, diagnosis, treatment, and prognosis to improve the knowledge of PLCH by pneumologists and internal medicine physicians.

ABSTRACTBackground and ObjectiveThe diagnosis of interstitial lung diseases (ILDs) often relies on the integration of various clinical, radiological, and histopathological data. Achieving high diagnostic accuracy in ILDs, particularly for distinguishing usual interstitial pneumonia (UIP), is challenging and requires a multidisciplinary approach. Therefore, this study aimed to develop a multimodal artificial intelligence (AI) algorithm that combines computed tomography (CT) and histopathological images to improve the accuracy and consistency of UIP diagnosis.MethodsA dataset of CT and pathological images from 324 patients with ILD between 2009 and 2021 was collected. The CT component of the model was trained to identify 28 different radiological features. The pathological counterpart was developed in our previous study. A total of 114 samples were selected and used for testing the multimodal AI model. The performance of the multimodal AI was assessed through comparisons with expert pathologists and general pathologists.ResultsThe developed multimodal AI demonstrated a substantial improvement in distinguishing UIP from non‐UIP, achieving an AUC of 0.92. When applied by general pathologists, the diagnostic agreement rate improved significantly, with a post‐model κ score of 0.737 compared to 0.273 pre‐model integration. Additionally, the diagnostic consensus rate with expert pulmonary pathologists increased from κ scores of 0.278–0.53 to 0.474–0.602 post‐model integration. The model also increased diagnostic confidence among general pathologists.ConclusionCombining CT and histopathological images, the multimodal AI algorithm enhances pathologists' diagnostic accuracy, consistency, and confidence in identifying UIP, even in cases where specialised expertise is limited. image

Despite ongoing efforts to employ structure-based methods to discover targeted protein degraders (TPD), the prevailing strategy remains synthesizing a focused set of heterobifunctional compounds and screening them for target protein degradation.

Peroxisomes are vital but often overlooked metabolic organelles. We found that excessive interferon signaling remodeled macrophage peroxisomes. This loss of peroxisomes impaired inflammation resolution and lung repair during severe respiratory viral infections. Peroxisomes were found to modulate lipid metabolism and mitochondrial health in a macrophage type-specific manner and enhanced alveolar macrophage-mediated tissue repair and alveolar regeneration after viral infection. Peroxisomes also prevented excessive macrophage inflammasome activation and IL-1β release, limiting accumulation of KRT8 high dysplastic epithelial progenitors following viral injury. Pharmacologically enhancing peroxisome biogenesis mitigated both acute symptoms and post-acute sequelae of COVID-19 (PASC) in animal models. Thus, macrophage peroxisome dysfunction contributes to chronic lung pathology and fibrosis after severe acute respiratory syndrome coronavirus 2 infection.