Microscopic Small Airway Abnormalities Identified in Early Idiopathic Pulmonary Fibrosis In Vivo Using Endobronchial Optical Coherence Tomography.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) affects subpleural lung, but is considered to spare small airways. Micro-CT studies demonstrated small airway reduction in end-stage IPF explanted lungs, raising questions about small airway involvement in early-stage disease. Endobronchial optical coherence tomography (EB-OCT) is a volumetric imaging modality that detects microscopic features from subpleural to proximal airways. We use EB-OCT to evaluate small airways in early IPF and control subjects in vivo. METHODS: EB-OCT was performed in 12 IPF and 5 control subjects (matched by age, sex, smoking-history, height, BMI). IPF subjects had early disease with mild restriction (FVC: 83.5% predicted), diagnosed per current guidelines and confirmed by surgical biopsy. EB-OCT volumetric imaging was acquired bronchoscopically in multiple, distinct, bilateral lung locations (total: 97 sites). IPF imaging sites were classified by severity into affected (all criteria for UIP present) and less affected (some but not all criteria for UIP present) sites. Bronchiole count and small airway stereology metrics were measured for each EB-OCT imaging site. RESULTS: Compared to control subjects (mean: 11.2 bronchioles/cm3; SD: 6.2), there was significant bronchiole reduction in IPF subjects (42% loss; mean: 6.5/cm3; SD: 3.4; p=0.0039), including in IPF affected (48% loss; mean: 5.8/cm3; SD: 2.8; p<0.00001) and IPF less affected (33% loss; mean: 7.5/cm3; SD: 4.1; p=0.024) sites. Stereology metrics showed IPF affected small airways were significantly larger and more distorted/irregular than in IPF less affected sites and control subjects. IPF less affected and control airways were statistically indistinguishable for all stereology parameters (p=0.36-1.0). CONCLUSION: EB-OCT demonstrated marked bronchiolar loss in early IPF (between 30 and 50%), even in areas minimally affected by disease, compared to matched controls. These findings support small airway disease as a feature of early IPF, providing novel insight into pathogenesis and potential therapeutic targets.

Diagnosis and Treatment of Lung Cancer in the Setting of Interstitial Lung Disease.

Interstitial lung disease (ILD) including idiopathic pulmonary fibrosis increases the risk of developing lung cancer. Diagnosing and staging lung cancer in patients with ILD is challenging and requires careful interpretation of computed tomography (CT) and fluorodeoxyglucose PET/CT to distinguish nodules from areas of fibrosis. Minimally invasive tissue sampling is preferred but may be technically challenging given tumor location, coexistent fibrosis, and pneumothorax risk. Current treatment options include surgery, radiation therapy, percutaneous thermal ablation, and systemic therapy; however, ILD increases the risks associated with each treatment option, especially acute ILD exacerbation.

Pulmonary amyloidosis as the presenting finding in a patient with multiple myeloma.

We present the case of a 58-year-old man who presented with dyspnea, cough, and weight loss and was ultimately diagnosed with pulmonary amyloidosis and multiple myeloma. Diagnosis was achieved with a lung biopsy which showed AL amyloid deposits involving the interstitium, vessels, and airway. He was treated with cyclophosphamide, bortezomib, and dexamethasone but died prior to completing treatment. His case is unique for the amyloid deposition found in all three lung compartments with clear pathophysiologic manifestations of each compartment, and the rapid disease progression that led to respiratory failure and death.

Pulmonary histopathology of interstitial lung disease associated with antisynthetase antibodies.

BACKGROUND: We aimed to determine if antibody type is an indicator of pulmonary histopathology, using antisynthetase antibody positive interstitial lung disease (ILD) cases with lung biopsy or autopsy findings. METHODS: We conducted a comprehensive review of the English language literature in PubMed to identify ILD histopathology results for cases with antibodies against anti-aminoacyl-transfer RNA (tRNA) synthetases (anti-ARS antibodies), including Jo1, PL-12, PL-7, KS, ES, and OJ. We additionally identified patients who had ILD, anti-ARS antibodies, and a lung biopsy between 2015 and 2020 at Beth Israel Deaconess Medical Center. For each case, we documented the specific anti-ARS antibody and major histopathologic patterns identified on biopsy or autopsy, including usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), and acute lung injury (ALI). To determine if histopathology varied by antibody type, we compared the proportion of each of four major patterns by antibody type using the Fisher's Exact test. RESULTS: We identified 310 cases with pathology findings and anti-ARS antibody positivity, including 12 cases from our institution. The proportion of NSIP differed significantly across antibody type, found in 31% of Jo1 (p < 0.01), 67% of EJ (p < 0.01), and 63% of KS (p < 0.01) cases. OP was common in Jo1 (23%, p = 0.07), but rare in EJ (4%, p = 0.04) and KS (4%, p = 0.04). UIP was common in PL-12 alone (36%, p = 0.03). CONCLUSION: The frequency of histopathologic findings in ILD with anti-ARS positivity varies significantly by antibody type, and NSIP occurs in less than half of all cases.

A Case Report of Steroid-Resistant Cryptogenic Organizing Pneumonia Managed with Intravenous Immunoglobulins.

Fewer than ten reported cases of cryptogenic organizing pneumonia (COP) have been managed with intravenous immunoglobulins (IVIg). We report a case of a 72-year-old man who presented with a worsening cough and diffuse opacities on chest radiograph. Following no improvement with antibiotics and negative complementary investigations for infectious, malignant, and autoimmune etiologies, COP was confirmed on lung biopsy. Due to continued clinical deterioration despite high-dose steroids and new severe steroid-induced hallucinations, the patient was placed on intravenous immunoglobulins (IVIg) and mycophenolate mofetil and made a satisfactory recovery. IVIg should be considered as an important steroid-sparing alternative in patients with COP.

Antifibrotic Therapy: Is There a Role in Myositis-Interstitial Lung Disease?

Interstitial lung disease (ILD) is a cause of substantial morbidity and mortality amongst autoimmune diseases, including myositis. Despite first-line therapy with immunosuppression, many inflammatory ILDs advance to a fibrotic stage. In such patients, progressive fibrosis may be amenable to treatment with antifibrotic medications, which were initially studied and approved for the treatment of idiopathic pulmonary fibrosis. We here review the available data that support the use of antifibrotics in connective tissue diseases and progressive fibrosing ILDs. There is now a growing body of evidence in both large randomized clinical trials and on the evolving pathophysiologic pathways to support the use of antifibrotics in select patients with autoimmune ILD and a fibrotic phenotype. Further study of antifibrotics in combination with immunosuppressive medications, and in the myositis-ILD population, is needed.

Controlled Delivery of 80 mg Aerosol Furosemide Does Not Achieve Consistent Dyspnea Relief in Patients.

PURPOSE: Aerosol furosemide may be an option to treat refractory dyspnea, though doses, methods of delivery, and outcomes have been variable. We hypothesized that controlled delivery of high dose aerosol furosemide would reduce variability of dyspnea relief in patients with underlying pulmonary disease. METHODS: Seventeen patients with chronic exertional dyspnea were recruited. Patients rated recently recalled breathing discomfort on a numerical rating scale (NRS) and the multidimensional dyspnea profile (MDP). They then performed graded exercise using an arm-ergometer. The NRS was completed following each exercise grade, and the MDP was repeated after a pre-defined dyspnea threshold was reached. During separate visits, patients received either aerosol saline or 80 mg of aerosol furosemide in a randomized, double-blind, crossover design. After treatment, graded exercise to the pre-treatment level was repeated, followed by completion of the NRS and MDP. Treatment effect was defined as the difference between pre- and post-treatment NRS at end exercise, expressed in absolute terms as % Full Scale. "Responders" were defined as those showing treatment effect ≥ 20% of full scale. RESULTS: Final analysis included 15 patients. Neither treatment produced a statistically significant change in NRS and there was no significant difference between treatments (p = 0.45). There were four "responders" and one patient whose dyspnea worsened with furosemide; two patients were responders with saline, of whom one also responded to furosemide. No adverse events were reported. CONCLUSIONS: High dose controlled delivery aerosol furosemide was not statistically different from saline placebo at reducing exercise-induced dyspnea. However, a clinically meaningful improvement was noted in some patients.

Ambient air pollution exposure and risk and progression of interstitial lung abnormalities: the Framingham Heart Study.

BACKGROUND: Ambient air pollution accelerates lung function decline among adults, however, there are limited data about its role in the development and progression of early stages of interstitial lung disease. AIMS: To evaluate associations of long-term exposure to traffic and ambient pollutants with odds of interstitial lung abnormalities (ILA) and progression of ILA on repeated imaging. METHODS: We ascertained ILA on chest CT obtained from 2618 Framingham participants from 2008 to 2011. Among 1846 participants who also completed a cardiac CT from 2002 to 2005, we determined interval ILA progression. We assigned distance from home address to major roadway, and the 5-year average of fine particulate matter (PM2.5), elemental carbon (EC, a traffic-related PM2.5 constituent) and ozone using spatio-temporal prediction models. Logistic regression models were adjusted for age, sex, body mass index, smoking status, packyears of smoking, household tobacco exposure, neighbourhood household value, primary occupation, cohort and date. RESULTS: Among 2618 participants with a chest CT, 176 (6.7%) had ILA, 1361 (52.0%) had no ILA, and the remainder were indeterminate. Among 1846 with a preceding cardiac CT, 118 (6.4%) had ILA with interval progression. In adjusted logistic regression models, an IQR difference in 5-year EC exposure of 0.14 µg/m3 was associated with a 1.27 (95% CI 1.04 to 1.55) times greater odds of ILA, and a 1.33 (95% CI 1.00 to 1.76) times greater odds of ILA progression. PM2.5 and O3 were not associated with ILA or ILA progression. CONCLUSIONS: Exposure to EC may increase risk of progressive ILA, however, associations with other measures of ambient pollution were inconclusive.

Severe pulmonary toxicity from immune checkpoint inhibitor treated successfully with intravenous immunoglobulin: Case report and review of the literature.

Immune checkpoint inhibitors are known to cause a variety of immune-related adverse events, including pneumonitis. When symptomatic, treatment typically consists of temporary or permanent cessation of the checkpoint inhibitor and several weeks of corticosteroid therapy. However, a subset of patients may suffer from severe pneumonitis, and the optimal treatment for this group is not known. Here we describe the case of a patient receiving pembrolizumab for non-small cell lung cancer who developed severe checkpoint inhibitor pneumonitis. After treatment with high-dose corticosteroids failed to produce a response, a course of intravenous immunoglobulin catalyzed rapid and durable improvement. In this review, we discuss the current evidence regarding the incidence and outcomes of severe checkpoint inhibitor pneumonitis and propose a role for intravenous immunoglobulin as a possible treatment strategy.

Radiologic and autopsy findings in a case of fatal immune checkpoint inhibitor-associated pneumonitis.

Oncologists are increasingly managing drug-induced pneumonitis in lung cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors. To date only few studies on the topic have described both radiologic and pathologic findings in these patients. Here, we report a fatal case of immune checkpoint inhibitor-associated pneumonitis initially presenting with an organizing pneumonia, but who rapidly developed acute respiratory distress syndrome (confirmed histologically at the time of autopsy). As such, this case illustrates the need for clinicians to maintain a high index of suspicion for immune checkpoint inhibitor associated pneumonitis and have a low threshold to perform CT imaging in any symptomatic patient receiving checkpoint inhibition therapy. CLINICAL PRACTICE POINTS.

Interstitial lung disease in patients with rheumatoid arthritis: spontaneous and drug induced.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by the destruction of articular joint structures. RA is a systemic condition that often affects multiple organs, including the heart, lungs, and kidneys. Pulmonary complications of RA are relatively common and include pleural effusion, rheumatoid nodules, bronchiectasis, obliterative bronchiolitis, and opportunistic infections. Interstitial lung disease (ILD) is a common occurrence in patients with RA, and can range in severity from an asymptomatic incidental finding to a rapidly progressing life-threatening event. Usual interstitial pneumonia and non-specific interstitial pneumonia are the two most common patterns, though others have been reported. Various disease-modifying anti-rheumatic drugs-in particular, methotrexate and the tumor necrosis factor-alpha inhibitors-have been associated with RA-ILD in numerous case reports and case series, though it is often difficult to distinguish association from causality. Treatment for RA-ILD typically involves the use of high-dose corticosteroids, often in conjunction with alternative immunosuppressant agents such as azathioprine or mycophenolate mofetil, and outcomes vary widely depending on the initial pattern of lung disease. Additional research into the mechanisms driving RA-ILD is needed to guide future therapy.

Pulmonary vaccination as a novel treatment for lung fibrosis.

Pulmonary fibrosis is an untreatable, uniformly fatal disease of unclear etiology that is the result of unremitting chronic inflammation. Recent studies have implicated bone marrow derived fibrocytes and M2 macrophages as playing key roles in propagating fibrosis. While the disease process is characterized by the accumulation of lymphocytes in the lung parenchyma and alveolar space, their role remains unclear. In this report we definitively demonstrate the ability of T cells to regulate lung inflammation leading to fibrosis. Specifically we demonstrate the ability of intranasal vaccinia vaccination to inhibit M2 macrophage generation and fibrocyte recruitment and hence the accumulation of collagen and death due to pulmonary failure. Mechanistically, we demonstrate the ability of lung Th1 cells to prevent fibrosis as vaccinia failed to prevent disease in Rag-/- mice or in mice in which the T cells lacked IFN-γ. Furthermore, vaccination 3 months prior to the initiation of fibrosis was able to mitigate the disease. Our findings clearly demonstrate the role of T cells in regulating pulmonary fibrosis as well as suggest that vaccinia-induced immunotherapy in the lung may prove to be a novel treatment approach to this otherwise fatal disease.