Pathologic Criteria for the Diagnosis of Usual Interstitial Pneumonia vs Fibrotic Hypersensitivity Pneumonitis in Transbronchial Cryobiopsies.

Transbronchial cryobiopsy (TBCB) is increasingly used for the diagnosis of fibrosing interstitial pneumonias, but there are few detailed descriptions of the pathologic findings in such cases. It has been proposed that a combination of patchy fibrosis and fibroblast foci with an absence of alternative features is diagnostic of usual interstitial pneumonia (UIP; ie, idiopathic pulmonary fibrosis [IPF]) in TBCB. In this study, we reviewed 121 TBCB in which a diagnosis of fibrotic hypersensitivity pneumonitis (FHP; n = 83) or IPF (n = 38) was made by multidisciplinary discussion and evaluated a range of pathologic features. Patchy fibrosis was found in 65 of 83 (78%) biopsies from FHP and 32of 38 (84%) biopsies from UIP/IPF cases. Fibroblast foci were present in 47 of 83 (57%) FHP and 27 of 38 (71%) UIP/IPF cases. Fibroblast foci/patchy fibrosis combined did not favor either diagnosis. Architectural distortion was seen in 54 of 83 (65%) FHP and 32 of 38 (84%) UIP/IPF cases (odds ratio [OR] for FHP, 0.35; P = .036) and honeycombing in 18 of 83 (22%) and 17 of 38 (45%), respectively (OR, 0.37; P = .014). Airspace giant cells/granulomas were present in 13 of 83 (20%) FHP and 1 of 38 (2.6%) UIP/IPF cases (OR for FHP, 6.87; P = .068), and interstitial giant cells/granulomas in 20 of 83 (24%) FHP and 0 of 38 (0%) UIP/IPF (OR, 6.7 x 106; P = .000). We conclude that patchy fibrosis plus fibroblast foci can be found in TBCB from both FHP and UIP/IPF. The complete absence of architectural distortion/honeycombing favors a diagnosis of FHP, as does the presence of airspace or interstitial giant cells/granulomas, but these measures are insensitive, and many cases of FHP cannot be separated from UIP/IPF on TBCB.

Clinical and Phenotypic Characterization of Common Variable Immunodeficiency Diagnosed in Younger and Older Adults.

PURPOSE: Common variable immunodeficiency (CVID) is the most prevalent symptomatic immunodeficiency in adults. Little is known about the manifestations of CVID presenting in older adults. Herein, we performed a phenotypic characterization of patients diagnosed older than age 40. METHODS: A retrospective chart review of 79 patients seen at UF Health between 2006 and 2020 with a verified diagnosis of CVID per the ICON 2016 criteria was conducted. Patients were classified according to four phenotypes: no-disease-related complications, autoimmune cytopenias, polyclonal lymphoproliferation, and unexplained enteropathy. Patients diagnosed with CVID from age 2 to 40 (n = 41, "younger cohort") were compared to patients diagnosed with CVID age 41 and older (n = 38, "older cohort"). RESULTS: Among the younger cohort, pathologic genetic variants, positive family history for immunodeficiency, autoimmunity (49% vs 24%, p = 0.03), and splenomegaly (46% vs 16%, p = 0.004) were more common, as was the "autoimmune cytopenias" phenotype (24% vs 3%, p = 0.007). Among the older cohort, lymphoma (11% vs 0%, p = 0.049) and the "no disease-related complications" phenotype (79% vs 57%, p = 0.03) were more commonly seen. Comorbidities such as bronchiectasis (27% vs 21%, p = 0.61), GI involvement (34% vs 24%, p = 0.33), and GLILD (5% vs 8%, p = 0.67) were equally present among both the younger and older cohorts, respectively. CONCLUSION: The lower incidence of autoimmunity and splenomegaly, as well as overlapping clinical features with immunosenescence, may make diagnosing CVID in older patients more challenging; however, the disease is not more indolent as the risks for lymphoma, bronchiectasis, and GLILD are similar to those of younger patients.

Lung transplantation for acute exacerbation of interstitial lung disease.

BACKGROUND: Acute exacerbations of interstitial lung diseases (AE-ILD) have a high mortality rate with no effective medical therapies. Lung transplantation is a potentially life-saving option for patients with AE-ILD, but its role is not well established. The aim of this study is to determine if this therapy during AE-ILD significantly affects post-transplant outcomes in comparison to those transplanted with stable disease. METHODS: We conducted a retrospective study of consecutive patients with AE-ILD admitted to our institution from 2015 to 2018. The comparison group included patients with stable ILD listed for lung transplant during the same period. The primary end-points were in-hospital mortality for patients admitted with AE-ILD and 1-year survival for the transplanted patients. RESULTS: Of 53 patients admitted for AE-ILD, 28 were treated with medical therapy alone and 25 underwent transplantation. All patients with AE-ILD who underwent transplantation survived to hospital discharge, whereas only 43% of the AE-ILD medically treated did. During the same period, 67 patients with stable ILD underwent transplantation. Survival at 1 year for the transplanted patients was not different for the AE-ILD group versus stable ILD group (96% vs 92.5%). The rates of primary graft dysfunction, post-transplant hospital length-of-stay and acute cellular rejection were similar between the groups. CONCLUSION: Patients with ILD transplanted during AE-ILD had no meaningful difference in overall survival, rate of primary graft dysfunction or acute rejection compared with those transplanted with stable disease. Our results suggest that lung transplantation can be considered as a therapeutic option for selected patients with AE-ILD.

Hypersensitivity Pneumonitis With and Without Autoimmune Features: A Clinical Comparative Analysis.

BACKGROUND: Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) caused by an immunological reaction to repeated inhalational exposure to antigens. The etiology and exact immunopathology are poorly understood. Autoimmunity overlapping with HP has been described but the role of concomitant autoimmunity in the clinical course and outcome of the HP is not clearly established. In this study, we examined patients diagnosed with HP and compare them to patients with concomitant HP and autoimmunity. METHODS: Patients were retrospectively screened from a single-center ILD registry. Patients > 18 years with an established multidisciplinary diagnosis of HP were included in the study. Patients with HP without autoimmune features and patients with HP with autoimmune features (HPAF) were assessed. We compared the demographics, clinical characteristics, treatment, and outcomes between the two groups. We used a Cox proportional hazards model to compare lung transplant-free survival outcomes of patients with HPAF to those with non-HPAF HP patients. RESULTS: Of 73 patients with HP, 43 were diagnosed with HPAF. Patients with HPAF had a higher echocardiographic probability of pulmonary hypertension as compared to non-HPAF HP patients [48.8 vs 23.3%, p = 0.028, Crude odds ratio (cOR) = 3.14]. Symptomatically, those with HPAF reported a higher prevalence of arthritis as compared to non-HPAF HP (20.9 vs 3.3%, p = 0.040, cOR = 7.68). No significant differences between pulmonary function tests, oxygen requirements, mortality, and lung transplantation rates were found between the two groups. There was no statistically significant difference in transplant-free survival (p = 0.836). CONCLUSION: Patients with HPAF had a higher echocardiographic probability of pulmonary hypertension as compared to patients with non-HPAF HP. The clinical characteristics and outcomes did not differ between the two groups and concomitant autoimmunity among the HP group did not portend a poorer prognosis.

New-Onset Atrial Fibrillation in the Critically Ill.

OBJECTIVE: To determine the association of new-onset atrial fibrillation with outcomes, including ICU length of stay and survival. DESIGN: Retrospective cohort of ICU admissions. We found atrial fibrillation using automated detection (≥ 90 s in 30 min) and classed as new-onset if there was no prior diagnosis of atrial fibrillation. We identified determinants of new-onset atrial fibrillation and, using propensity matching, characterized its impact on outcomes. SETTING: Tertiary care academic center. PATIENTS: A total of 8,356 consecutive adult admissions to either the medical or surgical/trauma/burn ICU with available continuous electrocardiogram data. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: From 74 patient-years of every 15-minute observations, we detected atrial fibrillation in 1,610 admissions (19%), with median burden less than 2%. Most atrial fibrillation was paroxysmal; less than 2% of admissions were always in atrial fibrillation. New-onset atrial fibrillation was subclinical or went undocumented in 626, or 8% of all ICU admissions. Advanced age, acute respiratory failure, and sepsis were the strongest predictors of new-onset atrial fibrillation. In propensity-adjusted regression analyses, clinical new-onset atrial fibrillation was associated with increased hospital mortality (odds ratio, 1.63; 95% CI, 1.01-2.63) and longer length of stay (2.25 d; CI, 0.58-3.92). New-onset atrial fibrillation was not associated with survival after hospital discharge (hazard ratio, 0.99; 95% CI, 0.76-1.28 and hazard ratio, 1.11; 95% CI, 0.67-1.83, respectively, for subclinical and clinical new-onset atrial fibrillation). CONCLUSIONS: Automated analysis of continuous electrocardiogram heart rate dynamics detects new-onset atrial fibrillation in many ICU patients. Though often transient and frequently unrecognized, new-onset atrial fibrillation is associated with poor hospital outcomes.

Examining the differential of digital ischaemia and review of paraneoplastic ischaemia.

There is a broad differential diagnosis of digital ischaemia that includes commonly encountered conditions of vascular or thromboembolic nature as well as less commonly seen such as those of vasculitic or rheumatological origin. A less frequently encountered pathology is digital ischaemia associated with malignancy. This paraneoplastic process is rare and infrequently described in the literature, though it has been observed in various solid and haematological malignancies. Here, we describe a patient case with an atypical presentation of digital ischaemia and present a brief review on prior reports of digital ischaemia related to cancer.

Sirolimus suppresses circulating fibrocytes in idiopathic pulmonary fibrosis in a randomized controlled crossover trial.

BACKGROUNDFibrocytes are BM-derived circulating cells that traffic to the injured lungs and contribute to fibrogenesis. The mTOR inhibitor, sirolimus, inhibits fibrocyte CXCR4 expression, reducing fibrocyte traffic and attenuating lung fibrosis in animal models. We sought to test the hypothesis that short-term treatment with sirolimus reduces the concentration of CXCR4+ circulating fibrocytes in patients with idiopathic pulmonary fibrosis (IPF).METHODSWe conducted a short-term randomized double-blind placebo-controlled crossover pilot trial to assess the safety and tolerability of sirolimus in IPF. Participants were randomly assigned to sirolimus or placebo for approximately 6 weeks, and after a 4-week washout, they were assigned to the alternate treatment. Toxicity, lung function, and the concentration of circulating fibrocytes were measured before and after each treatment.RESULTSIn the 28 study participants, sirolimus resulted in a statistically significant 35% decline in the concentration of total fibrocytes, 34% decline in CXCR4+ fibrocytes, and 42% decline in fibrocytes expressing α-smooth muscle actin, but no significant change in these populations occurred on placebo. Respiratory adverse events occurred more frequently during treatment with placebo than sirolimus; the incidence of adverse events and drug tolerability did not otherwise differ during therapy with drug and placebo. Lung function was unaffected by either treatment, with the exception of a small decline in gas transfer during treatment with placebo.CONCLUSIONAs compared with placebo, short-term treatment with sirolimus resulted in reduction of circulating fibrocyte concentrations in participants with IPF, with an acceptable safety profile.TRIAL REGISTRATIONClinicalTrials.gov, accession no. NCT01462006.FUNDINGNIH R01HL098329 and American Heart Association 18TPA34170486.

Sarcoidosis and burn pit exposure in military deployers to Iraq, Afghanistan, and Southwest Asia.

BACKGROUND AND AIM: Inhalational exposures have been hypothesized to play a role in the pathogenesis of sarcoidosis. Herein, we describe a cohort of US Military personnel diagnosed with sarcoidosis during or after deployment to Southwest Asia and Afghanistan, who experienced complex inhalational exposures to burn-pits and desert dust. METHODS: Consecutive military personnel at four sub-specialty clinics across the United States were screened for deployment to Southwest Asia and Afghanistan and diagnosis of sarcoidosis based on 1999 ATS/ERS/WASOG Statement on Sarcoidosis. Detailed demographic, deployment and exposure data was collected. The data combined was analyzed after de-identification and local IRB approval. RESULTS: Twenty-one patients met our case definition. Seventeen patients were male and 62% had extrapulmonary involvement, including 38% with musculoskeletal involvement.  Conclusions: Our study suggests that the sarcoidosis in military personnel to Southwest Asia can be diagnosed many years after deployment. To our knowledge, this is the first case series to describe a group of military personnel diagnosed with sarcoidosis and exposures specific to military deployment to Southwest Asia.

Role of Transbronchial Lung Cryobiopsy in the Diagnosis of Interstitial Lung Disease: A Meta-analysis of 68 Studies and 6300 Patients.

BACKGROUND: Diagnosis of interstitial lung disease (ILD) is based on multidisciplinary team discussion (MDD) with the incorporation of clinical, radiographical, and histopathologic information if available. We aim to evaluate the diagnostic yield and safety outcomes of transbronchial lung cryobiopsy (TBLC) in the diagnosis of ILD. METHODS: We conducted a meta-analysis by comprehensive literature search to include all studies that evaluated the diagnostic yields and/or adverse events with TBLC in patients with ILD. We calculated the pooled event rates and their 95% confidence intervals (CIs) for the diagnostic yield by MDD, histopathologic diagnostic yield, and various clinical adverse events. RESULTS: We included 68 articles (44 full texts and 24 abstracts) totaling 6386 patients with a mean age of 60.7±14.1 years and 56% men. The overall diagnostic yield of TBLC to achieve a definite or high-confidence diagnosis based on MDD was 82.3% (95% CI: 78.9%-85.2%) and histopathologic diagnosis of 72.5% (95% CI: 67.7%-76.9%). The overall rate of pneumothorax was 9.6% (95% CI: 7.9%-11%), while the rate of pneumothorax requiring drainage by a thoracostomy tube was 5.3% (95% CI: 4.1%-6.9%). The rate of moderate bleeding was 11.7% (95% CI: 9.1%-14.9%), while the rate of severe bleeding was 1.9% (95% CI: 1.4%-2.6%). The risk of mortality attributed to the procedure was 0.9% (95% CI: 0.7%-1.3%). CONCLUSION: Among patients with undiagnosed or unclassified ILD requiring tissue biopsy for diagnosis, transbronchial cryobiopsy represents a reliable alternative to surgical lung biopsy with decreased incidence of various clinical adverse events.

Diffuse pulmonary calcification in allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a condition that most often occurs in patients with asthma or cystic fibrosis. The diagnosis is usually confirmed by the combination of clinical, radiographic, and immunologic criteria as there is not individual test to establish the diagnosis. We describe the case of a 64-year-old male with a prior medical history of moderate persistent asthma who presented with worsening cough and was found to have IgE positive for Aspergillus fumigatus with findings of diffuse bilateral pulmonary calcifications on HRCT.

Cyclophosphamide for the treatment of Acute Exacerbation of Interstitial Lung Disease: A Review of the Literature.

Acute exacerbation of interstitial lung disease is a serious and life-threatening event but little is known about its treatment. Cyclophosphamide has been proposed in randomized clinic trials as a treatment option in progressive cases of systemic sclerosis related interstitial lung disease. However, in acute exacerbation of interstitial lung disease, we found only small case series, and retrospective studies, mostly with no comparative groups which described the role of cyclophosphamide. Results of these studies showed mixed outcomes, with no robust evidence that cyclophosphamide adds any benefit in treating acute exacerbations of interstitial lung disease. More well-designed studies including randomized clinical trials are needed to better understand the role of cyclophosphamide during exacerbations of interstitial lung disease. In this review article, we summarize the current evidence on the use of cyclophosphamide in interstitial lung disease with a focus on the acute exacerbation events.

Sarcoidosis among US Hispanics in a Nationwide Registry.

BACKGROUND: Sarcoidosis has been well studied in multiple races and ethnic groups. However, there is a paucity of data that describes sarcoidosis in Hispanics. We aimed to determine the prevalence of Hispanic ethnicity, clinical characteristics and impact of sarcoidosis among Hispanics from a US based national registry. METHODS: We conducted a national registry-based study investigating 3835 respondents to the Sarcoidosis Advanced Registry for Cures questionnaire. This registry is a web-based, self-reported questionnaire that provides data related to demographics, diagnostics, organ involvement, treatment modalities, and the physical and psychosocial impact of sarcoidosis. We compared Hispanic patients to non-Hispanics. We performed multivariate logistic regression analysis adjusting for age, gender, education, income and insurance status and looked at the association between Hispanic ethnicity with depression, chronic pain syndrome, chronic fatigue syndrome, impact on family finances, employment-based disability and job termination. RESULTS: Nine percent of the patients reported a Hispanic ethnicity and the majority of these patients self-identified as white women. The most common organs involved were the lungs (74.9%), central lymph nodes (53.8%), and peripheral lymph nodes (37.1%). Hispanics reported more peripheral nerves and peripheral lymph nodes involvement than non-Hispanics. Hispanics experienced more depression, sleep apnea, and chronic pain syndrome than non-Hispanics. The use of mobility assistive devices was more common among Hispanics, as well as employment-based disability, and disease-related job termination compared to non-Hispanics. The majority of Hispanics reported significantly more pain that interfered with the enjoyment of life than non-Hispanics. On multivariate logistic regression analysis, Hispanic ethnicity was associated with depression (adjusted odds ratio (aOR) = 1.5; 95% CI: 1.01-2.2), chronic pain syndrome (aOR = 1.7; 1.1-2.6), job termination due to sarcoidosis (aOR = 1.7; 1.1-2.7) and higher impact on family finances (aOR = 1.7; 1.1-2.5). CONCLUSION: The clinical presentation of sarcoidosis in Hispanic patients differs from that in non-Hispanic patients living in the United States. These differences should be considered when managing Hispanic patients with sarcoidosis. We encourage more studies that investigate phenotyping among Hispanics with sarcoidosis.

Prevalence and characteristics of self-reported hypothyroidism and its association with nonorgan-specific manifestations in US sarcoidosis patients: a nationwide registry study.

Little is known about the prevalence, clinical characteristics and impact of hypothyroidism in patients with sarcoidosis. We aimed to determine the prevalence and clinical features of hypothyroidism and its relation to organ involvement and other clinical manifestations in patients with sarcoidosis. We conducted a national registry-based study investigating 3835 respondents to the Sarcoidosis Advanced Registry for Cures Questionnaire between June 2014 and August 2019. This registry is based on a self-reported, web-based questionnaire that provides data related to demographics, diagnostics, sarcoidosis manifestations and treatment. We compared sarcoidosis patients with and without self-reported hypothyroidism. We used multivariable logistic regression and adjusted for potential confounders to determine the association of hypothyroidism with nonorgan-specific manifestations. 14% of the sarcoidosis patients self-reported hypothyroidism and were generally middle-aged white women. Hypothyroid patients had more comorbid conditions and were more likely to have multiorgan sarcoidosis involvement, especially with cutaneous, ocular, joints, liver and lacrimal gland involvement. Self-reported hypothyroidism was associated with depression (adjusted odds ratio (aOR) 1.3, 95% CI 1.01-1.6), antidepressant use (aOR 1.3, 95% CI 1.1-1.7), obesity (aOR 1.7, 95% CI 1.4-2.1), sleep apnoea (aOR 1.7, 95% CI 1.3-2.2), chronic fatigue syndrome (aOR 1.5, 95% CI 1.2-2) and was borderline associated with fibromyalgia (aOR 1.3, 95% CI 1-1.8). Physical impairment was more common in patients with hypothyroidism. Hypothyroidism is a frequent comorbidity in sarcoidosis patients that might be a potentially reversible contributor to fatigue, depression and physical impairment in this population. We recommend considering routine screening for hypothyroidism in sarcoidosis patients especially in those with multiorgan sarcoidosis, fatigue and depression.

The Role of Surgical Lung Biopsy in the Diagnosis of Fibrotic Interstitial Lung Disease: Perspective from the Pulmonary Fibrosis Foundation.

Diagnosis of interstitial lung disease (ILD) requires a multidisciplinary discussion approach that includes clinicians, radiologists, and pathologists. Surgical lung biopsy (SLB) is currently the recommended standard in obtaining pathologic specimens for patients with ILD requiring a tissue diagnosis. The increased diagnostic confidence and accuracy provided by microscopic pathology assessment of SLB specimens must be balanced with the associated risks in patients with ILD. This document was developed by the SLB Working Group of the Pulmonary Fibrosis Foundation, composed of a multidisciplinary group of ILD physicians, including pulmonologists, radiologists, pathologists, and thoracic surgeons. In this document, we present an up-to-date literature review of the indications, contraindications, risks, and alternatives to SLB in the diagnosis of fibrotic ILD; outline an integrated approach to the decision-making around SLB in the diagnosis of fibrotic ILD; and provide practical information to maximize the yield and safety of SLB.

Pulmonary hypertension in patients with interstitial pneumonia with autoimmune features.

Pulmonary hypertension in interstitial lung diseases is associated with increased mortality and hospitalizations and reduced exercise capacity. Interstitial pneumonia with autoimmune features (IPAF) is a recently described interstitial lung disease. The characteristics of pulmonary hypertension in IPAF patients are unknown. We sought to characterize patients with IPAF based on their echocardiographic probability of pulmonary hypertension and compare patients with and without pulmonary hypertension identified by right heart catheterization. We conducted a retrospective study of patients seen in the interstitial lung disease clinic from 2015 to 2018. Forty-seven patients with IPAF were identified. Patients were classified into low, intermediate and high echocardiographic pulmonary hypertension probabilities. A sub-group analysis of patients with pulmonary hypertension and without pulmonary hypertension (IPAF-PH vs. IPAF-no PH) identified by right heart catheterization was also performed. Linear regression analysis was performed to study the association between 6-min-walk-distance (6MWD) and pulmonary vascular resistance (PVR) while adjusting for age and body mass index. Right ventricular hypertrophy (>5 mm), right ventricular enlargement (>41 mm) and right ventricular systolic dysfunction defined as fractional area change% ≤35 was present in 76%, 24%, and 39% of patients, respectively. Pulmonary hypertension was identified in 12.7% of patients. IPAF-PH patients had higher mean pulmonary artery pressure and lower cardiac output compared to the IPAF-no PH group (34 mmHg vs. 19 mmHg, p = 0.002 and 4.0 vs. 5.7 L/min, p = 0.023, respectively). Lower 6MWD was associated with higher PVR on regression analysis (p = 0.002). Pulmonologists should be aware that a significant number of IPAF patients may develop pulmonary hypertension. Reduced 6MWD may suggest the presence of pulmonary hypertension in IPAF patients.

Breaking hearts and taking names: A case of sarcoidosis related effusive-constrictive pericarditis.

INTRODUCTION: Pericardial involvement of sarcoidosis is a rare cause for acute heart failure, and usually occurs as a result of the development of a pericardial effusion leading to cardiac tamponade. Even rarer still, is the manifestation of constrictive pericarditis. We report a case of sarcoidosis with lung, pleural, and pericardial involvement with effusive-constrictive pericarditis leading to cardiac tamponade. CASE PRESENTATION: A 34-year-old Caucasian man presented for evaluation of a history of worsening exertional dyspnea, edema, and weight loss. A high-resolution chest computed tomography showed diffuse pulmonary nodules with upper lobe predominance and in a perilymphatic distribution; large right pleural effusion; and large pericardial effusion with pericardial thickening. A transthoracic echocardiogram demonstrated early tamponade physiology for which a pericardial drain was placed. After removal of the drain he developed cardiogenic shock from cardiac tamponade attributed to the reaccumulation of a pericardial effusion and urgent pericardial window was performed. Serial echocardiography was concerning for organization and localization of the pericardial fluid. Cardiac magnetic resonance imaging demonstrated a significant reduction in pericardial slippage between the parietal and visceral layers around the heart collectively suggestive of constrictive pericarditis. Confirmation of effusive-constrictive pericarditis was noted on right heart catheterization. He then underwent pericardiectomy, which on histopathologic evaluation demonstrated non-necrotizing granulomas, thus confirming pericardial involvement of sarcoidosis. CONCLUSIONS: We report a case demonstrating unique manifestations of sarcoidosis; effusive-constrictive pericarditis presenting with acute congestive heart failure.