Impact of antigen identification on transplant free survival in interstitial lung disease.

INTRODUCTION: Antigen identification impacts diagnosis as well as prognosis in patients with hypersensitivity pneumonitis. An antigen may also be present in other etiologies of interstitial lung disease, however it is unknown whether identification impacts survival. METHODS: We evaluated a retrospective cohort in order to determine if antigen identification affects transplant free survival in patients with hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, connective tissue disease interstitial lung disease, and interstitial pneumonia with autoimmune features. Only patients with definite or high probability of hypersensitivity pneumonitis by American Thoracic Society guidelines were included in the analysis. RESULTS: Transplant free survival was improved with antigen identification in patients with hypersensitivity pneumonitis but not in patients with idiopathic pulmonary fibrosis, connective tissue disease interstitial lung disease, and interstitial pneumonia with autoimmune features. CONCLUSION: Our study suggests that removal of identified antigen in interstitial lung diseases other than hypersensitivity pneumonitis may not be impactful. Additionally, it further suggests that definitive diagnosis of hypersensitivity pneumonitis with bronchoalveolar lavage and transbronchial biopsy may be beneficial prior to recommending antigen removal.

Impact of radiographic honeycombing on transplant free survival and efficacy of immunosuppression in fibrotic hypersensitivity pneumonitis.

BACKGROUND: The distinction between hypersensitivity pneumonitis (HP) and idiopathic pulmonary fibrosis (IPF) was thought to be important due to the difference in mortality between the conditions as well as the response to treatment. However, recent work suggests that the clinical diagnosis may matter less than certain radiographic features, namely usual interstitial pneumonia (UIP) pattern. The purpose of this study is to evaluate whether radiographic honeycombing is more predictive of transplant-free survival (TFS) than other clinical, radiographic, or histologic findings that distinguish HP from IPF in the current guidelines and to evaluate the impact of radiographic honeycombing on the efficacy of immunosuppression in fibrotic HP. METHODS: We retrospectively identified IPF and fibrotic HP patients evaluated between 2003 and 2019. Univariable and multivariable logistic regression was performed for patients with fibrotic HP and IPF to evaluate TFS. To assess the impact of treatment with immunosuppression on TFS in fibrotic HP, a cox proportional hazard model adjusted for known predictors of survival in HP including age, gender, and baseline pulmonary function testing results was constructed, and p-interaction for the presence of honeycombing on high resolution computed tomography and use of immunosuppression was calculated. RESULTS: Our cohort included 178 with IPF and 198 with fibrotic HP. In a multivariable analysis, the presence of honeycombing had a greater impact on the TFS than the diagnosis of HP vs. IPF. Among the criteria used in the HP diagnostic guidelines, only typical HP scan impacted survival in a multivariable model, while identification of antigen and surgical lung biopsy findings had no impact on survival. We identified a trend toward worse survival on immunosuppression in those with HP with radiographic honeycombing. CONCLUSION: Our data suggests that honeycombing and baseline pulmonary function testing have a greater impact on TFS than the clinical diagnosis of IPF vs. fibrotic HP and that radiographic honeycombing is a predictor of poor TFS in fibrotic HP. We suggest that invasive diagnostic testing including surgical lung biopsy may not be useful in predicting mortality in HP patients with honeycombing and may potentially increase risk of immunosuppression.

Characteristics of a diagnostic bronchoscopy in hypersensitivity pneumonitis.

BACKGROUND: Bronchoalveolar lavage and transbronchial biopsy can increase diagnostic confidence in the diagnosis of hypersensitivity pneumonitis (HP). Improving the yield of bronchoscopy may help to improve diagnostic confidence while decreasing the risk of potential adverse outcomes associated with more invasive procedures such as surgical lung biopsy. The purpose of this study is to identify factors that were associated with a diagnostic BAL or TBBx in HP. METHODS: We conducted a retrospective cohort study of HP patients at a single center who underwent bronchoscopy during the diagnostic evaluation. Imaging characteristics, clinical characteristics including use of immunosuppressive medications and presence of active antigen exposure at the time of bronchoscopy, and procedural characteristics were collected. Univariable and multivariable analysis was performed. RESULTS: 88 patients were included in the study. 75 patients underwent BAL and 79 patients underwent TBBx. Patients who had an active fibrogenic exposure at the time of bronchoscopy had a higher BAL yield than those who were out of exposure at the time of bronchoscopy. TBBx yield was higher when more than 1 lobe was biopsied, with a trend toward higher yield of TBBx when nonfibrotic lung was biopsied compared to fibrotic lung. DISCUSSION: Our study suggests characteristics that may improve yield of BAL and TBBx in patients with HP. We suggest that bronchoscopy be performed when patients are in the antigen exposure and that TBBx samples are taken from more than 1 lobe in order to improve diagnostic yield of the procedure.

Impact of number and type of identified antigen on transplant-free survival in hypersensitivity pneumonitis.

BACKGROUND: Identification of inciting antigen can affect diagnostic confidence, quality of life, and prognosis in patients with HP. It is unknown whether the number and type of antigen affect results of diagnostic testing or prognosis, whether antigen identified by clinical history alone affects prognosis, and whether feather exposure is associated with outcomes similar to those of other antigens. METHODS: To evaluate whether the number or type of antigen identified by clinical history alone affects clinical outcomes, we evaluated a retrospective cohort of patients with a high or definite probability of HP based on recent guidelines. RESULTS: In our retrospective cohort, 136 patients met high or definite probability of HP and were included in the analysis. Median transplant-free survival was better in patients with antigen identified on clinical history alone than patients without identified antigen. Feather exposure was associated with improved TFS compared to patients without antigen identified; there was no difference in TFS between patients with feather exposure and either mold or live bird exposure. Mold antigen was associated with increased risk of fibrotic HP compared to avian antigen. Among patients with identified antigen, the number and type of antigen did not affect TFS. DISCUSSION: Our study suggests that clinical history is adequate for providing prognostic information to patients with HP and classifying the diagnostic probability of HP according to recent guidelines. Feather exposure should be considered an inciting antigen in patients with ILD.

Variables Associated With Response to Therapy in Patients With Interstitial Pneumonia With Autoimmune Features.

BACKGROUND/OBJECTIVE: We have limited knowledge regarding characteristics of patients with interstitial pneumonia with autoimmune features (IPAF) that are associated with response to immunosuppression. In this study, we used published IPAF criteria to characterize features associated with response to treatment. METHODS: We conducted a single-center medical records review study of 63 IPAF patients to evaluate for serological, clinical, and morphological characteristics that are associated with response to immunosuppression. Response was defined as % relative functional vital capacity decline of less than 10% and absence of death or lung transplant within the first year of continuous immunosuppressive therapy. Nonparametric measures of association and multivariate logistic regression were used to evaluate the relationship between baseline characteristics and immunosuppressive response. RESULTS: There was a trend of greater progression among men, ever smokers, those negative for antisynthetase antibodies, and those with usual interstitial pneumonia radiographic pattern, but no statistically significant relationship was found between baseline serological, clinical, or morphological features and response to immunosuppression. Patients on combination therapy with mycophenolate mofetil and prednisone had less disease progression (p = 0.018) than those on regimens that did not include both of these medications. CONCLUSIONS: In our cohort, baseline clinical assessment did not identify which patients with IPAF will respond to immunosuppressive therapy. Combination therapy with mycophenolate mofetil and prednisone was associated with lack of disease progression in our IPAF patients, including in IPAF-usual interstitial pneumonia. Further studies are needed to evaluate which IPAF patients would benefit from immunosuppressive therapy, antifibrotic therapy, or a combination of both.

Addition of antifibrotic therapy to immunosuppression in hypersensitivity pneumonitis: A case series.

Hypersensitivity pneumonitis has historically been treated with immunosuppression, but recently nintedanib was approved for the treatment of progressive fibrotic HP. One limitation of INBUILD is that the only immunosuppression (IS) permitted at the time of enrollment was glucocorticoids at a dose of less than 20mg per day, so the additive effect of antifibrotic (AF) therapy to IS in HP remains unclear. We present 5 cases of patients with HP for whom AF therapy was added to IS. Trends observed in the cohort include reduced decline in FVC, oxygen requirement, and symptoms in the year after adding AF to IS in 4 of the 5 patients. All 5 patients (100%) in our series demonstrated progression in the year prior to initiation of antifibrotic based on criteria outlined in the INBUILD trial, but only 1 of 5 (20%) progressed in the year after AF. There was a significant decrease in the rate of relative decline in % predicted FVC in the 12 months after initiation of antifibrotic compared to the 12 months prior to antifibrotic (0.4% ±7.6 vs -17.5% ±7.6, p = 0.0495). Compared to the 12 months prior to antifibrotic therapy, fewer patients met criteria for progression in the 12 months after initiating antifibrotic therapy (p = 0.048). Similarly, fewer patients met criteria for progression in the 6 months after initiating antifibrotic therapy compared to the 6 months prior (p = 0.048). A larger study with control groups on IS alone and AF alone is needed to confirm the role of AF therapy in combination with IS in patients with HP.

Utility of Bronchoalveolar Lavage and Transbronchial Biopsy in Patients with Interstitial Lung Disease.

PURPOSE: Bronchoalveolar lavage and transbronchial biopsy can be a useful tool in the evaluation of interstitial lung disease (ILD), but patient selection for this procedure remains poorly defined. Determining clinical characteristics that help with patient selection for bronchoscopy may improve confidence of ILD classification while limiting potential adverse outcomes associated with surgical lung biopsy. The purpose of this study is to identify factors that were associated with change in multidisciplinary ILD diagnosis (MDD) before and after incorporation of BAL and TBBx data. METHODS: We conducted a retrospective cohort study of ILD patients at a single center who underwent bronchoscopy in the diagnostic workup of ILD. We performed sequential MDD both pre- and post-bronchoscopy to calculate the frequency of change in diagnosis after incorporating information from BAL and TBBx and identify features associated with change in diagnosis. RESULTS: 245 patients were included in the study. Bronchoscopy led to a change in diagnosis in 58 patients (23.7%). The addition of TBBx to BAL increased diagnostic yield from 21.8 to 34.1% (p = 0.027). Identification of antigen, HRCT scan inconsistent with UIP, and absence of a pre-bronchoscopy diagnosis of CTD-ILD or IPAF were associated with a change in diagnosis after bronchoscopy. CONCLUSION: Our study suggests clinical features that may assist with patient selection for bronchoscopy. We suggest bronchoscopy in patients with identified antigen or an HRCT that is consistent with a non-IPF diagnosis. Appropriate patient selection for bronchoscopy may improve ILD diagnostic confidence and avoid potential complications from more invasive and higher risk procedures.

Telomere length and genetic variant associations with interstitial lung disease progression and survival.

Leukocyte telomere length (LTL), MUC5B rs35705950 and TOLLIP rs5743890 have been associated with idiopathic pulmonary fibrosis (IPF).In this observational cohort study, we assessed the associations between these genomic markers and outcomes of survival and rate of disease progression in patients with interstitial pneumonia with autoimmune features (IPAF, n=250) and connective tissue disease-associated interstitial lung disease (CTD-ILD, n=248). IPF (n=499) was used as a comparator.The LTL of IPAF and CTD-ILD patients (mean age-adjusted log-transformed T/S of -0.05±0.29 and -0.04±0.25, respectively) is longer than that of IPF patients (-0.17±0.32). For IPAF patients, LTL <10th percentile is associated with faster lung function decline compared to LTL ≥10th percentile (-6.43% per year versus -0.86% per year; p<0.0001) and worse transplant-free survival (hazard ratio 2.97, 95% CI 1.70-5.20; p=0.00014). The MUC5B rs35705950 minor allele frequency (MAF) is greater for IPAF patients (23.2, 95% CI 18.8-28.2; p<0.0001) than controls and is associated with worse transplant-free IPAF survival (hazard ratio 1.92, 95% CI 1.18-3.13; p=0.0091). Rheumatoid arthritis (RA)-associated ILD (RA-ILD) has a shorter LTL than non-RA CTD-ILD (-0.14±0.27 versus -0.01±0.23; p=0.00055) and higher MUC5B MAF (34.6, 95% CI 24.4-46.3 versus 14.1, 95% CI 9.8-20.0; p=0.00025). Neither LTL nor MUC5B are associated with transplant-free CTD-ILD survival.LTL and MUC5B MAF have different associations with lung function progression and survival for IPAF and CTD-ILD.

Utility of Bronchoalveolar Lavage and Transbronchial Biopsy in Patients with Hypersensitivity Pneumonitis.

INTRODUCTION: Making the diagnosis of HP is challenging due to a lack of consensus criteria and variability of both pathologic and radiographic findings. The purpose of this retrospective study was to determine the diagnostic utility of the combination of BAL lymphocyte count and TBBX in patients with HP. METHODS: We conducted a retrospective cohort study of all patients with a MDD diagnosis of HP at a single center. RESULTS: 155 patients were included in the study. 49% of patients who underwent BAL had a lymphocyte count > 20, 42% had a lymphocyte count > 30, and 34% had lymphocyte count > 40%. The median BAL lymphocyte count was higher in inflammatory HP compared to fibrotic HP. The addition of TBBX to BAL significantly increased the diagnostic yield regardless of the BAL lymphocyte cutoff used. The yield of bronchoscopy with TBBX and BAL when a lymphocyte count > 40% was used as a cutoff was 52%. CONCLUSIONS: Our study suggests that the combination of TBBX with BAL significantly increases the likelihood that the procedure will provide adequate additional information to allow a confident MDD diagnosis of HP and may reduce the need for SLB in the diagnostic workup of HP.

Series of rare lung diseases mimicking imaging patterns of common diffuse parenchymal lung diseases.

Diffuse parenchymal lung diseases (DPLDs) encompass a variety of restrictive and obstructive lung pathologies. In this article, the authors discuss a series of rare pulmonary entities and their high-resolution computed tomography imaging appearances, which can mimic more commonly encountered patterns of DPLDs. These cases highlight the importance of surgical lung biopsies in patients with imaging findings that do not show typical imaging features of usual interstitial pneumonia.

Pathology and radiology correlation of idiopathic interstitial pneumonias.

By nature, idiopathic interstitial pneumonias have been diagnosed in a multidisciplinary manner. As classifications have been subject to significant refinement over the last decade, the importance of correlating clinical, radiologic, and pathologic information to arrive at a diagnosis, which will predict prognosis in any given patient, has become increasingly recognized. In 2013, the American Thoracic Society and European Respiratory Society updated the idiopathic interstitial pneumonias classification scheme, addressing the most recent updates in the field. The purpose of this review is to highlight the correlations between radiologic and pathologic findings in idiopathic interstitial pneumonias while using updated classification schemes and naming conventions.

Pathology-radiology correlation of common and uncommon computed tomographic patterns of organizing pneumonia.

Organizing pneumonia (OP) is a common pattern of lung injury that can be associated with a wide range of etiologies. Typical and not-so-typical imaging features of OP occur, as both common and rare lung pathologies can mimic the same imaging pattern as that of OP. This article will attempt to describe the difference between confusing terminologies that have been used in the past for OP and existence of primary versus secondary OP. The role of a multidisciplinary approach as an essential component to correctly diagnose and effectively manage challenging cases of OP will be highlighted. Additionally, we will discuss the limitation of transbronchial and importance of open lung biopsy to make the correct diagnosis. One example of an emerging diagnosis in the spectrum of OP and diffuse alveolar damage is acute fibrinous and organizing pneumonia. Ultimately, the reader should feel comfortable recognizing the many variable presentations of OP and be able to participate knowledgeably in a multidisciplinary team after reading this article. OP is a disease entity with variable radiographic and distinct histological characteristics that requires a multidisciplinary approach to correctly diagnose cryptogenic OP. Classic radiologic findings of OP occur in as low as 60% of cases. Secondary causes include infections, neoplasms, inflammatory disorders, and iatrogenic. Acute fibrinous and organizing pneumonia can appear similarly, but miliary nodules are a clue to diagnosis.

Cobalt related interstitial lung disease.

Cobalt exposure in the hard metal and bonded diamond tool industry is a well-established cause of ILD. The primary theories regarding the underlying mechanism of cobalt related ILD include an immunologic mechanism and an oxidant injury mechanism. Cobalt related ILD may present in subacute and chronic forms and often has associated upper respiratory symptoms. The evaluation begins with a thorough occupational history and includes PFTs, HRCT, and bronchoalveolar lavage. HRCT findings are nonspecific and may resemble NSIP, UIP, sarcoidosis, or HP. The finding of cannibalistic multinucleated giant cells is diagnostic provided there is a history of exposure and appropriate changes on imaging; however, when these cells are not found on lavage, lung biopsy is required for diagnosis. Giant cell interstitial pneumonia is the classic pathologic pattern, but cobalt related ILD may also present with pathologic findings of UIP, DIP, or HP. When cobalt related ILD is suspected, removal from exposure is the most important step in treatment. Case reports suggest that treatment with steroids results in symptomatic, physiologic, and radiographic improvement.

Vibrio vulnificus septic shock due to a contaminated tattoo.

We present a case of Vibrio vulnificus septic shock and cellulitis in a patient with chronic liver disease that occurred after obtaining a leg tattoo with subsequent seawater exposure in the Gulf of Mexico. Initial suspicion for V. vulnificus was high and he was started on empiric doxycycline and ceftriaxone at admission. Blood and wound cultures grew oxidase positive and comma-shaped Gram-negative rods ultimately confirmed to be V. vulnificus. Despite aggressive initial treatment, the patient developed septic shock and died. This case highlights the association of chronic liver disease and high mortality associated with infections of V. vulnificus Health providers should remain vigilant for V. vulnificus infections in patients with chronic liver disease and raw oyster ingestion or seawater exposure.

Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive.

Heterozygous mutations in four telomere-related genes have been linked to pulmonary fibrosis, but little is known about similarities or differences of affected individuals.115 patients with mutations in telomerase reverse transcriptase (TERT) (n=75), telomerase RNA component (TERC) (n=7), regulator of telomere elongation helicase 1 (RTEL1) (n=14) and poly(A)-specific ribonuclease (PARN) (n=19) were identified and clinical data were analysed.Approximately one-half (46%) had a multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF); others had unclassifiable lung fibrosis (20%), chronic hypersensitivity pneumonitis (12%), pleuroparenchymal fibroelastosis (10%), interstitial pneumonia with autoimmune features (7%), an idiopathic interstitial pneumonia (4%) and connective tissue disease-related interstitial fibrosis (3%). Discordant interstitial lung disease diagnoses were found in affected individuals from 80% of families. Patients with TERC mutations were diagnosed at an earlier age than those with PARN mutations (51±11 years versus 64±8 years; p=0.03) and had a higher incidence of haematological comorbidities. The mean rate of forced vital capacity decline was 300 mL·year-1 and the median time to death or transplant was 2.87 years. There was no significant difference in time to death or transplant for patients across gene mutation groups or for patients with a diagnosis of IPF versus a non-IPF diagnosis.Genetic mutations in telomere related genes lead to a variety of interstitial lung disease (ILD) diagnoses that are universally progressive.

Chronic hypersensitivity pneumonitis: important considerations in the work-up of this fibrotic lung disease.

PURPOSE OF REVIEW: Chronic hypersensitivity pneumonitis is increasingly recognized as an important mimic of other fibrotic lung diseases. This review will summarize recent data regarding the importance and difficulty of determining causative exposures both for accurate diagnosis and prognosis, and describe the expanded pathologic spectrum of the disease, the effects of fibrosis on prognosis and challenges in the diagnostic evaluation. RECENT FINDINGS: Several recent publications show the potential pathologic patterns induced by chronic hypersensitivity pneumonitis are broader than the classic triad of bronchiolitis, interstitial infiltrates and granulomas. Other pathologic patterns include nonspecific interstitial pneumonia, usual interstitial pneumonia, organizing pneumonia, bronchiolitis and airway centric fibrosis. Detecting a causative antigen in fibrotic hypersensitivity pneumonitis is challenging but critically important both for accurate diagnosis and improved prognosis. The prognosis in hypersensitivity pneumonitis worsens in the presence of fibrosis, but it remains significantly better than idiopathic pulmonary fibrosis. SUMMARY: Hypersensitivity pneumonitis is increasingly recognized as an important cause of fibrotic interstitial lung disease. Hypersensitivity pneumonitis demonstrates a remarkable tendency to mimic other idiopathic interstitial pneumonias. A detailed exposure history remains a cornerstone of diagnosis and management.

Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation.

BACKGROUND: Short telomere lengths are found in a subset of patients with idiopathic pulmonary fibrosis, but their clinical significance is unknown. Our aim was to investigate whether patients with various blood leucocyte telomere lengths had different overall survival. METHODS: In this observational cohort study, we enrolled patients with interstitial lung disease from Dallas, TX (primary cohort), and from Chicago, IL, and San Francisco, CA (replication cohorts). We obtained genomic DNA samples from unrelated healthy controls in Dallas, TX, and spouses of patients were also enrolled as an independent control group. Telomere lengths were measured in genomic DNA samples isolated from peripheral blood obtained at the time of the initial enrolment assessment. The primary endpoint was transplant-free survival (ie, time to death or lung transplantation) in the Dallas cohort. Findings were validated in the two independent idiopathic pulmonary fibrosis cohorts (Chicago and San Francisco). FINDINGS: 370 patients were enrolled into the Dallas cohort between June 17, 2003, and Aug 25, 2011. The 149 patients with idiopathic pulmonary fibrosis had shorter telomere lengths than did the 195 healthy controls (mean age-adjusted log-transformed ratio of telomere to single copy gene was -0.16 [SD 0.23] vs 0.00 [0.18]; p<0.0001); however, telomere lengths of the Dallas patients with idiopathic pulmonary fibrosis (1.33 [SD 0.25]) were similar to the 221 patients with other interstitial lung disease diagnoses (1.46 [0.24]) after adjusting for age, sex, and ethnicity (p=0.47). Telomere length was independently associated with transplant-free survival time for patients with idiopathic pulmonary fibrosis (HR 0.22 [95% CI 0.08-0.63]; p=0.0048), but not for patients with interstitial lung disease diagnoses other than idiopathic pulmonary fibrosis (HR 0.73 [0.16-3.41]; p=0.69). The association between telomere length and survival in patients with idiopathic pulmonary fibrosis was independent of age, sex, forced vital capacity, or diffusing capacity of carbon monoxide, and was replicated in the two independent idiopathic pulmonary fibrosis replication cohorts (Chicago cohort, HR 0.11 [0.03-0.39], p=0.00066; San Francisco cohort, HR 0.25 [0.07-0.87], p=0.029). INTERPRETATION: Shorter leucocyte telomere lengths are associated with worse survival in idiopathic pulmonary fibrosis. Additional studies will be needed to establish clinically relevant thresholds for telomere length and how this biomarker might affect risk stratification of patients with idiopathic pulmonary fibrosis. FUNDING: US National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, Harroun Family Foundation, and Nina Ireland Lung Disease Program.