Diagnosis of Hypersensitivity Pneumonitis in Adults. An Official ATS/JRS/ALAT Clinical Practice Guideline.

Background: This guideline addresses the diagnosis of hypersensitivity pneumonitis (HP). It represents a collaborative effort among the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax.Methods: Systematic reviews were performed for six questions. The evidence was discussed, and then recommendations were formulated by a multidisciplinary committee of experts in the field of interstitial lung disease and HP using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.Results: The guideline committee defined HP, and clinical, radiographic, and pathological features were described. HP was classified into nonfibrotic and fibrotic phenotypes. There was limited evidence that was directly applicable to all questions. The need for a thorough history and a validated questionnaire to identify potential exposures was agreed on. Serum IgG testing against potential antigens associated with HP was suggested to identify potential exposures. For patients with nonfibrotic HP, a recommendation was made in favor of obtaining bronchoalveolar lavage (BAL) fluid for lymphocyte cellular analysis, and suggestions for transbronchial lung biopsy and surgical lung biopsy were also made. For patients with fibrotic HP, suggestions were made in favor of obtaining BAL for lymphocyte cellular analysis, transbronchial lung cryobiopsy, and surgical lung biopsy. Diagnostic criteria were established, and a diagnostic algorithm was created by expert consensus. Knowledge gaps were identified as future research directions.Conclusions: The guideline committee developed a systematic approach to the diagnosis of HP. The approach should be reevaluated as new evidence accumulates.

Long-term outcomes in chronic hypersensitivity pneumonitis.

INTRODUCTION: The objective of this study was to analyze mortality, possible predictors of long-term survival, and health-related quality of life of a large chronic hypersensitivity pneumonitis (CHP) patient sample. METHODS: Longitudinal study in patients diagnosed with CHP during 2004-2013, followed for at least 1 year. Patients remaining alive and consenting to participate had a follow-up visit during 2015, including a complete pulmonary function study and the EuroQol-5D and Beck Depression and Anxiety Inventories. RESULTS: Out of the 160 patients finally included, 87 remained alive. Seventy-three had died or underwent lung transplantation at the time of the study with a median survival of 7.0 (4.4-14.5) years. A Cox proportional risk model showed that factors associated with lower survival were as follows: increased age, a low percentage of lymphocytes in bronchoalveolar lavage (BAL), a decreased transfer factor of the lung for carbonmonoxide (DLCO), presence of honeycomb in the high-resolution chest scan (HRCT), and the usual interstitial pneumonia (UIP) histologic pattern. At follow-up, all patients presented an EuroQol-5D score <0.8 and 21(50%) and 9(28.6%) subjects presented a probable anxiety and depressive syndrome, respectively. CONCLUSION: CHP is a severe disease with a bad mid-term prognosis. Lymphocyte values in BAL and DLCO values at baseline, presence of honeycomb in HRCT, and UIP histologic pattern were found to be predictors of survival. Early accurate diagnosis of the disease is fundamental for prompt initiation of antigen avoidance.

Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline.

BACKGROUND: This document provides clinical recommendations for the diagnosis of idiopathic pulmonary fibrosis (IPF). It represents a collaborative effort between the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. METHODS: The evidence syntheses were discussed and recommendations formulated by a multidisciplinary committee of IPF experts. The evidence was appraised and recommendations were formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: The guideline panel updated the diagnostic criteria for IPF. Previously defined patterns of usual interstitial pneumonia (UIP) were refined to patterns of UIP, probable UIP, indeterminate, and alternate diagnosis. For patients with newly detected interstitial lung disease (ILD) who have a high-resolution computed tomography scan pattern of probable UIP, indeterminate, or an alternative diagnosis, conditional recommendations were made for performing BAL and surgical lung biopsy; because of lack of evidence, no recommendation was made for or against performing transbronchial lung biopsy or lung cryobiopsy. In contrast, for patients with newly detected ILD who have a high-resolution computed tomography scan pattern of UIP, strong recommendations were made against performing surgical lung biopsy, transbronchial lung biopsy, and lung cryobiopsy, and a conditional recommendation was made against performing BAL. Additional recommendations included a conditional recommendation for multidisciplinary discussion and a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other ILDs. CONCLUSIONS: The guideline panel provided recommendations related to the diagnosis of IPF.

Hypersensitivity Pneumonitis: Challenges in Diagnosis and Management, Avoiding Surgical Lung Biopsy.

This review presents an update of the currently available information related to hypersensitivity pneumonitis, with a particular focus on the contribution of several techniques in the diagnosis of this condition. The methods discussed include proper elaboration of a complete medical history, targeted auscultation, detection of specific immunoglobulin G antibodies against the most common antigens causing this disease, skin tests, antigen-specific lymphocyte activation assays, bronchoalveolar lavage, and cryobiopsy. Special emphasis is placed on the relevant contribution of specific inhalation challenge (bronchial challenge test). Surgical lung biopsy is presented as the ultimate recourse, to be used when the diagnosis cannot be reached through the other methods covered.

Treatment patterns, resource use and costs of idiopathic pulmonary fibrosis in Spain--results of a Delphi Panel.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a form of chronic fibrosing interstitial pneumonia characterized by progressive worsening of dyspnea and lung function, with a poor prognosis. The objective of this study was to determine treatment patterns, resource use and costs of managing Spanish patients with IPF. METHODS: A three-round Delphi consensus panel of 15 clinical experts was held between December 2012 and June 2013 using questionnaires to describe the management of patients with IPF. A cost analysis based on Delphi panel estimates was made from the Spanish National Health System (NHS) perspective, including the direct costs of IPF diagnosis and management. Unit costs were applied to Delphi panel estimates of health resource use. Univariate sensitivity analyses were made to evaluate uncertainties in parameters. RESULTS: The Delphi panel estimated that 20, 60 and 20% of IPF patients presented with stable disease, slow and rapid disease progression, respectively. The estimated annual cost per patient with stable disease, slow and rapid disease progression was €11,484, €20,978 and €57,759, respectively. This corresponds to a weighted average annual cost of €26,435 with itemized costs of €1,184 (4.5), €7,147 (27.0), €5,950 (22.5), €11,666 (44.1) and €488 (1.9%) for the diagnosis of IPF, treatment, monitoring, management of acute exacerbations and end-of-life care, respectively. The parameter that varied the annual cost per patient the most was resource use associated with acute exacerbations. CONCLUSIONS: The management of patients with IPF in Spain, especially patients with rapid disease progression, has a high economic impact on the NHS.

Diagnostic yield of specific inhalation challenge in hypersensitivity pneumonitis.

Reliable methods are needed to diagnose hypersensitivity pneumonitis. The aim of the study was to establish the diagnostic yield of specific inhalation challenge (SIC) in patients with hypersensitivity pneumonitis. All patients with suspected hypersensitivity pneumonitis in whom SIC was performed (n=113) were included. SIC was considered positive when patients showed a decrease of >15% in forced vital capacity (FVC) or >20% in diffusing capacity of the lung for carbon dioxide, or a decrease of 10% to 15% in FVC accompanied by a temperature increase of 0.5°C within 24 h of inhalation of the antigen. SIC was positive to the agents tested in 68 patients: 64 received a diagnosis of hypersensitivity pneumonitis and SIC results were considered false-positive in the remaining four patients. In the SIC-negative group (n=45), 24 patients received a diagnosis of hypersensitivity pneumonitis and SIC results were considered false-negative, and 21 patients were diagnosed with other respiratory diseases. The sensitivity and specificity of the test were 72.7% and 84%, respectively. Having hypersensitivity pneumonitis caused by an antigen other than birds or fungi predicted a false-negative result (p=0.001). In hypersensitivity pneumonitis, positive SIC testing virtually confirms the diagnosis, whereas negative testing does not rule it out, especially when the antigenic sources are not birds or fungi.

Bronchial inflammation in hypersensitivity pneumonitis after antigen-specific inhalation challenge.

BACKGROUND AND OBJECTIVE: The aim of this study is to compare the inflammatory profile before and after specific inhalation challenge (SIC) in induced sputum from patients with hypersensitivity pneumonitis (HP) and to investigate whether different causal antigens define the resulting profile. METHODS: A prospective study was conducted in 27 patients with HP: 15 patients due to exposure to birds (BHP) and 12 due to exposure to fungi (FHP), confirmed by SIC. Induced sputum was obtained before and/or 24 h after SIC. Cell types were determined by differential cell count using optical microscopy. Interferon-γ, interleukin (IL)-12p70, IL-2, IL-10, IL-8, IL-6, IL-4, IL-5, IL-1ß, tumour necrosis factor (TNF)-α and TNF-ß levels were measured in the supernatants. RESULTS: Following SIC, higher sputum neutrophilia levels (P = 0.048) and an increase in IL-8 levels (P = 0.017) were found in patients with FHP than in those with BHP. FHP patients also showed increased IL-1ß, IL12-p70 and IL5 levels (P = 0.011, P = 0.036 and P = 0.018, respectively) after SIC. In BHP, a trend towards increases in sputum eosinophils and TH2 cytokines (IL4, IL5) was seen following SIC (P = 0.059, P = 0.068 and P = 0.075 respectively). CONCLUSIONS: This study shows that bronchial inflammation is present in patients with HP evidenced by increases in sputum neutrophils and eosinophils following exposure to the offending antigen during SIC.

Diagnostic utility of exhaled breath condensate analysis in conjunction with specific inhalation challenge in individuals with suspected work-related asthma.

BACKGROUND: Establishing the role of exhaled breath condensate (EBC) analysis in work-related asthma (WRA), and more specifically, in conjunction with specific inhalation challenge (SIC), is difficult. OBJECTIVE: To measure EBC pH, and nitrite/nitrate concentrations before and after SIC in individuals with suspected WRA exposed to either high-molecular-weight (HMW) or low-molecular-weight (LMW) agents and evaluate whether these changes are useful to distinguish between occupational asthma (OA) and work-exacerbated asthma (WEA). METHODS: One hundred twenty-five consecutive workers undergoing SIC were enrolled. Exhaled breath condensate was collected at the end of the baseline day and 24 hours after exposure to the offending agent. In all EBC samples, pH was measured, and nitrite and nitrate concentrations were determined. RESULTS: Specific inhalation challenge was positive in 66 individuals, who were then diagnosed with OA. Work-exacerbated asthma was diagnosed in 14, and in 45 patients establishing a direct relationship between the symptoms and work exposure was not possible. In patients with WEA, EBC pH values after SIC were significantly lower than those before SIC (P = .0047). Using the receiver operating characteristic (ROC) curve, we found that an EBC pH decrease of greater than 0.4 units after SIC achieved the most satisfactory sensitivity 79% (confidence interval [CI]: 49-94) and specificity of 100% (CI: 68-100), considering only patients with asthma and without OA. A decrease in EBC pH of 0.4 or more common in those exposed to HMW agents (8/19, 42%) than in those exposed to LMW agents (7/47, 15%). CONCLUSIONS: Exhaled breath condensate pH in conjunction with SIC may be useful for diagnosing WEA.

Genetic-based reference values for angiotensin-converting enzyme (ACE) according to I/D polymorphism in a Spanish population sample.

BACKGROUND: Serum angiotensin-converting enzyme (ACE) activity has been related to sarcoidosis and other granulomatous diseases. It has been demonstrated that serum ACE activity is influenced by ACE gene I/D polymorphism. The aim of this study was to establish ACE activity reference values according to genotype in a Spanish population to improve diagnostic sensitivity and treatment monitoring in sarcoidosis patients. METHODS: A sample population of 150 blood donors was included in the study. Serum ACE activity and genotype were determined and the reference intervals, defined as the 95% central range of the population (2.5th-97.5th percentiles) were obtained for all three genotypes (DD, DI, II) and for the entire sample. RESULTS: Genotype frequencies were 37% DD (n=54), 43% DI (n=63), and 20% II (n=30). Individuals with DD genotype showed the highest ACE activity (mean 39.0 U/L, SD 13.6), ID genotype showed intermediate levels (mean 29.5 U/L, SD 10.2) and II genotype lowest levels (mean 19.1 U/L, SD 4.9). ACE activity differed significantly between these groups: F (2144)=33.15, p<0.05. The corresponding reference intervals for ACE activity were 13.3-63.9 U/L in the overall sample, 12.3-65.6 U/L in genotype DD, 9.5-49.5 U/L in DI and 9.6-28.7 in II. CONCLUSIONS: The preliminary reference values for ACE activity in healthy Spanish individuals according to I/D polymorphism are presented. Significant differences in these values were found between the genotype groups.

Pilot Study Using Recombinant Antigens r-PROE and r-IGLL1 for the Serodiagnosis of Feather Duvet Lung.

BACKGROUND: Feather duvet lung (FDL) is an underestimated form of acute and chronic hypersensitivity pneumonitis. Serological tests for FDL need to be validated. We investigated the ability of recombinant pigeon Proproteinase E (r-PROE) and Immunoglobulin-lambda-like-polypeptide-1 (r-IGLL1) proteins to support the serological diagnosis of FDL, and propose them as a serological tool for clinicians to differentiate cases from FDL and Bird fancier's lung (BFL). METHODS: Specific IgG antibodies against r-PROE and r-IGLL1, analyzed with ELISA, were measured in patients diagnosed with FDL (n=31), BFL (n=15) controls exposed (n=15) and unexposed to feathers (n=15). RESULTS: The sensitivity and specificity of the r-PROE ELISA for the serological diagnosis of FDL cases versus exposed and unexposed controls were 74.2% and 86.7% respectively, with an index threshold of 0.5 (AUC: 0.89). In addition, this serological test was effective to support the serological diagnosis of FDL and BFL cases with significantly different thresholds. The r-IGLL1 ELISA was only effective for the serological diagnosis of BFL. Also, these two serological tests were useful for the diagnosis of both chronic and acute forms. CONCLUSIONS: The new diagnostic test for FDL using r-PROE protein should help to detect overt and hidden cases of FDL. The combination of both test will help the clinician in distinguish between the etiology of birds or feathers duvet.

High eosinophil levels and poor evolution in occupational asthma due to cyanoacrylate exposure.

We present the case of a 41-year-old woman who developed occupational asthma (OA) due to cyanoacrylate while working in a company that manufactured and marketed plastic products. Specific inhalation challenge confirmed the diagnosis of OA to cyanoacrylate. The patient expressed marked eosinophilic inflammation and marked deterioration of pulmonary function while in persistent contact with the causal agent. The possible etiologic mechanisms implicated in the origin of this type of OA are discussed. Patients diagnosed with this condition are advised to avoid exposure to cyanoacrylates.

Pilot Study Using Recombinant Antigens r-PROE and r-IGLL1 for the Serodiagnosis of Feather Duvet Lung.

BACKGROUND: Feather duvet lung (FDL) is an underestimated form of acute and chronic hypersensitivity pneumonitis. Serological tests for FDL need to be validated. We investigated the ability of recombinant pigeon Proproteinase E (r-PROE) and Immunoglobulin-lambda-like-polypeptide-1 (r-IGLL1) proteins to support the serological diagnosis of FDL, and propose them as a serological tool for clinicians to differentiate cases from FDL and Bird fancier's lung (BFL). METHODS: Specific IgG antibodies against r-PROE and r-IGLL1, analyzed with ELISA, were measured in patients diagnosed with FDL (n=31), BFL (n=15) controls exposed (n=15) and unexposed to feathers (n=15). RESULTS: The sensitivity and specificity of the r-PROE ELISA for the serological diagnosis of FDL cases versus exposed and unexposed controls were 74.2% and 86.7% respectively, with an index threshold of 0.5 (AUC: 0.89). In addition, this serological test was effective to support the serological diagnosis of FDL and BFL cases with significantly different thresholds. The r-IGLL1 ELISA was only effective for the serological diagnosis of BFL. Also, these two serological tests were useful for the diagnosis of both chronic and acute forms. CONCLUSIONS: The new diagnostic test for FDL using r-PROE protein should help to detect overt and hidden cases of FDL. The combination of both test will help the clinician in distinguish between the etiology of birds or feathers duvet.

Hypersensitivity Pneumonitis and (Idiopathic) Pulmonary Fibrosis Due to Feather Duvets and Pillows.

INTRODUCTION: Exposure to feather bedding may be an unnoticed cause of hypersensitivity pneumonitis (HP) and idiopathic pulmonary fibrosis (IPF). Thus, an in-depth clinical study of the diagnosis of patients with suspected HP and IPF is required in order to determine their etiologies. The objective of the present study is to raise awareness of HP and pulmonary fibrosis due to exposure to feather bedding, and to study the prevalence and describe long-term outcomes. METHODS: We describe a series of 33 patients diagnosed with HP and pulmonary fibrosis due to feather bedding exposure and followed over a 10-year period. The patients were from a subgroup of 127 individuals with HP undergoing in-depth evaluation using a diagnostic protocol at a regional referral center. RESULTS: Eleven (33%) patients were clinically diagnosed with acute HP and 22 (67%) with chronic HP. Ten (45%) chronic HP patients showed a high resolution computed tomography (HRCT) pattern of usual interstitial pneumonia (UIP) with suspected IPF. The prevalence of HP was 6.2/100 000 feather bedding users (compared with 54.6 per 100 000 bird-breeders). The survival rates of patients over the 10-year period was 100% for acute HP and 64% for chronic HP. CONCLUSIONS: In a series of HP patients, the diagnosis was attributed to feather bedding exposure in 26%. UIP pattern on HRCT was present in nearly half of the chronic cases. The survival of patients with chronic HP at ten years was 64%, despite avoiding further exposure.

Ammonium persulfate can initiate an asthmatic response in mice.

BACKGROUND: Persulfate salts are the main cause of occupational asthma (OA) in hairdressers. The aim of this study was to verify whether ammonium persulfate ((NH(4))(2)S(2)O(8), AP) is capable of triggering an asthma-like response in mice. METHODS: BALB/c mice were dermally treated on days 1 and 8, with dimethylsulfoxide (DMSO), 1% AP or 5% AP (20 microl/ear). On day 15, the auricular lymph nodes were removed and an in vitro lymphocyte proliferation test (LPT) was performed. AP was tested for its ability to elicit an asthmatic response using a locally developed mouse model of chemical-induced asthma. On days 1 and 8, BALB/c mice received 20 microl AP (5%) or DMSO on each ear. On day 15, they received an intranasal instillation of AP (1%) or saline. Afterwards, ventilatory, inflammatory and immunological parameters were assessed. RESULTS: The LPT showed that in vitro stimulation of lymphocytes with AP leads to specific proliferation of lymphocytes from AP-sensitised mice. In vivo, AP induced, in AP-sensitised mice only, an 'early' ventilatory response (increased Penh (enhanced pause)) immediately after challenge, and airway hyper-reactivity to methacholine 22 h later. Pulmonary inflammation was mainly characterised by neutrophils (10-15%). AP-sensitised mice showed an increase in total number of T helper (Th) and B lymphocytes together with an increased in vitro secretion of interleukin-4 (IL-4), IL-10 and IL-13 and an increase in total serum immunoglobulin E. CONCLUSIONS: In a mouse model, it was confirmed that dermal sensitisation to AP can lead to asthma-like responses after a single administration via the airway.

Noninvasive home mechanical ventilation in elderly patients.

STUDY OBJECTIVE: To determine the short- and long-term benefits of noninvasive home mechanical ventilation (NIHMV) in patients aged 65 and older who were eligible for this treatment. DESIGN AND SETTING: This retrospective, comparative, longitudinal study was carried out in a tertiary care hospital in Barcelona (Spain). PATIENTS AND METHODS: The study included all patients in whom NIHMV with a nasal mask was established in the period from 1998 to 2001. Patients were divided into 3 groups according to age: group 1 (n = 10) > or =75; group 2 (n = 40) 65-74, and group 3 (n = 41) <65 years old. Clinical characteristics, pulmonary function results, and arterial blood gas findings were assessed in all patients before starting ventilation and after 6 months. MEASUREMENTS AND RESULTS: Statistically significant improvements in PaO(2) (13.4, 10, and 15.3 mm Hg for groups 1-3) and PaCO(2) (-17.6, -9.6 and -12.8 mm Hg for groups 1-3) were found at 6 months (p < 0.001 in all cases). There were no significant differences between the groups in blood gas parameters and treatment compliance. The incidence of related adverse events was not statistically different between the study groups (40%, 35% and 32% for groups 1-3; p = 0.859). CONCLUSIONS: NIHMV is effective in all patients for whom it is indicated, regardless of their age.

Exposure Assessment Tools for Hypersensitivity Pneumonitis. An Official American Thoracic Society Workshop Report.

This report is based on proceedings from the Exposure Assessment Tools for Hypersensitivity Pneumonitis (HP) Workshop, sponsored by the American Thoracic Society, that took place on May 18, 2019, in Dallas, Texas. The workshop was initiated by members from the Environmental, Occupational, and Population Health and Clinical Problems Assemblies of the American Thoracic Society. Participants included international experts from pulmonary medicine, occupational medicine, radiology, pathology, and exposure science. The meeting objectives were to 1) define currently available tools for exposure assessment in evaluation of HP, 2) describe the evidence base supporting the role for these exposure assessment tools in HP evaluation, 3) identify limitations and barriers to each tool's implementation in clinical practice, 4) determine which exposure assessment tools demonstrate the best performance characteristics and applicability, and 5) identify research needs for improving exposure assessment tools for HP. Specific discussion topics included history-taking and exposure questionnaires, antigen avoidance, environmental assessment, specific inhalational challenge, serum-specific IgG testing, skin testing, lymphocyte proliferation testing, and a multidisciplinary team approach. Priorities for research in this area were identified.

Classification of hypersensitivity pneumonitis: a hypothesis.

BACKGROUND: Regardless of the causative antigen, hypersensitivity pneumonitis (HP) is usually classified as 'acute', 'subacute' or 'chronic'. Considerable confusion still surrounds this classification because there are no widely accepted criteria to distinguish the various stages. The objective of this study was to determine whether the current classification of HP truly reflects categories of patients with distinct clinical features. METHODS: Data obtained from a large prospective multicenter cohort study (the HP Study) were used to divide a cohort of patients with HP into a limited number of categories (clusters) with maximally differing clinical patterns, without prejudgment. The results of this cluster analysis were compared with the current classification of HP (acute, subacute or chronic). RESULTS: 168 patients were included in the analysis. A 2-cluster solution best fitted the data. Patients in cluster 1 (41 patients) had more recurrent systemic symptoms (chills and body aches) and normal chest radiographs than those in cluster 2 (127 patients) who showed significantly more clubbing, hypoxemia, restrictive patterns on pulmonary function tests and fibrosis on high-resolution computed tomography (HRCT). All p values were <0.0001, using Fisher's exact test. Nodular opacities were seen on HRCT as often in cluster 1 as in cluster 2. There was considerable disagreement between the current classification of HP and the results of our analysis. CONCLUSION: The current classification of acute, subacute and chronic HP is not supported by our analysis. Subacute HP is particularly difficult to define.