A first look at the reliability, validity and responsiveness of L-PF-35 dyspnea domain scores in fibrotic hypersensitivity pneumonitis.

BACKGROUND: Dyspnea impairs quality of life (QOL) in patients with fibrotic hypersensitivity pneumonitis (FHP). The Living with Pulmonary Fibrosis questionnaire (L-PF) assesses symptoms, their impacts and PF-related QOL in patients with any form of PF. Its scores have not undergone validation analyses in an FHP cohort. METHODS: We used data from the Pirfenidone in FHP trial to examine reliability, validity and responsiveness of the L-PF-35 Dyspnea domain score (Dyspnea) and to estimate its meaningful within-patient change (MWPC) threshold for worsening. Lack of suitable anchors precluded conducting analyses for other L-PF-35 scores. RESULTS: At baseline, Dyspnea's internal consistency (Cronbach's coefficient alpha) was 0.85; there were significant correlations with all four anchors (University of California San Diego Shortness of Breath Questionnaire scores r = 0.81, St. George's Activity domain score r = 0.82, percent predicted forced vital capacity r = 0.37, and percent predicted diffusing capacity of the lung for carbon monoxide r = 0.37). Dyspnea was significantly different between anchor subgroups (e.g., lowest percent predicted forced vital capacity (FVC%) vs. highest, 33.5 ± 18.5 vs. 11.1 ± 9.8, p = 0.01). There were significant correlations between changes in Dyspnea and changes in anchor scores at all trial time points. Longitudinal models further confirmed responsiveness. The MWPC threshold estimate for worsening was 6.6 points (range 5-8). CONCLUSION: The L-PF-35 Dyspnea domain appears to possess acceptable psychometric properties for assessing dyspnea in patients with FHP. Because instrument validation is never accomplished with one study, additional research is needed to build on the foundation these analyses provide. TRIAL REGISTRATION: The data for the analyses presented in this manuscript were generated in a trial registered on ClinicalTrials.gov; the identifier was NCT02958917.

Nationwide Study of the Epidemiology, Diagnosis, and Treatment of Hypersensitivity Pneumonitis in Korea.

BACKGROUND: Hypersensitivity pneumonitis (HP) is a condition with an uncertain global incidence, and information on its diagnosis and management is limited. This study aimed to address these knowledge gaps. METHODS: This study utilized customized claims data from the Health Insurance Review and Assessment Service (HIRA) in South Korea from January 2010, to December 2021. Patients with HP were identified based on the diagnosis code (International Classification of Diseases, 10th Revision, J67) between 2011 and 2020. Incident HP cases were defined as new HP claims, excluding those with claims in the previous year. The study examined various factors such as age, sex, comorbidities, diagnostic methods, and treatment patterns. Additionally, multivariate logistic regression analysis was performed to identify risk factors associated with treatment initiation. RESULTS: A total of 8,678 HP incident cases were confirmed, with age- and sex-adjusted annual incidence rates ranging from 1.14/100,000 in 2020 to 2.16/100,000 in 2012. The mean age of patients with incident HP was 52 years, with a higher incidence observed among males. Additionally, the most common comorbidity was asthma. Bronchoscopy was performed on 16.9% of patients, and 25.4% of patients did not receive treatment within 1 year of diagnosis. Among those who received treatment, prednisone was the most used systemic steroid, and azathioprine was the most commonly used second-line immunosuppressant. Factors associated with treatment initiation included the female sex, having asthma or gastroesophageal reflux disease (GERD), and undergoing bronchoscopy. CONCLUSION: This study provides valuable insights into the incidence, diagnosis, and treatment patterns of HP in South Korea using nationwide medical claims data.

The effectiveness and pharmacoeconomic study of using different corticosteroids in the treatment of hypersensitivity pneumonitis.

PURPOSE: Interstitial lung diseases (ILDs) are caused by inflammation and/or fibrosis of alveolar walls resulting in impaired gas exchange. Hypersensitivity pneumonitis (HP) is the third most common type of ILDs. Corticosteroids are the mainstay treatment for HP. The use of intramuscular (IM) betamethasone or intravenous (IV) dexamethasone as weekly pulse doses has shown higher benefit than daily oral prednisolone for HP patients. The aim of this study is to directly compare different corticosteroids in terms of effectiveness and in monetary values and perform an economic evaluation. METHODS: One hundred and seven patients were tested for pulmonary function tests (PFTs) and inflammatory markers to assess the treatment effectiveness. A cost-effectiveness analysis (CEA) was performed. ICERs between 3 treatment groups were calculated. RESULTS: Post treatment, Krebs von den Lungen-6 (KL-6) levels significantly improved in betamethasone group from 723.22 ± 218.18 U/ml to 554.48 ± 129.69 U/ml (p = 0.001). A significant improvement in erythrocyte sedimentation rate (ESR) occurred in the dexamethasone group from 56.12 ± 27.97 mm to 30.06 ± 16.04 mm (p = 0.048). A significant improvement in forced expiratory volume (FEV1), forced vital capacity (FVC) and six-minute walk distance (6MWD) was observed within the three treatment groups. A significant improvement in oxygen desaturation percentage (SpO2) occurred within dexamethasone and betamethasone groups. Betamethasone and dexamethasone were found more cost-effective than prednisolone as their ICERs fell in quadrant C. Furthermore, ICER between betamethasone and dexamethasone was performed; a small difference in cost was found compared to the higher benefit of betamethasone. CONCLUSION: Betamethasone and dexamethasone were found to be more effective than prednisolone in improving the inflammatory reaction and the clinical features of HP patients. Betamethasone was found to be the best intervention in terms of cost against the effect.

Vasoreactive pulmonary artery hypertension in non-fibrotic hypersensitive pneumonitis.

Group III pulmonary hypertension (PH) is common in patients with hypersensitivity pneumonitis (HSP). Group I PH and vasoreactivity in HSP have not been reported. We describe a case of an elderly veterinarian woman who presented with progressive shortness of breath and desaturation on exertion. The patient was diagnosed with non-fibrotic HSP after consistent findings on chest CT, transbronchial biopsy and a positive HSP serological panel. The patient relocated her birds, and prednisone was started. Due to persistent symptoms, she underwent a right heart catheterisation, which showed PH with vasoreactivity; subsequently, nifedipine was started. Over a 9-month follow-up, there was an improvement in symptoms and a complete resolution of PH and CT scan changes. Our case highlights the rare possibility of group I PH in HSP. It illustrates the importance of confirming the aetiology of PH and initiating treatment early to resolve symptoms.

Hypersensitivity Pneumonitis: Challenges of a Complex Disease.

Hypersensitivity pneumonitis (HP) is a complex interstitial lung disease caused by chronic inhalation of a wide variety of antigens in susceptible and sensitized individuals, commonly associated with an occupational exposure. An impressive number of inciting antigens causing hypersensitivity pneumonitis have been found to cover a wide range of occupations. As working practices have changed over time, especially in industrialized countries, new names for occupational HP have emerged. This review emphasizes the main diagnostic issues arising from the high variability of clinical presentation and the broad spectrum of causal antigens. Furthermore, it provides an overview of current methods to unveil possible causes of hypersensitivity pneumonitis, highlights HP's current diagnostic and treatment challenges and the remaining areas of uncertainty, and presents prevention strategies.

Clinical characteristics and outcomes of hypersensitivity pneumonitis in South Korea.

BACKGROUND: Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) that results from an immune-mediated reaction involving various antigens in susceptible individuals. However, the clinical characteristics and outcomes of HP in South Korea are not well understood. OBJECTIVES: This study was conducted to identify the clinical characteristics and outcomes of HP in South Korea. DESIGN: This is a retrospective observational study investigating patients with pathologically confirmed HP at our center, along with a comprehensive review of published HP cases in the Republic of Korea. METHODS: This retrospective study analyzed 43 patients with pathologically proven HP at a single tertiary hospital in Korea between 1996 and 2020. In addition, case reports of HP published in Korea were collected. The clinical characteristics, etiologies, treatment, and outcomes of patients from our center, as well as case reports, were reviewed. Patients from our hospital were divided into fibrotic and nonfibrotic subtypes according to the ATS/JRS/ALAT guidelines. RESULTS: Among 43 patients with biopsy-proven HP, 12 (27.9%) and 31 (72.1%) patients were classified into the fibrotic and nonfibrotic subtypes, respectively. The fibrotic HP group was older (64.6 ± 8.5 versus 55.2 ± 8.3, p = 0.002) with less frequent complaints of fever (0% versus 45.2%, p = 0.013) compared to the nonfibrotic HP group. The most common inciting antigen was household mold (21, 48.8%), followed by inorganic substances (6, 14.0%). Inciting antigens were not identified in eight (18.6%) patients. Treatment of corticosteroids was initiated in 34 (79.1%) patients. An analysis of 46 patients from Korea by literature review demonstrated that reported cases were relatively younger and drugs were the most common etiology compared to our cohort. CONCLUSION: The analysis of reported cases, as well as our cohort, showed that exposure history and clinical manifestations are heterogeneous for patients with HP in South Korea.

Pirfenidone in fibrotic hypersensitivity pneumonitis: a double-blind, randomised clinical trial of efficacy and safety.

BACKGROUND: Fibrotic hypersensitivity pneumonitis (FHP) is an irreversible lung disease with high morbidity and mortality. We sought to evaluate the safety and effect of pirfenidone on disease progression in such patients. METHODS: We conducted a single-centre, randomised, double-blinded, placebo-controlled trial in adults with FHP and disease progression. Patients were assigned in a 2:1 ratio to receive either oral pirfenidone (2403 mg/day) or placebo for 52 weeks. The primary end point was the mean absolute change in the per cent predicted forced vital capacity (FVC%). Secondary end points included progression-free survival (PFS, time to a relative decline ≥10% in FVC and/or diffusing capacity of the lung for carbon monoxide (DLCO), acute respiratory exacerbation, a decrease of ≥50 m in the 6 min walk distance, increase or introduction of immunosuppressive drugs or death), change in FVC slope and mean DLCO%, hospitalisations, radiological progression of lung fibrosis and safety. RESULTS: After randomising 40 patients, enrolment was interrupted by the COVID-19 pandemic. There was no significant between-group difference in FVC% at week 52 (mean difference -0.76%, 95% CI -6.34 to 4.82). Pirfenidone resulted in a lower rate of decline in the adjusted FVC% at week 26 and improved PFS (HR 0.26, 95% CI 0.12 to 0.60). Results for other secondary end points showed no significant difference between groups. No deaths occurred in the pirfenidone group and one death (respiratory) occurred in the placebo group. There were no treatment-emergent serious adverse events. CONCLUSIONS: The trial was underpowered to detect a difference in the primary end point. Pirfenidone was found to be safe and improved PFS in patients with FHP. TRIAL REGISTRATION MUMBER: NCT02958917.

Management of fibrotic hypersensitivity pneumonitis.

PURPOSE OF REVIEW: Recent guidelines have updated the classification of hypersensitivity pneumonitis, stratifying by the presence or absence of fibrosis as either fibrotic or nonfibrotic hypersensitivity pneumonitis. Fibrotic hypersensitivity pneumonitis represents up to 10% of interstitial lung disease in large cohort studies, and is occasionally even more common in some regions; however, there are many unknown aspects to the diagnosis and management. The goal of this review article is to summarize the management of fibrotic hypersensitivity pneumonitis. RECENT FINDINGS: Historically, the only treatment options for patients with hypersensitivity pneumonitis were antigen avoidance and corticosteroids, although other immunosuppressive therapies are increasingly endorsed by experts in the field. There is accumulating evidence that antifibrotic medications can be useful as a second-line therapy in some patients with fibrotic hypersensitivity pneumonitis who have progression despite immunosuppression. There remains no direct comparison of immunosuppressive vs. antifibrotic medication for the management of fibrotic hypersensitivity pneumonitis, but some clinical, radiological and pathological features may suggest greater likelihood of benefit from one option or the other. SUMMARY: We anticipate that future treatment of fibrotic hypersensitivity pneumonitis will consider a variety of patient features to suggest the most prominent underlying biology that will then be used to guide initial pharmacotherapy; however, additional data are still needed.

[A CASE OF SUMMER-TYPE HYPERSENSITIVITY PNEUMONITIS DURING IMMUNOSUPPRESSIVE TREATMENT FOR SYSTEMIC SCLEROSIS].

A 70-year-old woman undergoing long-term treatment for systemic scleroderma and secondary Sjögren syndrome developed fever during tapering of steroids. Chest CT showed centrilobular granular shadow and ground glass opacities. The pathology of transbronchial lung biopsy and the findings of bronchoalveolar lavage fluid were consistent with hypersensitivity pneumonitis and positive for anti-Trichosporon asahii antibody. Because her symptoms and imaging findings improved after house cleaning, she was diagnosed with summertype hypersensitivity pneumonitis. When lung lesions are found in patients with collagen disease, it is necessary to distinguish various diseases. In particular, allergic diseases can be difficult to diagnose by steroid therapy. In order to make an accurate diagnosis, medical history and image interpretation should be performed carefully and histologically searched as much as possible.

[Update in interstitial lung disease 2021].

The significant scientific advances about interstitial lung disease from November 2020 to October 2021 which were published in the Chinese and international journals were systematically reviewed in this paper. The year 2021 brought advances in our understanding of the real-world adoption of the antifibrotic medications pirfenidone and nintedanib for US idiopathic pulmonary fibrosis patients, the European statement on the diagnosis and evaluation and treatment of pulmonary fibrosis, the CHEST guideline on the diagnosis and evaluation of hypersensitivity pneumonitis, Chinese expert viewpoints on the progressive fibrosing interstitial lung disease, and international updates on the diagnosis and management of connective tissue disease-associated interstitial lung diseases.

Hypersensitivity pneumonia associated with metallic straw of mate (chimarrão): A case report.

This case report describes a 61-year-old male who sought treatment for sudden symptoms of dry cough, chest pain and severe dyspnea. On admission, the patient had hypoxemia and predominantly medullary infiltrate that we could observe on his imaging exams. After hospital discharge, he presented two similar episodes, with clinical and radiological improvement with oxygen therapy alone. He denied exposure to birds, mold or chemical agents. However, the patient noticed the onset of symptoms soon after drinking chimarrão. Given the compatible clinical, radiological and laboratory history, the diagnosis of hypersensitivity pneumonitis was performed. The patient was instructed by the medical team not to consume the drink anymore, remaining asymptomatic for more than two years.

Efficacy of treatment with corticosteroids for fibrotic hypersensitivity pneumonitis: a propensity score-matched cohort analysis.

BACKGROUND: Fibrotic hypersensitivity pneumonitis (HP) is a chronic interstitial lung disease caused by allergic responses to repeated exposures to a causative antigen. Therapeutic evidence of the use of corticosteroids to treat fibrotic HP remains lacking, although corticosteroids are recognized as a major treatment option. The purpose of this study was to evaluate the efficacy of corticosteroid treatment in patients with fibrotic HP in a propensity score-matched cohort. METHODS: A retrospective review of the medical records from 2005 to 2019 in a single center was conducted, and 144 patients with fibrotic HP were identified. Semiquantitative scores for lung abnormalities on HRCT were evaluated. Patients who received (PDN group) and did not receive (non-PDN group) corticosteroid treatment were matched using a propensity score method. Survival rates, serial changes in pulmonary function and annual changes in HRCT scores were compared in the matched cohort. RESULTS: In the matched analysis, 30 individuals in the PDN group were matched with 30 individuals in the non-PDN group, the majority of whom had ILD without extensive fibrosis. The survival rate was significantly better in the PDN group (P = 0.032 for the stratified Cox proportional hazards model; HR, 0.250). The absolute changes in FVC at 6, 12, and 24 months from baseline were significantly better in the PDN group. Fewer patients in the PDN group experienced annual deterioration, as reflected in the HRCT score, due to ground-glass attenuation, consolidation, reticulation, traction bronchiectasis and honeycombing. CONCLUSION: We demonstrated that corticosteroids improved survival and slowed fibrotic progression in a matched cohort, the majority of whom had ILD without extensive fibrosis. Fibrotic HP with less severe fibrosis may benefit from corticosteroid treatment. We propose that the early initiation of corticosteroids should be considered for fibrotic HP when worsening fibrosis is observed.

[Girl with hypersensitivity pneumonitis. A case report]. / Niña con neumonitis por hipersensibilidad. Reporte de un caso.

BACKGROUND: Hypersensitivity pneumonitis entails several inflammatory lung diseases that preferentially affect the alveolar and perialveolar tissue. It is a very rare disease in children, with a complicated diagnosis due to the fact that antigen exposure usually goes unnoticed. CASE REPORT: A 12-year-old girl with dry cough, dyspnea, wheezing, and tachypnea, with partial improvement after treatment with inhaled bronchodilators and corticoids. The spirometry showed a restrictive pattern and reduced lung diffusion capacity; in the CT scan, centrilobular ground-glass opacities were observed, and a lymphocyte count of CD4/CD8 of 2.46 (lymphocytosis) was obtained from the bronchoalveolar lavage. IgG positivity to bird feathers was obtained. CONCLUSIONS: The treatment of hypersensitivity pneumonitis is based on avoiding exposure to the causative agent, which is determined by the prognosis; for which taking an extensive medical history is of paramount importance. Corticosteroids can be prescribed based on the clinical response, the pulmonary function, and the radiological improvement.

Antecedentes: La neumonitis por hipersensibilidad agrupa varias enfermedades inflamatorias pulmonares que afectan preferentemente el tejido alveolar y perialveolar. En niños se trata de una enfermedad muy rara, con diagnóstico complicado debido a que la exposición antigénica suele pasar desapercibida. Caso clínico: Niña de 12 años que presentaba tos seca, disnea, sibilancias y taquipnea con mejoría parcial al tratamiento con broncodilatadores y corticoides inhalados. En la espirometría presentó un patrón restrictivo y una capacidad de difusión pulmonar reducida; en la tomografía computarizada se observaron opacidades centrolobulillares en vidrio esmerilado y del lavado broncoalveolar se obtuvo un cociente de linfocitosis CD4/CD8 de 2.46. Se obtuvo IgG positiva a plumas de aves. Conclusiones: El manejo de la neumonitis por hipersensibilidad se basa en evitar la exposición al agente causante, lo que determina el pronóstico; de ahí que resulta de vital importancia realizar una historia clínica exhaustiva. Pueden indicarse corticosteroides en función de la respuesta clínica, la función pulmonar y la mejoría radiológica.

Hypersensitivity Pneumonitis in a Pediatric Patient.

Hypersensitivity pneumonitis (HP) is a rarely diagnosed interstitial lung disease with variable manifestations. It results from repeated inhalation of certain antigens, e.g. mold, avian antigen, etc. in susceptible patients. The diagnosis is made by exposure history, relevant clinical presentation, and specific radiologic features. It is treated by avoidance of triggers and use of corticosteroids. We report a 7.5-year girl with HP. She was admitted for cough and severe respiratory distress. Key Words: Hypersensitivity pneumonitis, Antigen, Allergy, Child.

Hypersensitivity pneumonitis: Lessons from a randomized controlled trial in children.

INTRODUCTION: Hypersensitivity pneumonitis (HP) in children is a severe interstitial lung disease and potentially, a chronic condition, if not treated appropriately. No evidence-based guidelines are available; in particular, the role of systemic glucocorticoid therapy is unclear. METHODS: The aim of this randomized, double-blind, placebo-controlled, parallel-group, multi-center, phase II trial in pediatric HP was to assess the outcome of HP in children after 6 months of treatment and to compare 3 months of treatment with oral prednisolone or placebo. RESULTS: After 1.5 years and the inclusion of only four children, we terminated the study prematurely. Two of the children randomized to prednisolone did not achieve the predefined response of FVC to normal. One child treated with placebo recovered to normal, similar to another child treated with prednisolone. All children treated with steroids developed drug-related side effects. DISCUSSION: This uncompleted study illustrates the urgent medical need for evidence-based treatment protocols for this condition. We discuss the hurdles which were specific for completion of this trial in a rare condition. Among other options, we suggest the inclusion of children into an all-age study of HP, as in adults the same questions are unanswered.

Beneficial impact of cathelicidin on hypersensitivity pneumonitis treatment-In vivo studies.

Cathelicidin (CRAMP) is a defence peptide with a wide range of biological responses including antimicrobial, immunomodulatory and wound healing. Due to its original properties the usefulness of CRAMP in the treatment of pulmonary fibrosis was assessed in a murine model of hypersensitivity pneumonitis (HP). The studies were conducted on mouse strain C57BL/6J exposed to a saline extract of Pantoea agglomerans cells (HP inducer). Cathelicidin was administered in the form of an aerosol during and after HP development. Changes in the composition of immune cell populations (NK cells, macrophages, lymphocytes: Tc, Th, Treg, B), were monitored in lung tissue by flow cytometry. Extracellular matrix deposition (collagens, hydroxyproline), the concentration of cytokines involved in inflammatory and the fibrosis process (IFNγ, TNFα, TGFß1, IL1ß, IL4, IL5, IL10, IL12α, IL13) were examined in lung homogenates by the ELISA method. Alterations in lung tissue morphology were examined in mouse lung sections stained with haematoxylin and eosin as well as Masson trichrome dyes. The performed studies revealed that cathelicidin did not cause any negative changes in lung morphology/structure, immune cell composition or cytokines production. At the same time, CRAMP attenuated the immune reaction induced by mice chronic exposure to P. agglomerans and inhibited hydroxyproline and collagen deposition in the lung tissue of mice treated with bacteria extract. The beneficial effect of CRAMP on HP treatment was associated with restoring the balance in quantity of immune cells, cytokines production and synthesis of extracellular matrix components. The presented study suggests the usefulness of cathelicidin in preventing lung fibrosis; however, cathelicidin was not able to reverse pathological changes completely.

Elevated Serum Amyloid a Levels Are not Specific for Sarcoidosis but Associate with a Fibrotic Pulmonary Phenotype.

Elevated Serum Amyloid A (SAA) levels have been found in several inflammatory diseases, including sarcoidosis. SAA is suggested to be involved in sarcoidosis pathogenesis by involvement in granuloma formation and maintenance. We hypothesized that SAA serum levels would be higher in sarcoidosis compared to other non-infectious granulomatous and non-granulomatous diseases. SAA levels were measured in serum from sarcoidosis, Hypersensitivity pneumonitis (HP), and (eosinophilic) granulomatosis with polyangiitis ((E)GPA) patients. Idiopathic pulmonary fibrosis (IPF) patients were included as non-granulomatous disease group. SAA levels of patients with sarcoidosis (31.0 µg/mL), HP (23.4 µg/mL), (E)GPA (36.9 µg/mL), and IPF (22.1 µg/mL) were all higher than SAA levels of healthy controls (10.1 µg/mL). SAA levels did not differ between the diagnostic groups. When SAA serum levels were analyzed in sarcoidosis subgroups, fibrotic sarcoidosis patients showed higher SAA levels than sarcoidosis patients without fibrosis (47.8 µg/mL vs. 29.4 µg/mL, p = 0.005). To conclude, the observation that fibrotic sarcoidosis patients have higher SAA levels, together with our finding that SAA levels were also increased in IPF patients, suggests that SAA may next to granulomatous processes also reflect the process of fibrogenesis. Further studies should clarify the exact role of SAA in fibrosis and the underlying mechanisms involved.

Insights on chronic hypersensitivity pneumonitis' treatment: Factors associated with a favourable response to azathioprine.

BACKGROUND: The use of immunosuppressive and antifibrotic agents for the treatment of chronic hypersensitivity pneumonitis (CHP) appears promising, but there is still no evidence supporting the clinical decision regarding the implementation of each specific pharmacological strategy. METHODS: Patients diagnosed with CHP and treated with azathioprine (AZA) were retrospectively selected from a single centre for Interstitial Lung Diseases. Baseline clinical data, as well as functional, imaging, bronchoalveolar lavage (BAL) and histology features were assessed. Longitudinal data on functional parameters were collected and comparatively analysed with patients' characteristics. RESULTS: In this cohort of 80 patients, of those who reached 12 months of treatment, 78.3% presented a preserved forced vital capacity, with 59 being eligible to be classified as AZA responders (n = 36) or non-responders (n = 23). BAL lymphocytosis was associated with a favourable response to AZA treatment (OR 1.051; 95% CI 1.015-1.089), although it didn't identify all responders. CONCLUSIONS: AZA revealed to be effective in disease stabilisation in most patients, while ineffective for a subset. BAL lymphocytosis appears as a potentially valuable strategy to identify AZA responders, although with limited accuracy. Further studies are needed to clarify other response markers to immunosuppressive agents, in order to optimize the therapeutic options for this condition.