Granulomatous Interstitial Lung Disease Research Articles

Lung function trajectories in Common Variable Immunodeficiencies: an observational retrospective multicenter study

Respiratory disease is a frequent cause of morbidity and mortality in Common Variable Immunodeficiencies (CVIDs), however lung function trajectories are poorly understood. To determine lung physiology measurements in CVID, their temporal trajectory and association with clinical and immunological parameters. Retrospective study from 5 Italian centres. CVIDs patients with longitudinal Pulmonary Function Tests (PFTs) measurements and available chest CT scan, were included. Applying the ERS/ATS 2021 standard, PFTs were expressed as percentile value (pct) within the normal distribution of healthy individuals, with the 5th pct identified the lower limit of normal (LLN). The association of lung function with clinical and immunological parameters was investigated. 185 CVIDs patients were included. 64% had at least one lung comorbidity (bronchiectasis 41% and Granulomatous Interstitial Lung Diseases 24%). At first spirometry, the median FEV1 was 3.07 L [IQR 2.40 - 3.80], placing at the 32nd pct [6th-61st], and the median FVC was 3.70 L [3.00 - 4.54], placing at the 29th pct [7th-49th]. 23% of patients had an FEV1 < LLN and 21% had an FVC < LLN. Switched-memory B cells <2% were associated with both FEV1<LLN (OR 7.58) and FVC<LLN (OR 3.55). In 112 patients with at least 5 years of PFT follow-up, we found no significant difference between measured and predicted annual decline of FEV1 (25.6 vs 20.7 mL/year) and FVC (15.6 vs 16.2 mL/year). Our findings suggest that lung volumes of the majority of CVID patients placed in the lower third of normal distribution of healthy individuals. After diagnosis the rate of lung decline was not accelerated.

A Multichannel CT and Radiomics-Guided CNN-ViT (RadCT-CNNViT) Ensemble Network for Diagnosis of Pulmonary Sarcoidosis.

Pulmonary sarcoidosis is a multisystem granulomatous interstitial lung disease (ILD) with a variable presentation and prognosis. The early accurate detection of pulmonary sarcoidosis may prevent progression to pulmonary fibrosis, a serious and potentially life-threatening form of the disease. However, the lack of a gold-standard diagnostic test and specific radiographic findings poses challenges in diagnosing pulmonary sarcoidosis. Chest computed tomography (CT) imaging is commonly used but requires expert, chest-trained radiologists to differentiate pulmonary sarcoidosis from lung malignancies, infections, and other ILDs. In this work, we develop a multichannel, CT and radiomics-guided ensemble network (RadCT-CNNViT) with visual explainability for pulmonary sarcoidosis vs. lung cancer (LCa) classification using chest CT images. We leverage CT and hand-crafted radiomics features as input channels, and a 3D convolutional neural network (CNN) and vision transformer (ViT) ensemble network for feature extraction and fusion before a classification head. The 3D CNN sub-network captures the localized spatial information of lesions, while the ViT sub-network captures long-range, global dependencies between features. Through multichannel input and feature fusion, our model achieves the highest performance with accuracy, sensitivity, specificity, precision, F1-score, and combined AUC of 0.93 ± 0.04, 0.94 ± 0.04, 0.93 ± 0.08, 0.95 ± 0.05, 0.94 ± 0.04, and 0.97, respectively, in a five-fold cross-validation study with pulmonary sarcoidosis (n = 126) and LCa (n = 93) cases. A detailed ablation study showing the impact of CNN + ViT compared to CNN or ViT alone, and CT + radiomics input, compared to CT or radiomics alone, is also presented in this work. Overall, the AI model developed in this work offers promising potential for triaging the pulmonary sarcoidosis patients for timely diagnosis and treatment from chest CT.

Imbalanced distribution of regulatory T cells and Th17.1 cells in the peripheral blood and BALF of sarcoidosis patients: relationship to disease activity and the fibrotic radiographic phenotype.

Sarcoidosis is a granulomatous interstitial lung disease involving a complex interplay among different cluster of differentiation 4 (CD4+) thymus cell (T-cell) subsets. Originally described as a type 1 T-helper (Th1) inflammatory disease, recent evidence suggests that both effector and regulatory T-cell subgroups play a critical role in sarcoidosis, but this remains controversial. We aimed to investigate the distribution of CD4+ T-cell subpopulations in sarcoidosis patients and its potential associations with clinical disease activity and a radiographic fibrotic phenotype. We measured the frequencies of regulatory T cells (Tregs), Th1, Th17, and Th17.1 cells in the peripheral blood and/or bronchoalveolar lavage fluid (BALF) of 62 sarcoidosis patients, 66 idiopathic pulmonary fibrosis (IPF) patients, and 41 healthy volunteers using flow cytometry. We also measured the changes in these T-cell subpopulations in the blood at the follow-up visits of 11 sarcoidosis patients. An increased percentage of Tregs was observed in the peripheral blood of sarcoidosis patients, with a positive association to disease activity and a fibrotic radiographic phenotype. We found a higher frequency of Tregs, a lower proportion of Th17.1 cells, and a lower ratio of Th17.1 cells to total Tregs in the peripheral blood of both active and fibrotic sarcoidosis patients, compared with IPF patients or healthy donors. In contrast, a lower frequency of Tregs and a higher proportion of Th17.1 cells was found in the BALF of sarcoidosis patients than in that of IPF patients. There was an imbalance of Tregs and Th17.1 cells between the peripheral blood and BALF in sarcoidosis patients. Following immunoregulatory therapy, the proportion of circulating Tregs in sarcoidosis patients decreased. A higher proportion of Tregs in the peripheral blood of sarcoidosis patients was related to disease activity, fibrotic phenotype, and the need for immunoregulatory therapy. The imbalanced distribution of Tregs and Th17.1 cells in patients' peripheral blood and BALF suggests that the lung microenvironment has an effect on the immunological pathogenesis of sarcoidosis. Therefore, further studies on the functional analysis of Tregs and Th17.1 cells in sarcoidosis patients are warranted.

Safety and efficacy of bronchoscopy with transbronchial lung biopsy in interstitial lung diseases: our experience

Background Interstitial lung diseases (ILDs) are a heterogeneous group of disorders with wide spectrum whose accurate diagnosis and proper treatment pose a great challenge. Our study is focused on safety and efficacy of bronchoscopy with transbronchial lung biopsy (TBLB) in patients with ILD. Methodology A prospective observational study of 68 patients was conducted in our tertiary care center. Diagnostic role, yield, and safety of TBLB in ILD were studied by comparing with high-resolution computed tomography (HRCT) patterns and histopathology. Results A total of 136 cases of ILD were referred to us in the said period. Of these, 75 patients underwent bronchoscopy and 68 underwent bronchoscopy with TBLB. Among them, the most common HRCT pattern was chronic hypersensitivity pneumonitis (HP) 47.06%. ILDs were subdivided as, with known cause (13.24%), 64.71% granulomatous ILDs (17.65% sarcoidosis and 47.06% chronic HP) and 22.06% idiopathic interstitial pneumonitis IIP). Pathological diagnosis of ILD was obtained in 54.41%. Based on etiological classification, pathological diagnosis was obtained in 46.67% IIP, 11.11% ILD with known cause, and 65.9% granulomatous ILD. A total of 16.2% patients had complications with no mortality. Complications associated with TBLB in IIP with non-IIP cases as well as usual interstitial pneumonia (UIP) with non-UIP cases were statistically significant. Conclusion Bronchoscopy was safe and well tolerated. Most important limiting factor was awareness about bronchoscopy and unwillingness for the procedure on understanding the risks of the same in ILD. TBLB is a useful diagnostic procedure for our ILDs as a part of multidisciplinary approach with total yield of 54.41% and more yield in chronic HP and sarcoidosis. We experienced a low rate of complications.

Interstitial lung diseases : Classification, differential diagnosis and treatment approaches in a heterogeneous group of chronic lung disorders

Interstitial lung diseases (ILD) comprise aheterogeneous group of chronic lung disorders of different etiologies that can not only affect the interstitium but also the alveolar space and the bronchial system. According to the "Global Burden of Disease Study" there has been an increase in incidence over the last decades and it is expected that the number of ILD-associated deaths will double over the next 20years. ILD are grouped into those of unknown cause, e.g. idiopathic pulmonary fibrosis (IPF), and ILD of known cause, which include drug-induced and connective tissue disease-associated ILD as well as granulomatous ILD such as sarcoidosis and hypersensitivity pneumonitis. In addition, some ILD present aprogressive fibrosing phenotype, which influences therapeutic decisions. Predominantly inflammatory entities are treated with immunosuppressives, whereas predominantly fibrosing ILD are treated with antifibrotic drugs; in some cases, acombination of both is necessary. The spectrum of differential diagnoses in ILD is broad, but definite diagnosis is essential for treatment selection; therefore, the multidisciplinary ILD board plays apivotal role.

Advances and Challenges of the Decade: The Ever-Changing Clinical and Genetic Landscape of Immunodeficiency

In the past 10 years, we have witnessed major advances in clinical immunology. Newborn screening for severe combined immunodeficiency has become universal in the United States and screening programs are being extended to severe combined immunodeficiency and other inborn errors of immunity globally. Early genetic testing is becoming the norm for many of our patients and allows for informed selection of targeted therapies including biologics repurposed from other specialties. During the COVID-19 pandemic, our understanding of essential immune responses expanded and the discovery of immune gene defects continued. Immunoglobulin products, the backbone of protection for antibody deficiency syndromes, came into use to minimize side effects. New polyclonal and monoclonal antibody products emerged with increasing options to manage respiratory viral agents such as SARS-CoV-2 and respiratory syncytial virus. Against these advances, we still face major challenges. Atypical is becoming typical as phenotypes of distinct genetic disease overlap whereas the clinical spectrum of the same genetic defect widens. Therefore, clinical judgment needs to be paired with repeated deep immune phenotyping and upfront genetic testing, as technologies rapidly evolve, and clinical disease often progresses with age. Managing patients with organ damage resulting from immune dysregulation poses a special major clinical challenge and management often lacks standardization, from autoimmune cytopenias, granulomatous interstitial lung disease, enteropathy, and liver disease to endocrine, rheumatologic, and neurologic complications. Clinical, translational, and basic science networks will continue to advance the field; however, cross-talk and education with practicing allergists/immunologists are essential to keep up with the ever-changing clinical and genetic landscape of inborn errors of immunity.

Common variable immunodeficiency (CVID) with granulomatous interstitial lung disease (GLILD) and SARS COVID-19 infection: case report and review of literature

BackgroundWe present a case of CVID complicated by granulomatous interstitial lung disease (GLILD). This patient clinical course was further complicated by COVID-19 infection. This is only the 2nd known case report of COVID 19 in CVID with GLILD. The clinical course and outcome of COVID 19 infection with common variable immunodeficiency (CVID) and GLILD is not well known.Case presentationOur patient met the clinical features of CVID secondary to low IgG/IgA, recurrent infections, and failure to respond to pneumococcal vaccination. He was treated with monthly maintenance IVIG therapy. Our patient also was diagnosed with co-existing GLILD that despite IVIG treatment was progressing. The patient needed to be started on Rituxan and Mycophenolate mofetil to achieve control but unfortunately became infected with COVID19 delaying his treatment for GLILD. Our patient only suffered from mild COVID 19 infection and was able to make antibodies to this. We believe severe infection was avoided as his CVID was well controlled with IVIG therapy despite progression of his granulomatous interstitial lung disease.ConclusionIn conclusion, our patient with CVID with co-existing biopsy proven granulomatous interstitial lung disease despite being very high risk for severe COVID 19 infections only had mild infection. This was believed to be due to well controlled CVID with IVIG therapy.

Diagnostic Dilemma on Novel Pathogenic Variant of Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4) in a Family with Chronic ITP and Immune Dysregulation

Inborn errors of immunity are increasingly linked to autoimmune cytopenias, especially in families with immunodeficiency and immune dysregulation. We present a large family study with several members presenting with chronic immune thrombocytopenia (ITP) and variable combinations of immune dysregulation and infections. The proband and kindred were diagnosed with a novel variant of unknown significance (VUS) in CTLA-4. Diagnostic approach to confirm the association between clinical phenotype and the pathogenicity of this novel variant is described. Retrospective chart review yielded demographic information, clinical history, immunological phenotype, genetic panel testing and treatment response. Functional testing included CTLA-4 expression and transendocytosis assay. Proband a 50-year-old female, presented with recurrent pneumonia, chronic diarrhea, hypothyroidism, granulomatous interstitial lung disease, and ITP. Immune phenotyping confirmed hypogammaglobulinemia requiring immunoglobulin replacement therapy. Proband, along with three other family members, had a novel CTLA4-VUS (c.173G>C p.Cys58Ser). Proband and her adult cousin had chronic ITP and hypogammaglobulinemia; however, two children with this VUS only had history of milk-induced colitis and asthma, respectively. Internalization of CD80/86 was impaired in CTLA-4 trans-endocytosis assay performed on T cells from proband’s cousin, revealing a functional impairment of CTLA-4. For the proband, abatacept (CTLA4-Ig) was initiated and resulted in marked improvement in respiratory and gastrointestinal symptoms along with decreased frequency of infections. The segregation of clinical phenotype within the family, functional testing, and response to abatacept support this CTLA-4 VUS as pathogenic variant. Our study highlights the importance of genetic testing and functional studies in patients with immune dysregulation and immunodeficiency.

A Case of Mild COVID-19 in a Teenager with Common Variable Immunodeficiency and Granulomatous Interstitial Lung Disease on Replacement Immunoglobulin and Infliximab

Common variable immunodeficiency (CVID) is a disorder of the immune system. Patients are generally diagnosed in their adolescence and require regular immunoglobulin replacement. Due to their immune dysregulation, they are at increased risk of infections, autoimmune disease, and cancer.

P29 Use of novel biologic therapies for arthropathy affecting common variable immunodeficiency patients

Abstract Background CVID is the most common adult immunodeficiency with an incidence of 1:25000. It is characterised by hypogammaglobulinaemia and recurrent bacterial infections. Patients also develop granulomatous interstitial lung disease and are at increased risk of lymphoma. Autoimmune disease, most commonly AIHA, ITP and thyroiditis, occurs at a rate of 25%. Previous studies suggested that 3% of patients have inflammatory arthritis, but from our experience a higher proportion complain of chronic arthralgias. Treating arthropathy in CVID is challenging; examination and inflammatory markers may be normal and there is concern about the risk of infections if using methotrexate or biologics. Methods We present a series of 7 patients with arthropathy in CVID. We chose DMARDs based on the individual case, tailor-made to the patients clinical and immunologic status. Results Patients had longstanding symptoms, with a median duration of 11 years. All patients had disabling joint pain, in three it was the most prominent symptom of their illness. All patients had pain/swelling in a typical symmetrical small joint polyarthritis distribution. Fatigue was also prominent. On examination three patients had clear evidence of synovitis, one had tenderness but no swelling, and three had no evidence of synovitis; there was no deformity. No patient had positive autoantibodies. Three had chronically raised CRP/ESR, one had raised inflammatory markers during flares, but the other three had normal markers. Prednisolone (10-15 mg) controlled arthritic symptoms. There was little response to conventional DMARDS or rituximab. Two patients treated with abatacept showed improvement in symptoms, but one died from PJP pneumonia. Two patients treated with baricitinib showed improvement in symptoms but one relapsed after 5 months (Table 1). Conclusion Arthopathy is a common, and probably under-diagnosed, feature of CVID. It is difficult to treat, with a poor response seen to most DMARDs. We have seen promising results with Baricitinib and propose using it first line in patients with disabling rheumatic symptoms. There may be a role for abatacept in co-existent severe joint and lung disease. A striking proportion, 4/7 (versus 10% in general CVID population), of patients had a causal genetic mutation identified. Arthropathy may, therefore, push immunologists towards genetic testing. Disclosures R. Henneberry None. S. Burns None. R. Stratton None. D.M. Lowe None.

ACE overexpression in myeloid cells increases oxidative metabolism and cellular ATP

ACE overexpression in myeloid cells increases oxidative metabolism and cellular ATP

Multidisciplinary management of interstitial lung diseases: A real-life study.

The guidelines on idiopathic pulmonary fibrosis (IPF) diagnosis established the crucial role of multidisciplinary discussion (MDD) in the diagnosis of interstitial lung diseases (ILD). However, real-life evaluation of MDD remains scarce. Our aim was to study the impact of a well-structured MDD on etiological assessment, diagnosis, and management of ILD. We collected and analysed all relevant data on patients concerning diagnosis and treatment before and after MDD during the year 2017. One hundred fifty patients were included in the analysis. MDD had a significant impact on management: 42% of diagnoses were revised and the number of unclassifiable ILD was significantly reduced. Lung biopsy was performed in 26 patients (12 cryobiopsies and 14 surgical biopsies). The most prevalent diagnoses were connective-tissue disease associated ILD (32%), idiopathic pulmonary fibrosis (23%), hypersensitivity pneumonitis (13%) and granulomatous ILD (7%). MDD led to a change or initiation of treatment in 55% of cases. Nine patients were evaluated for transplantation, 23 patients were screened for academic or sponsored clinical trials and an 8-fold increase in rehabilitation inclusion was observed. Our results confirm the benefits of MDD on ILD management and diagnosis. MDD also facilitates access to non-pharmacological therapies and clinical trials.

Iatrogenic pulmonary lesions.

Treatment of patients often includes the administration of medications and sometimes radiation. While the intent is to treat an underlying condition, in some cases, adverse effects occur due to these agents. Most of these adverse effects are mild, however, some can be severe and life-threatening. Furthermore, while these effects are often reversible upon cessation of exposure, especially if the inciting agent is recognized and withdrawn early, others might be permanent or even progressing. Most common histopathologic findings in drug-induced interstitial lung disease include nonspecific interstitial pneumonia (cellular and/or fibrotic), organizing pneumonia with or without bronchiolitis, eosinophilic pneumonia, pulmonary edema, diffuse alveolar damage, hypersensitivity pneumonitis, granulomatous interstitial lung disease, chronic bronchiolitis, and pulmonary hemorrhage. Pulmonary vascular changes or constrictive bronchiolitis can also occur. Drugs that are more commonly associated with lung toxicity include nitrofurantoin, amiodarone, and chemotherapeutic agents such as bleomycin and methotrexate. More recently introduced immune modulating agents including rituximab and immune checkpoint inhibitors such as anti-CTLA4, anti-PD-1 and anti-PD-L1 agents have also been associated with adverse effects in the lung. Radiation therapy to the chest can trigger acute or chronic lung toxicity. While newer radiation techniques are aimed to decrease and minimize side effects other risk factors such as additional chemotherapy, oxygen, and older age may be rising. Foreign substances such as talc, hydrogel, and medical devices such as hydrophilic polymer coated catheter may rarely also lead to pulmonary complications. It is important that clinicians and pathologists are aware of these potential adverse effects of drugs, radiation and medical devices and raise the possibility of drug-induced lung toxicity after exclusion of other differential diagnoses. It is the role of the clinician to provide the pathologist with an appropriate drug history. Early intervention to a drug-induced lung toxicity might prevent progression of side effects and permanent changes.

Cryoprobe transbronchial lung biopsy: How we do it?

Transbronchial lung biopsy (TBLB) is commonly utilized for diagnosis of diffuse parenchymal lung diseases. TBLB has a high yield in granulomatous interstitial lung diseases like sarcoidosis, but small size of biopsies limits its utility in idiopathic interstitial pneumonia. Surgical lung biopsy provides large size tissue, but there is associated morbidity, longer hospital stay, the risk of air leak, and mortality. Cryoprobe-TBLB, a relatively newer diagnostic procedure, provides larger biopsies than TBLB that are usually crush artifact free and enable the pathologist to provide diagnosis with greater confidence. We describe our technique of performing cryoprobe-TBLB.

Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is the most common primary immunodeficiency of young adolescents and adults which also affects the children. The disease remains largely under-diagnosed in India and Southeast Asian countries. Although in majority of cases it is sporadic, disease may be inherited in a autosomal recessive pattern and rarely, in autosomal dominant pattern. Patients, in addition to frequent sino-pulmonary infections, are also susceptible to various autoimmune diseases and malignancy, predominantly lymphoma and leukemia. Other characteristic lesions include lymphocytic and granulomatous interstitial lung disease, and nodular lymphoid hyperplasia of gut. Diagnosis requires reduced levels of at least two immunoglobulin isotypes: IgG with IgA and/or IgM and impaired specific antibody response to vaccines. A number of gene mutations have been described in CVID; however, these genetic alterations account for less than 20% of cases of CVID. Flow cytometry aptly demonstrates a disturbed B cell homeostasis with reduced or absent memory B cells and increased CD21(low) B cells and transitional B cell populations. Approximately one-third of patients with CVID also display T cell functional defects. Immunoglobulin therapy remains the mainstay of treatment. Immunologists and other clinicians in India and other South East Asian countries need to be aware of CVID so that early diagnosis can be made, as currently, majority of these patients still go undiagnosed.

Bronchoalveolar Lavage and Other Methods to Define the Human Respiratory Tract Milieu in Health and Disease

During fiber-optic bronchoscopy (FOB), surface sampling of the human respiratory airways and alveolar unit can be done with bronchoalveolar lavage (BAL), plus selective sites can be brushed for cells and transbronchial biopsies made in adjacent tissue. This permits analysis of the respiratory tract's milieu in healthy normals, in those with disease, and in control subjects. These combined procedures have been an established approach for obtaining specimens for research and for clinical assessment for over four decades. However, now new less invasive sampling methods are emerging. This review emphasizes BAL and the cellular and noncellular components recovered in fluid that have contributed to improving knowledge of how the respiratory tree's innate immunity can protect, and how airway structures can become deranged and manifest disease. After a discussion of training for FOB and procedural issues, a spectrum of respiratory diseases studied with BAL is presented, including airway illness (asthma and chronic obstructive pulmonary disease), diffuse interstitial lung diseases [idiopathic pulmonary fibrosis, rheumatoid interstitial lung disease (ILD), granulomatous ILDs], lung infections, lung malignancy, and upper and lower tract airway problems. Some recent studies with exhaled breath condensate analyses are given.

Granulomatous interstitial lung disease in a long-term drug abuser

It is the habit of some drug consumers to dissolve the powder of crushed pills, intended for oral use, in water and inject this solution intravenously. Insoluble particles than obstruct pulmonary vessels causing microscopic pulmonary emboli. These foreign bodies migrate and penetrate into the perivascular space and interstitium, resulting in chronic inflammation and foreign body giant cell reaction. As a result of this a granulomatous interstitial fibrosis can develop, which has also been described as pulmonary talcosis. We are reporting the case of a 22 year old male with a history of long-term intravenous drug abuse. He presented to our hospital complaining of dyspnoea, cough and generalized weakness. We describe an extensive diagnostic process concluded by an open lung biopsy establishing a definitive diagnosis of this rare granulomatous lung disease. This case underlines the importance of a thorough diagnostic work up and the pathogenic potential of foreign material reaching the lung via blood circulation in amongst the differential diagnoses of interstitial lung diseases, especially occurring in this group of patients.

T cell activation profiles in different granulomatous interstitial lung diseases – a role for CD8+CD28null cells?

Lymphocytes play a crucial role in lung inflammation. Different interstitial lung diseases may show distinct lymphocyte activation profiles. The aim of this study was to examine the expression of a variety of activation markers on T lymphocyte subsets from blood and bronchoalveolar lavage fluid (BALF) of patients with different granulomatous interstitial lung diseases and healthy controls. Bronchoalveolar lavage cells and blood cells from 23 sarcoidosis patients, seven patients with hypersensitivity pneumonitis and 24 healthy controls were analysed. Lymphocyte activation status was determined by flow cytometry. Lymphocytes were stained with antibodies against CD3, CD4, CD8, CD25, CD28, CD69, very late antigen-1 (VLA)-1, VLA-4 and human leucocyte antigen D-related (HLA-DR). In general, CD28, CD69 and VLA-1 expression on BALF CD4+ lymphocytes and HLA-DR expression on BALF CD8+ lymphocytes was different in patients with hypersensitivity pneumonitis and sarcoidosis patients with parenchymal involvement. This BALF lymphocyte phenotype correlated with carbon monoxide diffusing lung capacity (Dlco) values across interstitial lung diseases (ILD) (r2 = 0.48, P = 0.0002). In sarcoidosis patients, CD8+CD28(null) blood lymphocytes correlated with lower Dlco values (r = -0.66, P = 0.004), chronic BALF lymphocyte activation phenotype (r2 = 0.65, P < 0.0001), radiographic staging (stage I versus stage II and higher, P = 0.006) and with the need for corticosteroid treatment (P = 0.001). Higher expression of CD69, VLA-1 and HLA-DR and lower expression of CD28 on BALF lymphocytes suggests prolonged stimulation and chronic lymphocyte activation in patients with ILD. In sarcoidosis, blood CD8+CD28(null) cells might be a new biomarker for disease severity but needs further investigation.

Pathogenesis and treatment of hypersensitivity pneumonitis

Hypersensitivity pneumonitis (HP) is a granulomatous interstitial lung disease resulting from an immunologic reaction to the repeated inhalation of organic dusts and active chemicals. There are 50 or more groups of HP, but the prevalence varies from country to country, and even within a country, depending on a variety of occupational or environmental inhalants. In Western coutries farmer's lung, bird fancier's disease, humidifier lung, and air-conditioner disease are common, but in Japan summer-type HP is the most prevalent group. Summer-type HP is a house-related illnes induced by Trichosporon asahii and Trichosporon mucoides which contaminate the patients' home environments in hot and humid conditions. The polysaccharide antigen contains mannan backbone attached with short side chains consi-sting of mannose, xylose, and glucuronic acid residues. Both immune complex-mediated and T cell-mediated immune responses to the yeast are involved in the induction and development of the disease. Host factors such as HLA-DQw3 and cigarette smoking also play an important role in the develop-ment or suppression of the disease. An assay for serum anti-Trichosporon antibody by a Triko Kit is very useful for the serodiagnosis, and sanitization by cleaning, disinfecting, and removing from the colonizing location of Trichosporon prevents recurrence of the disease. Summer-type HP induced by Trichosporon is a new type of HP. It can be found in other countries including most Western countries, because Trichosporon asahii and Trichosporon mucoides distribute in the temperate and subtropical areas of the world.

Serum Angiotensin-Converting Enzyme Activity, Concentration, and Specific Activity in Granulomatous Interstitial Lung Disease, Tuberculosis, and COPD

Angiotensin-converting enzyme (ACE) activity in serum is used as an aid to the diagnosis and follow-up of patients with sarcoidosis. A theoretical limitation of measurements of activity is that these may be affected by the presence of pharmacologic or endogenous inhibitors of ACE. Immunoassays of ACE concentration avoid this problem and, when combined with tests of ACE activity, permit calculation of specific activity of ACE. In this study, we set out to develop a sensitive radioimmunoassay for ACE to compare results obtained with this method with results of ACE activity and calculated ACE specific activity in patients suffering from a variety of lung diseases. In a group of control subjects (n = 32), the ACE concentration was 453.7 +/- 159.8 (SD) ng/mL; 95% confidence interval (CI), 398.34 to 509.06, but levels were significantly elevated in sarcoidosis (979.3 +/- 558.6 ng/mL; 95% CI, 827.5 to 1,131.1; n = 51; p < 0.001 vs control subjects), silicosis (646.5 +/- 239.1 ng/mL; 95% CI, 544.2 to 748.8; n = 21; p < 0.01), and miliary tuberculosis (647.0 +/- 217.1 ng/mL; 95% CI, 551.9 to 742.1; n = 29; p < 0.01). The levels were normal in COPD, interstitial pulmonary fibrosis, and active cavitary pulmonary tuberculosis. The overall correlation between ACE activity and concentration measurements was strong (r = 0.93). No evidence of endogenous ACE inhibition was observed in any of the disease categories studied except in COPD where an elevation of ACE specific activity was observed, raising the possibility that in this condition different isozymes of ACE with higher specific activity might be released.