Longitudinal changes in serum immunoglobulin G testing in patients with fibrotic avian hypersensitivity pneumonitis.

BACKGROUND: Evaluation of the antigen responsible for fibrotic hypersensitivity pneumonitis (HP) is challenging. Serum immunoglobulin (Ig) G testing against HP-associated antigens is performed. Although single-serum IgG testing has been investigated, multiple-serum IgG testing has not yet been studied. METHODS: This study included patients who underwent histopathological examination and positive inhalation challenge test as well as those with moderate or high HP guideline confidence level. Serum IgG testing against pigeon serum was conducted twice using two methods: enzyme linked-immunosorbent assay (ELISA) and ImmunoCAP. The association between changes in serum IgG antibody titers and changes in forced vital capacity (FVC) and other parameters was investigated. RESULTS: In this study, 28 patients (mean age, 64.5 years; mean FVC, 85.3%) with fibrotic avian HP were selected, of whom 20 and 8 underwent surgical lung biopsy and transbronchial lung cryobiopsy, respectively. Of the 28 patients, 19 had been keeping birds for more than 6 months. A correlation was observed between the annual changes in serum IgG antibody titers by ELISA and changes in relative FVC (r = - 0.6221, p < 0.001). Furthermore, there was a correlation between the annual changes in serum IgG antibody titers by ImmunoCAP and changes in relative FVC (r = - 0.4302, p = 0.022). Multiple regression analysis revealed that the change in serum IgG antibody titers by both ELISA and ImmunoCAP also influenced the relative FVC change (p = 0.012 and p = 0.015, respectively). Moreover, 13 patients were given additional treatments between the first and second blood test; however, the additional treatment group was not significantly different in relative FVC change compared to the group with no additional treatment (p = 0.982). CONCLUSIONS: In patients with fibrotic avian HP, the annual changes in serum IgG testing were correlated with FVC changes, highlighting the importance of serum IgG testing over time.

Serum levels of IgG antibodies against Aspergillus fumigatus and the risk of hypersensitivity pneumonitis and other interstitial lung diseases.

Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) caused by the inhalation of antigens. Antigen-specific IgG antibodies (sIgG) are used as biomarkers of exposure when diagnosing HP, but little is known about the longitudinal relation between antibody levels and risk of HP or other ILD. In a follow-up design, we explored the relationship between sIgG antibodies against Aspergillus fumigatus and the diagnosis of HP in 647 subjects suspected of HP. We showed that IgG levels above the reference value resulted in a hazard ratio of 9.5 for subsequent HP. Our findings support a relationship between high levels of sIgG against A. fumigatus and risk of HP.

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.

Waterproofing spray-associated pneumonitis review: Comparison with acute eosinophilic pneumonia and hypersensitivity pneumonitis.

ABSTRACT: Waterproofing spray-associated pneumonitis (WAP) proceeds to acute respiratory failure and is characterized by diffuse bilateral ground-glass opacities on computed tomography; however, the detailed characteristics of WAP are unknown. Therefore, this study identified the characteristics of WAP from comparisons with those of acute eosinophilic pneumonia (AEP) and hypersensitivity pneumonitis (HP), which show similar features to WAP.Adult patients with WAP, AEP, and HP treated in Fukujuji Hospital from 1990 to 2018 were retrospectively enrolled. Furthermore, data from patients with WAP were collected from publications in PubMed and the Japan Medical Abstracts Society and combined with data from our patients.Thirty-three patients with WAP, eleven patients with AEP, and thirty patients with HP were reviewed. Regarding age, sex, smoking habit, and laboratory findings (white blood cell count, C-reactive protein level, and serum Krebs von den Lungen-6 level), WAP and AEP were not significantly different, while WAP and HP were significantly different. The duration from symptom appearance to hospital visit was shorter in patients with WAP (median 1 day) than in patients with AEP (median 3 days, P = .006) or HP (median 30 days, P < .001). The dominant cells in the bronchoalveolar lavage fluid of patients with WAP, AEP, and HP were different (macrophages, eosinophils, and lymphocytes, respectively).The characteristic features of WAP were rapid disease progression and macrophage dominance in the bronchoalveolar lavage fluid, and these characteristics can be used to distinguish among WAP, AEP, and HP.

Questionnaires or Serum Immunoglobulin G Testing in the Diagnosis of Hypersensitivity Pneumonitis among Patients with Interstitial Lung Disease.

Rationale: Hypersensitivity pneumonitis (HP) results from exposure to a variety of stimuli, which are challenging to identify. Questionnaires and serum immunoglobulin G (IgG) testing are methods to identify potentially causative exposures.Objectives: To perform a systematic review to determine the usefulness of questionnaires and serum IgG testing in identifying exposures that may have caused HP.Methods: This systematic review informed an international, multidisciplinary panel that developed a clinical practice guideline on the diagnosis of HP for the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax. MEDLINE, the Cochrane Library, and EMBASE were searched from January 1946 to October 2019 for studies that used a questionnaire or serum IgG testing to identify exposures that may have caused HP. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to appraise the quality of the evidence.Results: Searches identified 1,141 and 926 potentially relevant articles for questionnaires and serum IgG testing, respectively. The full texts of 32 and 49 articles, respectively, were reviewed. Two observational studies for questionnaires and 15 accuracy studies for serum IgG testing were selected. Questionnaires were better at detecting potentially relevant exposures than clinical history (100% vs. 26%; risk ratio [RR], 3.80; 95% confidence interval [95% CI], 1.79-8.06) and serum IgG testing (100% vs. 63%; RR, 1.58; 95% CI, 1.12-2.23) but did not differ from serum IgG testing plus bronchial challenge testing (59% vs. 65%; RR, 0.90; 95% CI, 0.65-1.24). Longer, detailed questionnaires were more likely to lead to identification of potential exposures. Only 70% of potential exposures identified by questionnaires were subsequently confirmed by environmental testing. Serum IgG testing distinguished HP from healthy exposed and unexposed control subjects with high sensitivity (90% and 92%, respectively) and high specificity (91% and 100%, respectively) but did not distinguish HP as effectively from interstitial lung diseases (ILDs; sensitivity of 83% and specificity of 68%).Conclusions: Using a questionnaire may help clinicians identify potentially relevant exposures when evaluating a patient with newly identified ILD for HP. Serum IgG testing may also lead to identification of potentially relevant exposures, but its usefulness for distinguishing HP from other types of ILD is poor.

The Transcription Factor SCX is a Potential Serum Biomarker of Fibrotic Diseases.

Fibrosing diseases are causes of morbidity and mortality around the world, and they are characterized by excessive extracellular matrix (ECM) accumulation. The bHLH transcription factor scleraxis (SCX) regulates the synthesis of ECM proteins in heart fibrosis. SCX expression was evaluated in lung fibroblasts and tissue derived from fibrotic disease patients and healthy controls. We also measured SCX in sera from 57 healthy controls, and 56 Idiopathic Pulmonary Fibrosis (IPF), 40 Hypersensitivity Pneumonitis (HP), and 100 Systemic Sclerosis (SSc) patients. We report high SCX expression in fibroblasts and tissue from IPF patients versus controls. High SCX-serum levels were observed in IPF (0.663 ± 0.559 ng/mL, p < 0.01) and SSc (0.611 ± 0.296 ng/mL, p < 0.001), versus controls (0.351 ± 0.207 ng/mL) and HP (0.323 ± 0.323 ng/mL). Serum levels of the SCX heterodimerization partner, TCF3, did not associate with fibrotic illness. IPF patients with severely affected respiratory capacities and late-stage SSc patients presenting anti-topoisomerase I antibodies and interstitial lung disease showed the highest SCX-serum levels. SCX gain-of-function induced the expression of alpha-smooth muscle actin (α-SMA/ACTA2) in fibroblasts when co-overexpressed with TCF3. As late and severe stages of the fibrotic processes correlated with high circulating SCX, we postulate it as a candidate biomarker of fibrosis and a potential therapeutic target.

Age-associated B Cells Appear in Patients with Granulomatous Lung Diseases.

Rationale: A subpopulation of B cells (age-associated B cells [ABCs]) is increased in mice and humans with infections or autoimmune diseases. Because depletion of these cells might be valuable in patients with certain lung diseases, the goal was to find out if ABC-like cells were at elevated levels in such patients.Objectives: To measure ABC-like cell percentages in patients with lung granulomatous diseases.Methods: Peripheral blood and BAL cells from patients with sarcoidosis, beryllium sensitivity, or hypersensitivity pneumonitis and healthy subjects were analyzed for the percentage of B cells that were ABC-like, defined by expression of CD11c, low levels of CD21, FcRL 1-5 (Fc receptor-like protein 1-5) expression, and, in some cases, T-bet.Measurements and Main Results: ABC-like cells in blood were at low percentages in healthy subjects and higher percentages in patients with sarcoidosis as well as at high percentages among BAL cells of patients with sarcoidosis, beryllium disease, and hypersensitivity pneumonitis. Treatment of patients with sarcoidosis led to reduced percentages of ABC-like cells in blood.Conclusions: Increased levels of ABC-like cells in patients with sarcoidosis may be useful in diagnosis. The increase in percentage of ABC-like cells in patients with lung granulomatous diseases and decrease in treated patients suggests that depletion of these cells may be valuable.

A 78-Year-Old Man With Repeated Dyspnea and Neutrophilia in Peripheral Blood and BAL.

CASE PRESENTATION: A 78-year-old man with asthma and COPD presented with shortness of breath, cough, and severe malaise for 4 days. Upon arrival, the patient was conscious and body temperature was 37.5°C. Arterial oxygen saturation (Spo2) was 80% on room air. Laboratory data demonstrated a WBC count of 17,400/µL (89.5% neutrophils) and C-reactive protein of 5.00 mg/dL. CT scan of chest revealed scattered ground-glass in the upper right lobe and thickening of the bronchial wall. Based on these findings, acute bronchopneumonia was diagnosed and antibacterial therapy was started. The day after admission, the patient's general condition and shortness of breath had gradually improved. We treated and observed him carefully for 10 days in the hospital on antibacterial therapy because of his underlying comorbidities (asthma and COPD) and his ongoing hypoxemia. Three days after discharge, the patient re-presented with shortness of breath, hypoxemia, and loss of appetite. The patient was hospitalized for a second time.

Change in Serum Biomarker CA 15-3 as an Early Predictor of Response to Treatment and Survival in Hypersensitivity Pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis (HP) is an interstitial lung disease with a heterogeneous course of disease and treatment response. Cancer antigen 15-3 (CA 15-3), part of mucin 1, is believed to reflect epithelial cell injury and lung permeability and could be a potential biomarker for treatment response in HP. OBJECTIVE: To assess the value of CA 15-3 as a predictive biomarker in non-fibrotic and fibrotic HP during immunosuppressive therapy. DESIGN: Serum levels of CA 15-3 and pulmonary function tests (PFTs) were retrospectively retrieved from 48 HP patients treated with prednisone or cyclophosphamide at initiation of therapy (baseline), after 3 and 6 months. Pearson's correlation coefficient was computed to assess correlations between change in serum levels and PFT. Survival was evaluated using Kaplan-Meier curves. RESULTS: After 6 months of immunosuppressive therapy CA 15-3 levels decreased significantly compared to baseline (p = 0.001). Change in CA 15-3 after 6 months correlated with FVC change (r = - 0.469; p = 0.001). Correlations with FVC change were observed in prednisone-treated HP (r = - 0.514; p = 0.005) and fibrotic HP (r = - 0.417; p = 0.007). Three-month CA 15-3 change correlated with 6-month FVC change (r = - 0.599; p < 0.001). CA 15-3 declines of at least 7.9% after 6 months were associated with increased survival compared to minor CA 15-3 changes (HR 0.34; p = 0.020). CONCLUSION: Serum CA 15-3 correlates with PFT during 6 months of immunosuppressive therapy in HP. Interestingly, early CA 15-3 changes could predict future PFT. Furthermore, a decrease in CA 15-3 is related to longer survival. Therefore, serum CA 15-3 is a promising biomarker for implementation in HP care.

Serum CXCL9 and CCL17 as biomarkers of declining pulmonary function in chronic bird-related hypersensitivity pneumonitis.

The clinical course of chronic hypersensitivity pneumonitis (HP) with fibrosis is similar to that of idiopathic pulmonary fibrosis (IPF). Current research is expected to identify biomarkers effective in predicting the deterioration of lung function in a clinical setting. Our group analyzed the relationships between the following parameters in chronic bird-related HP: patient characteristics, serum markers, lung function, HRCT findings, BALF profiles, and the worsening of lung function. We also analyzed serum levels of CXCL9, CCL17, and Krebs von den Lungen 6 (KL-6) as serum markers. Patients showing declines in vital capacity (VC) of over 5% at 6 months after first admission were categorized as the "decline group"; the others were categorized as the "stable group." The serum level of CCL17 and the percentage of BALF macrophages were significantly higher in the decline group compared to the stable group. Serum levels of CXCL9 and CCL17 were significant variables in a multivariate logistic regression analysis of factors associated with VC decline. Patients with a chemokine profile combining lower serum CXCL9 and higher serum CCL17 exhibited significantly larger VC decline in a cluster analysis. Higher serum CCL17 and lower serum CXCL9 were important predictors of worsening lung function in patients with chronic bird-related HP.

The Its Not JUST Idiopathic pulmonary fibrosis Study (INJUSTIS): description of the protocol for a multicentre prospective observational cohort study identifying biomarkers of progressive fibrotic lung disease.

Introduction: The Its Not JUST Idiopathic pulmonary fibrosis Study (INJUSTIS) is a multicentre, prospective, observational cohort study. The aims of this study are to identify genetic, serum and other biomarkers that may identify specific molecular mechanisms, reflecting disease endotypes that are shared among patients with progressive pulmonary fibrosis regardless of aetiology. Furthermore, it is anticipated that these biomarkers will help predict fibrotic activity that may identify patterns of disease behaviour with greater accuracy than current clinical phenotyping. Methods and analysis: 200 participants with the multidisciplinary team confirmed fibrotic lung disease (50 each of rheumatoid-interstitial lung disease (ILD), asbestosis, chronic hypersensitivity pneumonitis and unclassifiable ILD) and 50 idiopathic pulmonary fibrosis participants, recruited as positive controls, will be followed up for 2 years. Participants will have blood samples, lung function tests, quality of life questionnaires and a subgroup will be offered bronchoscopy. Participants will also be given the option of undertaking blinded home handheld spirometry for the first 3 months of the study. The primary end point will be identification of a biomarker that predicts disease progression, defined as 10% relative change in forced vital capacity (FVC) or death at 12 months. Ethics and dissemination: The trial has received ethical approval from the National Research Ethics Committee Nottingham (18/EM/0139). All participants must provide written informed consent. The trial will be overseen by the INJUSTIS steering group that will include a patient representative, and an independent chairperson. The results from this study will be submitted for publication in peer-reviewed journals and disseminated at regional and national conferences. Trial registration number: NCT03670576.

Serum AGE/RAGEs as potential biomarker in idiopathic pulmonary fibrosis.

BACKGROUND: The soluble receptor for advanced glycation end-products (sRAGE) has been suggested that it acts as a decoy for capturing advanced glycation end-products (AGEs) and inhibits the activation of the oxidative stress and apoptotic pathways. Lung AGEs/sRAGE is increased in idiopathic pulmonary fibrosis (IPF). The objective of the study was to evaluate the AGEs and sRAGE levels in serum as a potential biomarker in IPF. METHODS: Serum samples were collected from adult patients: 62 IPF, 22 chronic hypersensitivity pneumonitis (cHP), 20 fibrotic non-specific interstitial pneumonia (fNSIP); and 12 healthy controls. In addition, 23 IPF patients were re-evaluated after 3-year follow-up period. Epidemiological and clinical features were recorded: age, sex, smoking habits, and lung function. AGEs and sRAGE were evaluated by ELISA, and the results were correlated with pulmonary functional test values. RESULTS: IPF and cHP groups presented a significant increase of AGE/sRAGE serum concentration compared with fNSIP patients. Moreover, an inverse correlation between AGEs and sRAGE levels were found in IPF, and serum sRAGE at diagnosis correlated with FVC and DLCO values. Additionally, changes in serum AGEs and sRAGE correlated with % change of FVC, DLCO and TLC during the follow-up. sRAGE levels below 428.25 pg/ml evolved poor survival rates. CONCLUSIONS: These findings demonstrate that the increase of AGE/sRAGE ratio is higher in IPF, although the levels were close to cHP. AGE/sRAGE increase correlates with respiratory functional progression. Furthermore, the concentration of sRAGE in blood stream at diagnosis and follow-up could be considered as a potential prognostic biomarker.

Mimicking hypersensitivity pneumonitis as an uncommon initial presentation of chronic granulomatous disease in children.

Dry cough, dyspenea and diffuse centrilobular nodules in both lungs of radiologic findings similar to hypersensitivity pneumonitis (HP) are rare initial presentation in chronic granulomatous disease (CGD). CGD is remarkable for increased susceptibility to bacterial and fungal infections as well as high sensitivity to inciting antigens such as Aspergillus species due to dysregulated inflammation. We identified three children who had an initial presentation mimicking HP and were subsequently diagnosed as CGD. All patients developed invasive pulmonary A. fumigatus infection (IPAI) following systemic glucocorticoid therapy. Two of the three patients were found to have mutations in NCF1 gene and one patient in NCF2 gene. As HP is uncommon in children, we should consider the possibility of CGD in children with HP, even in mimicking HP patients with suggestive inhalation history and negative fungal cultures. A prompt diagnosis of CGD is essential to enable initiation of prophylactic antibacterial and antifungal therapies.

The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study.

BACKGROUND: Patients with hypersensitivity pneumonitis are at risk of developing pulmonary fibrosis, which is associated with reduced survival. In families with multiple affected members, individuals might be diagnosed as having idiopathic pulmonary fibrosis (IPF) or chronic (fibrotic) hypersensitivity pneumonitis, which suggests these disorders share risk factors. We aimed to test whether the genomic risk factors associated with the development and progression of IPF are also associated with the development of fibrosis and reduced survival in people with chronic hypersensitivity pneumonitis. METHODS: We did an observational study of two independent cohorts of patients with chronic hypersensitivity pneumonitis, one from the University of California San Francisco, CA, USA (UCSF), and one from the University of Texas Southwestern, TX, USA (UTSW). We measured two common single-nucleotide polymorphisms associated with IPF (MUC5B rs35705950 and TOLLIP rs5743890) and telomere length in peripheral blood leucocytes, and assessed their associations with chronic hypersensitivity pneumonitis risk, survival, and clinical, radiographic, and pathological features. We compared findings with those in patients with IPF from the UCSF and UTSW cohorts, and healthy controls from the European population of the 1000 Genomes Project Phase 3, version 1. FINDINGS: The cohorts included 145 patients from UCSF and 72 from UTSW. The minor allele frequency (MAF) was greater for MUC5B rs35705950 in patients with chronic hypersensitivity pneumonitis than in healthy controls (24·4% in UCSF and 32·3% in UTSW vs 10·7%, both p<0·0001), but not for TOLLIP rs5743890. The MAFs were similar to those for IPF (UCSF 33·3%, p=0·09; UTSW 32·0%, p=0·95). In the combined UCSF and UTSW chronic hypersensitivity pneumonitis cohort, we saw associations between extent of radiographic fibrosis and MUC5B rs35705950 minor alleles (adjusted odds ratio [OR] 1·91, 95% CI 1·02-3·59, p=0·045) and short telomere length (adjusted OR per unit change in mean natural logarithm-transformed ratio of telomere repeat copy number to single gene copy number 0·23, 0·09-0·59, p=0·002). Telomere length less than the tenth percentile for age was also significantly associated with reduced survival (log-rank p=0·006). INTERPRETATION: The associations between MUC5B rs35705950 and short telomere length with extent of fibrosis, histopathological features of usual interstitial pneumonia, and reduced survival in patients with chronic hypersensitivity pneumonitis suggest shared pathobiology with IPF, and might help to stratify risk. FUNDING: National Institutes of Health and Nina Ireland Program for Lung Health.

Blood-Injection-Injury (B-I-I) Specific Phobia Affects the Outcome of Hypoxic Challenge Testing.

BACKGROUND: Blood-injection-injury (B-I-I) phobia is capable of producing inaccurate hypoxic challenge testing results due to anxiety-induced hyperventilation. CASE REPORT: A 69-yr-old woman with a history of hypersensitivity pneumonitis, restrictive spirometry, exercise desaturation requiring supplementary oxygen on mobilizing, reduced DLco, and B-I-I phobia was referred for hypoxic challenge testing (HCT) to assess in-flight oxygen requirements. HCT was performed by breathing a 15% FIo2 gas mixture, simulating the available oxygen in ambient air onboard aircraft pressurized to an equivalent altitude of 8000 ft. Spo2 fell to a nadir value of 81% during HCT, although it rapidly increased to 89% during the first of two attempts at blood gas sampling. A resultant blood gas sample showed an acceptable Po2 outside the criteria for recommending in-flight oxygen and a reduced Pco2. Entering the nadir Spo2 value into the Severinghaus equation gives an estimated arterial Po2 of 6 kPa (45 mmHg), which was felt to be more representative of resting values during HCT, and in-flight oxygen was recommended. DISCUSSION: While hyperventilation is an expected response to hypoxia, transient rises in Spo2 coinciding with threat of injury are likely to be attributable to emotional stress-induced hyperventilation, characteristic of B-I-I specific phobia and expected during the anticipation of exteroceptive threat, even in normal subjects. In summary, should excessive hyperventilation be detected during HCT and coincide with transient increases in Spo2, HCT should be repeated using Spo2 only as a guide to the level of hypoxemia, and Spo2 maintained using supplementary oxygen in accordance with alternative methods described in guidelines.Spurling KJ, McGoldrick VP. Blood-injection-injury (B-I-I) specific phobia affects the outcome of hypoxic challenge testing. Aerosp Med Hum Perform. 2017; 88(5):503-506.

Serum YKL-40 as predictor of outcome in hypersensitivity pneumonitis.

YKL-40, a chitinase-like protein mainly secreted by macrophages, neutrophils and epithelial cells, is increased in patients with idiopathic interstitial pneumonia and sarcoidosis. We aimed to investigate the role of YKL-40 as a biomarker in hypersensitivity pneumonitis (HP).72 HP patients, 100 interstitial lung disease (ILD) controls and 60 healthy controls were studied. YKL-40 was measured by ELISA in serum and bronchoalveolar lavage fluid (BALF) at baseline and follow-up. The relationship between YKL-40 levels, clinical variables and disease outcome was evaluated.Baseline serum YKL-40 levels were significantly higher in HP patients than in healthy controls (p<0.001), but lower than in patients with other ILDs. Baseline BALF YKL-40 levels in HP patients were the highest among ILD patients. In HP patients, serum YKL-40 correlated with the diffusing capacity of the lung for carbon monoxide at baseline (p<0.01) and over time (p<0.001). HP patients whose disease progressed or who died had higher baseline YKL-40 levels than those who remained stable and survived (p<0.001). At a cut-off of 119 ng·mL-1, the baseline serum YKL-40 level predicted disease progression (hazard ratio 6.567; p<0.001), and at a cut-off of 150 ng·mL-1 was associated with mortality (hazard ratio 9.989; p<0.001).Serum YKL-40 may be a useful prognostic biomarker in HP patients.

Fungal peptides from pneumonitis hypersensitivity etiologic agents are able to induce specific cellular immune response.

PURPOSE: Hypersensitivity pneumonitis (HP) is an immunoallergic disease due to chronic exposure to high quantities of different microorganisms such as Mycobacterium immunogenum (Mi), a mycobacterium, and Lichtheimia corymbifera (Lc), a filamentous fungus. It has recently been demonstrated that the protein DLDH (dihydrolipoyl dehydrogenase), is common to these microorganisms. This study aimed to investigate the immune potential of overlapping peptide pools covering the MiDLDH and LcDLDH. EXPERIMENTAL DESIGN: A selection of 34 peptides, from the MiDLDH and LcDLDH, able to interact with Major Histocompatibility Complex (MHC) 1 and MHC 2, was obtained using three different epitope prediction websites. By means of ELISPOT assays, we compared the frequency of Interferon gamma (IFNγ) secreting peripheral blood mononuclear cells (PBMC) after stimulation with overlapping peptide pools. Tests were performed using cells from 35 healthy blood donors. RESULTS: One peptide pool containing five peptides from MiDLDH and able to interact with MHC 2 induced a marked IFNγ specific immune response (Pool F, p<0.001, Wilcoxon signed-rank test). CONCLUSION: This study demonstrated that peptides from microorganisms involved in HP were able to induce a high IFNγ specific immune response after stimulation of PBMCs from healthy blood donors which could be useful to develop an effective prevention strategy.

[The expression and clinical role of KL-6 in serum and BALF of patients with different diffuse interstitial lung diseases].

OBJECTIVE: To detect the levels of KL-6 in the serum and the bronchoalveolar lavage fluid (BALF) of patients with different type of diffuse interstitial lung diseases(DILD), and to analyze its correlation with pulmonary function, pulmonary HRCT scores and other parameters. METHOD: Seventy-three patients with DILD were enrolled, including 34 patients with idiopathic pulmonary fibrosis (IPF), 10 patients with stage Ⅰ sarcoidosis(SAR Ⅰ), 15 patients with hypersensitivity pneumonia (HP), 14 patients with connective tissue diseases (CTD). Enzyme-linked immune sorbent assay (ELISA) was used to detect the levels of KL-6 in the serum and the BALF of these patients. RESULTS: In the IPF group, FVC predicted percentage and DLCO predicted percentage were significantly lower than those of the SAR Ⅰ group[(70±14)% vs (82±6)%, (49±13)% vs(81±6)%, P<0.05], but were no different compared to the CTD-ILD group(P>0.05). In the IPF group, the percentage of neutrophils in BALF was higher than that of the SAR Ⅰ group[(9±7)% vs (6±4)%, P<0.05]], and the percentage of lymphocytes and CD4/CD8 ratio in BALF were lower than those of the SAR Ⅰ group[(12±7)% vs (23±13)%, (1.5±0.8) vs(4.0±5.1), P<0.05]. In the IPF group, the level of KL-6 in serum was higher than that of the SAR Ⅰ and the HP group[(858±516)U/ml vs (339±168)U/ml, (553±287)U/ml, P<0.05], but was no different compared to the CTD-ILD group (P>0.05). In the CTD-ILD group, the level of KL-6 in serum was higher than that of the SAR Ⅰ [(687±350) U/ml vs (339±168)U/ml, P<0.05]]. In the IPF group, the level of KL-6 in BALF was (437±252)U/ml, and was higher than that of other 3 groups(P<0.05). In the IPF group, the level of serum KL-6 was negatively correlated with FVC and DLCO(r=-0.46, -0.58, P<0.01), the level of serum KL-6 was positively correlated with pulmonary HRCT reticular pattern and honeycombing scores(r=0.62, 0.41, P<0.05). CONCLUSIONS: In patients with IPF, the levels of KL-6 in serum and BALF were increased and the level of KL-6 in serum was correlated with FVC, DLCO and pulmonary HRCT reticular pattern and honeycombing scores.KL-6 may be a marker for the diagnosis of IPF.