Role of serum surfactant protein-D as a prognostic predictor in fibrotic hypersensitivity pneumonitis

BackgroundSerum Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) are candidate diagnostic and activity markers for fibrotic hypersensitivity pneumonitis (HP), although their correlation with prognosis remains unclear. We aimed to evaluate the prognostic usefulness of serum KL-6 and SP-D in patients with fibrotic HP.MethodsThis was a retrospective medical record review of 185 patients with fibrotic HP at a single center from 2005 to 2019. The baseline and minimum serum KL-6 and SP-D levels over two years were recorded. The contribution of KL-6 and SP-D levels to the incidence of progressive fibrosing interstitial lung disease (PF-ILD) and mortality were evaluated using multivariate analysis.ResultsThe respective baseline and minimum levels were 1441 and 808 U/ml for KL-6 and 254 and 132 ng/mL for SP-D. A high minimum SP-D level was significantly associated with a high incidence of PF-ILD by logistic regression, independent of baseline forced vital capacity and honeycombing. Similarly, a high minimum SP-D level was significantly associated with high mortality by Cox proportional hazard model analysis. The stratified minimum SP-D levels of <100, 100–200, and >200 revealed significantly distinct groups in the entire cohort, with PF-ILD incidence rates of 28%, 48%, and 74% and median survival times of 120, 74, and 45 months, respectively.ConclusionsHigh minimum SP-D levels over two years were correlated with an unfavorable prognosis in our cohort. Patient with consistently high SP-D levels during the clinical course may have a poor prognosis and be a candidate for early treatment intensification.     

Leukemic pneumonitis as a poor prognostic factor in chronic myelomonocytic leukemia.

We report the case of a 69-year-old man with chronic myelomonocytic leukemia (CMML) that was complicated by fatal respiratory failure. Bilateral pulmonary infiltrates were demonstrated by chest roentgenograms and worsened with an increase in the leukocyte count. Postmortem examination confirmed the presence of leukemic monocyte infiltration of the pulmonary interstitial spaces. In CMML with marked monocytosis, respiratory failure may be one of the important causes of death in addition to infection and bleeding.     

Clinical utility of a standardized chronic hypersensitivity pneumonitis exposure questionnaire

Background and Objective

Identification of an exposure is integral to the diagnosis, management, and prognostication of chronic hypersensitivity pneumonitis (CHP). Standardized questionnaires may aid in the identification of exposures, however, there currently are no evidence-based patient-validated questionnaires available. Key qualifiers (including duration and frequency) which indicate exposure relevance are also poorly defined. This study assessed the use of a standardized CHP exposure questionnaire in the identification of exposures and diagnostic confidence of CHP.

Methods

People with a multi-disciplinary meeting (MDM) diagnosis from five Australian interstitial lung disease (ILD) expert centres who provided informed consent were included. Participants completed a previously developed standardized CHP Exposure Questionnaire. Responses were collected with the participant's MDM data, including diagnosis, diagnostic confidence, and clinician-elicited exposures.

Results

One hundred thirty participants (IPF = 58, CHP = 24, CTD-ILD = 17, unclassifiable = 19, other = 12) were included. In 33% of CHP participants, a standardized questionnaire elicited an exposure where the clinician did not. 63% of these had provisional low confidence CHP; and an exposure history would have increased the diagnostic confidence in these cases. Using the standardized questionnaire, 96% of CHP participants reporting any exposure, compared with 75% of non-HP ILD participants. CHP participants were 3.5 times more likely (p = 0.004) to report their symptoms improved on avoidance, and 2.3 times more likely (p = 0.018) to report daily frequent exposure, compared with non-HP ILDs.

Conclusion

A standardized questionnaire which elicits exposure characteristics in addition to presence or absence of relevant exposures can increase the diagnostic confidence of CHP and reduce the proportion of antigen-indeterminate CHP.     

Clubbing in hypersensitivity pneumonitis. Its prevalence and possible prognostic role

To know the prevalence and prognostic significance of finger clubbing in hypersensitivity pneumonitis induced by avian antigen, this physical sign was evaluated in 82 patients who were followed up from 1 to 5 years (mean, 2.6 years). According to clinical, roentgenographic, and functional criteria, the patients were classified in one of three stages at admission as well as at least 1 year later. Digital clubbing was retrospectively recorded as present or absent by physical examination. Our results showed that 44 patients (51%) included in this study presented clubbing at the time of diagnosis. Sixteen of these patients presented with worsening of their lung disease, whereas only 5 of the 38 patients without clubbing incurred a worsening of their condition. This finding suggests that digital clubbing is frequent in pigeon breeder's disease and may help to predict clinical deterioration.     

Periostin as a predictor of prognosis in chronic bird-related hypersensitivity pneumonitis

BackgroundPeriostin is an established biomarker of Th2 immune response and fibrogenesis. Recent research has indicated that periostin plays an important role in the pathogenesis of idiopathic interstitial pneumonias. To clarify the relationship between periostin and pathogenesis in chronic bird-related hypersensitivity pneumonitis (HP) and to reveal the usefulness of serum periostin levels in diagnosing and managing chronic bird-related HP.MethodsWe measured serum periostin in 63 patients with chronic bird-related HP, 13 patients with idiopathic pulmonary fibrosis, and 113 healthy volunteers. We investigated the relationship between serum periostin and clinical parameters, and evaluated if the baseline serum periostin could predict the prognosis.ResultsSerum periostin was significantly higher in patients with chronic bird-related HP compared to the healthy volunteers. In chronic bird-related HP, serum periostin had significant positive correlations with serum KL-6 levels, the CD4/CD8 ratio in bronchoalveolar lavage fluid, and fibrosis score on HRCT, and a significant negative correlation with the diffusing capacity of the lungs for carbon monoxide. Chronic bird-related HP patients with serum periostin levels exceeding ≥92.5 ng/mL and ≥89.5 ng/mL had a significantly worse prognosis and significantly higher frequency of acute exacerbation, respectively. Higher serum periostin (92.5 ng/mL or higher; binary response for serum periostin) was an independent prognostic factor in multivariate analysis.ConclusionsSerum periostin may reflect the extent of lung fibrosis and play an important role in pathogenesis of chronic bird-related HP. Elevated serum periostin could be a predictor of prognosis in patients with chronic bird-related HP.     

Recent advances in hypersensitivity pneumonitis

Hypersensitivity pneumonitis (HP) is a pulmonary disease with symptoms of dyspnea and cough resulting from the inhalation of an allergen to which the subject has been previously sensitized. The diagnosis of HP most often relies on an array of nonspecific clinical symptoms and signs developed in an appropriate setting, with the demonstration of interstitial markings on chest radiographs, serum precipitating antibodies against offending antigens, a lymphocytic alveolitis on BAL, and/or a granulomatous reaction on lung biopsies. The current classification of HP in acute, subacute, and chronic phases is now challenged, and a set of clinical predictors has been proposed. Nonspecific interstitial pneumonitis, usual interstitial pneumonia, and bronchiolitis obliterans organizing pneumonia may be the sole histologic expression of the disease. Presumably, like in idiopathic interstitial pneumonia, acute exacerbations of chronic HP may occur without further exposure to the offending antigen. New offending antigens, such as mycobacteria causing hot tub lung and metalworking fluid HP, have recently been identified and have stimulated further research in HP.     

Sarcoidosis in hypersensitivity pneumonitis.

An abnormal chest x-ray film showing hilar adenopathy, diffuse interstitial pulmonary infiltrations, or both, combined with a tissue biopsy revealing noncaseating granuloma, are suggestive of sarcoidosis; however, non-caseating granuloma may also be found in other forms of pulmonary disease. Immunologic and environmental evaluation of three patients with the diagnosis of sarcoidosis made by the above criteria, revealed hypersensitivity pneumonitis in all. Since therapeutic considerations in these two diseases are different (avoidance being the mainstay in hypersensitivity pneumonitis), all methods to ensure a correct diagnosis should be employed.     

CT findings of hypersensitivity pneumonitis

CT findings of 22 cases of hypersensitivity pneumonitis (HP) were evaluated on 1 cm slices. All cases were diagnosed by transbronchial lung biopsy and clinical information. The study population included 8 men and 14 women with a mean age of 43 years. The causative antigens were considered to be so-called summer type in 17 cases, air humidifier in 1, pigeon in 1 and paint spray (isocyanate was suspected) in 3. CT examination were performed at a mean of 1.5 weeks after admission. In conclusion, characteristic CT findings of HP include combination of small nodular shadows and slight elevation of lung density. The size of nodular shadows was usually within 1 cm diameter, and their distribution was considered to be a centrilobular pattern, representing alveolitis and granuloma formation in a secondary lobule. It was though that the slight elevation of lung density developed when the disease extended all over the secondary lobule and the nodules developed when the disease was limited to the centrilobular lesion. In most cases, significant changes in proximal bronchi and pulmonary vasculatures could not be detected. The presence of segmental or lobar distribution of the shadows was also suggested. In addition to the typical findings, various other findings were also revealed; irregular shaped dense shadows, subpleural curvilinear shadow and honeycombing formation, especially in chronic cases. These findings have caused some difficulty in distinguishing HP from other interstitial diseases. More precise information can probably be obtained by thin slice CT than by 1 cm slice thicknesses, nevertheless, the standard method of CT should yield a useful diagnostic imaging.     

The alveolitis of hypersensitivity pneumonitis

In the pathogenesis of hypersensitivity pneumonitis (HP) several immune mechanisms are involved. The initial phase, 4-48 h after antigen inhalation, appears to be immune complex mediated and is characterized by an early increase in bronchoalveolar lavage (BAL) neutrophils and the histopathologic features of oedema, neutrophil infiltration of the alveolar wall, and vasculitis. After 12 h to several days, the immune response possibly shifts to a cell-mediated reaction, and the alveolitis consists of cytotoxic effector cells as well as suppressor cells which may be required to modulate the B cell response of antibody production by plasma cells. In this phase, lymphocytes of the OKT8 positive phenotype, natural killer cells, and occasionally a few plasma cells are increased in BAL fluid. The characteristic histopathologic finding is a mononuclear infiltrate consisting of lymphocytes, plasma cells, and foamy histiocytes. After weeks to months, a delayed type hypersensitivity reaction may lead to a slight predominance of OKT4 positive cells in BAL fluid and to granuloma formation. Finally, after months to years, repeated immune-mediated injury to the alveolar wall with release of proteolytic enzymes and fibroblast growth factors may result in pulmonary fibrosis and end stage lung with concomitant increase in BAL neutrophils as in other fibrotic diseases.     

Clinical diagnosis of hypersensitivity pneumonitis

The diagnosis of hypersensitivity pneumonitis (HP) is difficult and often relies on histopathology. Our objective was to identify diagnostic criteria and to develop a clinical prediction rule for this disease. Consecutive patients presenting a condition for which HP was considered in the differential diagnosis underwent a program of simple standardized diagnostic procedures. High-resolution computed tomography scan and bronchoalveolar lavage (BAL) defined the presence or absence of HP. Patients underwent surgical lung biopsy when the computed tomography scan, BAL, and other diagnostic procedures failed to yield a diagnosis. A cohort of 400 patients (116 with HP, 284 control subjects) provided data for the rule derivation. Six significant predictors of HP were identified: (1) exposure to a known offending antigen, (2) positive precipitating antibodies to the offending antigen, (3) recurrent episodes of symptoms, (4) inspiratory crackles on physical examination, (5) symptoms occurring 4 to 8 hours after exposure, (6) and weight loss. The area under the receiver operating characteristic curve was 0.93 (95% confidence interval: 0.90-0.95). The rule retained its accuracy when validated in a separate cohort of 261 patients. The diagnosis of HP can often be made or rejected with confidence, especially in areas of high or low prevalence, respectively, without BAL or biopsy.     

New aspects of hypersensitivity pneumonitis

PURPOSE OF REVIEW: Hypersensitivity pneumonitis (HP) represents a complex pulmonary disorder of varying intensity and clinical presentation, which is characterized by a diffuse Tc1 immune response of lung parenchyma and airways in patients previously sensitized to one of more than 300 etiologic agents that may favor the HP reaction. This review describes recent data that have clarified some of the events that govern the development of the hypersensitivity reaction following exposure to the causative agents involved in this disease. RECENT FINDINGS: A number of recent data clearly demonstrate that several cytokines and chemokines, which are secreted at sites of disease activity, participate in the pulmonary inflammatory responses taking place in the lung of patients with HP. SUMMARY: The past few years have seen outstanding advances in the understanding of immunologic and molecular events involved in the pathogenesis of HP. It is possible that these data could allow the discovery of therapeutic targets in individuals chronically exposed to HP antigens and evolving towards pulmonary fibrosis.     

Expression of tumour necrosis factor receptors by bronchoalveolar cells in hypersensitivity pneumonitis.

Tumour necrosis factor receptors (TNFR) and the Fas receptor (FasR) have been implicated in the pathogenesis of interstitial lung diseases. The current authors examined the expression of TNFR-1, TNFR-2 and FasR by bronchoalveolar cells in hypersensitivity pneumonitis (HP). Cell surface receptor expression on bronchoalveolar lavage cells was analysed by immunocytochemistry in 11 HP patients, 11 idiopathic pulmonary fibrosis (IPF) patients and 10 controls. TNFR-1, TNFR-2 and FasR were expressed on a higher percentage of alveolar macrophages (AM) in HP compared with controls and IPF patients. TNFR-2 and FasR expression on lymphocytes was also higher in HP than in controls and in IPF. TNFR-1, TNFR-2 and FasR expression correlated positively with the percentage of lymphocytes, and negatively with the percentage of AM in HP. Expression of TNFR-1 on AM and TNFR-2 on lymphocytes correlated with the percentage of neutrophils in HP. In conclusion, this study shows evidence of altered expression of tumour necrosis factor superfamily receptors in hypersensitivity pneumonitis.     

Lung T cells in hypersensitivity pneumonitis

Monoclonal antibodies OKT3 (all T cells), OKT4 (T-helper/inducer), and OKT8 (T-suppressor/cytotoxic) were used to determine surface phenotypes of bronchoalveolar lavage and peripheral blood lymphocytes in patients with chronic hypersensitivity pneumonitis. Similar studies were done in asymptomatic pigeon breeders, patients with sarcoidosis, and nonsmoking controls. Increased numbers of lavage T cells were found in patients with hypersensitivity pneumonitis and sarcoidosis and in asymptomatic pigeon breeders. The predominant T-cell subset in patients with hypersensitivity pneumonitis and in asymptomatic pigeon breeders was T8 +; in contrast, the predominant subset in those with sarcoidosis was T4 +. Peripheral blood T-cell subsets were normal in all groups. Thus, most lung T lymphocytes in chronic hypersensitivity pneumonitis belong to the T8 + subset; the local cellular immune response in hypersensitivity pneumonitis and sarcoidosis are different; and the pattern of alveolitis, as determined by bronchoalveolar lavage, is not the sole determinant of lung impairment after exposure to hypersensitivity pneumonitis antigens.     

Gold-induced hypersensitivity pneumonitis in a patient with rheumatoid arthritis

A case of gold-induced hypersensitivity pneumonitis in a patient with rheumatoid arthritis is reported. Its differentiation from interstitial pulmonary fibrosis associated with rheumatoid arthritis is discussed and the low T4/T8 ratio in the bronchoalveolar lavage fluid of these patients is highlighted.