Hypersensitivity pneumonitis: insights in diagnosis and pathobiology

Hypersensitivity pneumonitis (HP) is a complex syndrome resulting from repeated exposure to a variety of organic particles. HP may present as acute, subacute, or chronic clinical forms but with frequent overlap of these various forms. An intriguing question is why only few of the exposed individuals develop the disease. According to a two-hit model, antigen exposure associated with genetic or environmental promoting factors provokes an immunopathological response. This response is mediated by immune complexes in the acute form and by Th1 and likely Th17 T cells in subacute/chronic cases. Pathologically, HP is characterized by a bronchiolocentric granulomatous lymphocytic alveolitis, which evolves to fibrosis in chronic advanced cases. On high-resolution computed tomography scan, ground-glass and poorly defined nodules, with patchy areas of air trapping, are seen in acute/subacute cases, whereas reticular opacities, volume loss, and traction bronchiectasis superimposed on subacute changes are observed in chronic cases. Importantly, subacute and chronic HP may mimic several interstitial lung diseases, including nonspecific interstitial pneumonia and usual interstitial pneumonia, making diagnosis extremely difficult. Thus, the diagnosis of HP requires a high index of suspicion and should be considered in any patient presenting with clinical evidence of interstitial lung disease. The definitive diagnosis requires exposure to known antigen, and the assemblage of clinical, radiologic, laboratory, and pathologic findings. Early diagnosis and avoidance of further exposure are keys in management of the disease. Corticosteroids are generally used, although their long-term efficacy has not been proved in prospective clinical trials. Lung transplantation should be recommended in cases of progressive end-stage illness.     

Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis (HP) represents a group of lung disorders caused by the inhalation of a wide variety of organic particles by susceptible individuals. HP occurs mainly in nonsmokers, but smoking may promote an insidious and chronic disease. The prevalence of HP is difficult to estimate accurately since several antigens can produce the disease, but the range spans infancy to old age. Regardless of the causative antigen or its environmental setting, the clinical manifestations are essentially the same. Three different clinical presentations have been recognized: acute, subacute, and chronic. In the acute form, patients show flu-like symptomatology, followed by dyspnea and dry cough. Symptoms subside a few hours or days later. The subacute and chronic forms result from recurrent low-level antigen exposure and are characterized by progressive dyspnea and dry cough. Other constitutional symptoms such as fatigue, anorexia, and weight loss can be apparent. Fever may occur in the subacute form. Importantly, chronic HP may evolve insidiously or may result from repeated acute/subacute episodes. Recurrent acute, subacute, and chronic HP may progress to irreversible lung fibrosis or provoke emphysematous changes.HP can be difficult to identify, and precise diagnosis requires a history of exposure and a constellation of clinical, imaging, laboratory, bronchoalveolar lavage and pathologic findings. General laboratory tests show an increase of acute phase reactants. Specific precipitating antibodies, when present, are evidence of antigen exposure, and are a hallmark for diagnosis. Chest radiograph usually reveals widespread ground-glass attenuation, and nodular or reticulonodular shadowing. High-resolution CT features include diffuse or patchy ground-glass opacities with small poorly defined nodules and air trapping. Pulmonary function tests are characterized by a predominantly restrictive ventilatory defect with loss of lung volume and hypoxemia at rest that worsens with exercise. Bronchoalveolar lavage reveals a significant increase in lymphocytes, mostly over 40%. In the acute form there is also an increase in neutrophils. Antigen-induced lymphocyte proliferation, and environmental or laboratory-controlled inhalation challenge, may be used for diagnostic purposes and can help to establish a diagnosis of insidious forms of HP. In subacute or chronic cases, lung biopsy may be necessary. Typical findings include bronchiolitis, lymphocytic alveolitis, and loosely formed granulomas, although occasionally other morphologic patterns such as nonspecific interstitial pneumonia may exist. Treatment focuses on avoiding further exposure to the offending antigen(s). Corticosteroids are recommended in subacute and chronic forms. The usual regimen consists of initial high doses of systemic corticosteroid (e.g. prednisone 0.5-1.0 mg/kg/day), followed by gradual tapering.     

Clinicopathological features of chronic hypersensitivity pneumonitis

OBJECTIVE: Only limited information exists concerning the clinical and pathological features of chronic hypersensitivity pneumonitis (HP) in Japan and elsewhere. We present data on clinicopathological features of chronic HP obtained through a Japanese nationwide survey. METHODOLOGY: We studied the clinical and pathological findings in 10 patients with chronic HP who underwent surgical lung biopsy or postmortem examination. RESULTS: There were three types of clinical course: six of the 10 patients had persistent symptoms followed by repeated acute episodes; two showed a subacute onset with persistent symptoms; and two exhibited an insidious onset. Five patients made no attempt to avoid antigen exposure and they all had progressive disease. Pathological findings indicated that lesions were mainly centrilobular with or without epithelioid cell granulomas in specimens obtained during the acute or subacute stage. In contrast, most patients in the chronic stage predominantly showed interstitial fibrosis with a usual interstitial pneumonia pattern. CONCLUSIONS: The pathological findings of chronic HP depend on the stage of the disease at tissue sampling.     

Chronic summer-type hypersensitivity pneumonitis initially misdiagnosed as idiopathic interstitial pneumonia

The clinical features of chronic hypersensitivity pneumonitis (HP) are similar to idiopathic interstitial pneumonias (IIPs) including idiopathic pulmonary fibrosis (IPF). We report 2 cases of chronic summer-type HP with insidious onset. They were misdiagnosed as having IIPs before referral to our hospital. Anti-trichosporon antibodies were positive in these cases. Their disease progressed due to the intermittent or continuous exposure to the antigen. Chronic summer-type HP should be included in the list of differential diagnosis of chronic interstitial lung diseases. Environmental investigation for an accurate diagnosis is important to convince the patient of the necessity to strictly avoid any future exposure to antigen.     

Chronic hypersensitivity pneumonitis

Hypersensitivity pneumonitis (HP) is a complex syndrome caused by the inhalation of environmental antigens. Chronic HP may mimic other fibrotic lung diseases, such as idiopathic pulmonary fibrosis. Recognition of the antigen is important for diagnosis; avoidance of further exposure is critical for treatment. Fibrosis on biopsy or high-resolution computed tomography is a predictor of increased mortality. Additional research is needed to understand why the disease develops only in a minority of exposed individuals and why cases of chronic HP may progress without further antigen exposure.     

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.     

呼出气一氧化氮在间质性肺疾病诊疗中的应用

间质性肺疾病(ILD)作为一组以急慢性炎症导致肺间质慢性炎症及进行性纤维化的疾病,其发病机制及诊治并未完全清楚。呼出气一氧化氮(eNO)作为一种气道炎症分子标志物已成功应用于哮喘等气道炎症性疾病的诊疗中,但其对于 ILD 的诊治价值尚未明确。本文通过学习 eNO对 ILD 研究的相关文献探讨 eNO 对 ILD 诊治的临床价值。     

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

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

Experimental models of hypersensitivity pneumonitis.

Experimental models of hypersensitivity pneumonitis are important tools for the study of the pathogenesis of this disease. In this paper we review the characteristics of the main animal models developed until now. The HP models in rats seem to be particularly appropriate for studying pigeon fancier's disease and the HP induced by chemicals, as well as for studying mediators of acute lesions induced by immunocomplexes. However, the HP models developed in rats are of less value in the evaluation of other aspects of the pathogenesis of this clinical entity in humans. The murine models of HP offer several advantages: the ease and simplicity of intranasal administration, the ability to produce acute and subacute pulmonary lesions similar to those found in humans, the possibility of reproducing lesions similar to those of nonaffected exposed subjects and the possibility of pharmacologically modulating the process. Their disadvantages lie in the different pulmonary lymphocyte response and the difficulty in reproducing a model of chronic fibrosis. The HP models in rabbits are extraordinarily useful for evaluating the immunological mechanisms through which subjects repeatedly exposed to the antigen do not develop clinical manifestations. However, the rabbit has several immunological differences when compared to humans, and the effect of some immunomodulators in this animal is different. The models of HP in guinea-pigs have as advantages the ease in handling the animals, the possibility of pharmacological manipulation, and the ability to induce an acute phase that is very similar to that observed in humans. The drawback, however, is the low lymphocyte response and the striking eosinophilic reaction that contrast with the bronchoalveolar data found in HP in humans. In conclusion, there is no ideal model to reproduce all the findings observed in humans, suggesting that the experimental animal and the method of developing HP should be selected on the basis of concrete research aims.     

Hypersensitivity pneumonitis.

A case of hypersensitivity pneumonitis (HP) is presented and briefly discussed. The clinical characteristics, diagnosis, pathogenesis, and management of this syndrome are reviewed followed by clinical pearls and pitfalls for the practicing allergist. Most patients with acute HP recover completely with removal from the offending antigen. Treating symptoms only and not avoiding antigen triggers may lead to severe pulmonary fibrosis.     

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.     

Role of surgical lung biopsy in separating chronic hypersensitivity pneumonia from usual interstitial pneumonia/idiopathic pulmonary fibrosis: analysis of 31 biopsies from 15 patients

BACKGROUND: Lung biopsy has been proposed as a criterion for diagnosis of chronic hypersensitivity pneumonia (HP), especially in patients without proven antigen exposure. Histologic findings in some suspected HP patients overlap with usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP). We reviewed our experience to determine the specificity of histologic findings in surgical lung biopsies from patients with clinical diagnoses of HP. METHODS: Surgical lung biopsies from patients with chronic HP, idiopathic pulmonary fibrosis, and idiopathic NSIP were reviewed retrospectively without knowledge of the clinical diagnosis. Each specimen was assigned a histologic diagnosis, and selected histologic findings were tabulated. Clinical data were abstracted from medical records. RESULTS: Fifteen patients with clinical diagnoses of chronic HP underwent biopsy of one to three lobes. Ten showed features diagnostic of HP in all specimens. Two had discordant findings that included HP in one specimen and UIP or nonspecific changes in others. Biopsies from two showed only UIP, and one showed NSIP. Diagnostic features were present in all samples from 9 of the 11 patients with more than one biopsy site (81.8%). Three patients died of disease, including both patients from whom biopsies showed only UIP. CONCLUSIONS: Most patients with a clinical diagnosis of chronic HP have supportive histologic findings in surgical lung biopsies. A subset of HP patients has findings indistinguishable from UIP. Sampling from more than one lobe may be helpful in separating HP from idiopathic pulmonary fibrosis.     

Acute inflammatory and immunologic responses against antigen in chronic bird-related hypersensitivity pneumonitis

BackgroundHypersensitivity pneumonitis (HP) is an immune-mediated lung disease induced by the inhalation of a wide variety of antigens and a persistent antigen exposure induces inevitably pulmonary fibrosis in chronic HP. Although neutrophils, Th1 and Th17 cells contribute to lung inflammation in acute phase of HP, there is no clear explanation as to how the immunological reaction occurs just after the inhalation of causative antigens in the chronic phase of HP.MethodsWe examined the inflammatory and immunologic profiles before and after the inhalation provocation test (IPT) in serum and bronchoalveolar lavage fluid (BALF) from patients with chronic bird-related HP (BRHP) and other interstitial lung diseases (ILDs). We analyzed BALF samples from 39 patients (19 BRHP and 20 other ILDs) and serum samples from 25 consecutive patients (20 BRHP and 5 other ILDs) who underwent the IPT.ResultsA significant increase of neutrophils was observed in the BALF from the BRHP patients following the IPT. Neutrophil chemoattractants, namely, granulocyte colony-stimulating factor, IL-6, IL-8, IL-17, and CXCL2 significantly increased in both the serum and BALF of the BRHP patients after the IPT. Serum IFN-γ and CXCL10, cytokines/chemokines that contributed to Th1 inflammation, were also significantly increased in BRHP following the IPT.ConclusionsThis study demonstrated the exposure to the causative antigen provoked acute neutrophilic and Th1 immunologic responses similar to acute HP even in the chronic phase of HP.     

Hypersensitivity pneumonitis

Hypersensitivity pneumonitis (HP) or extrinsic allergic alveolitis is a non-IgE mediated hypersensitivity disease initiated by inhalation and subsequent sensitisation to organic antigens. These diseases have been described in different occupational groups and present in acute, subacute or chronic forms based on the exposure to antigens and host response. Clinical features are dependent upon the stage of the disease and can include fever, chills, cough, dyspnoea, and weight loss. The immunopathogenesis involves both cellular immunity and antibody responses to inhaled antigens. Antibody response to the implicated antigen can be demonstrated in HP patients, but such antibodies are also detected in antigen exposed asymptomatic individuals. Bronchoalveolar lavage demonstrates lymphocytosis and preponderance of CD8+ cells. Pulmonary function studies demonstrate a restrictive pattern with diffusion defects. The diagnosis is difficult as no single test is confirmatory, hence information from clinical, radiological, physiological, and immunological evaluations may be used together for a confirmative diagnosis of hypersensitivity pneumonitis. The treatment of choice is avoidance of antigen but systemic corticosteroids may be effective in suppressing the inflammatory response. The prognosis depends on early diagnosis and effective antigen avoidance.     

Sarcoidosis: a review for the internist

Sarcoidosis is a systemic granulomatous lung disease of unknown origin affecting people of any age, mainly young adults. The disease is extremely heterogeneous with an unpredictable clinical course. Different phenotypes have been identified: an acute syndrome can be distinguished from subacute and chronic variants. About 20% of patients are chronically progressive and may develop lung fibrosis. Sarcoidosis usually involves the lungs and thoracic lymph nodes, although the skin, eyes, bones, liver, spleen, heart, upper respiratory tract and nervous system can also be affected. No reliable indicators of clinical outcome are available, and there is no single serological biomarker with demonstrated unequivocal diagnostic and prognostic value. Diagnosis requires histological confirmation although a presumptive diagnosis may be acceptable in special conditions. This review examines the diagnostic approach to sarcoidosis involving a multidisciplinary team of specialists in which the internist has the task of identifying all pulmonary and extrapulmonary localizations of the disease and of managing complications and comorbidities.     

Hypersensitivity pneumonitis: a comprehensive review.

Hypersensitivity pneumonitis is a dynamic and heterogeneous group of diseases resulting from inhalational exposure to a variety of organic and inorganic dusts. In the United States, it has predominantly been considered an occupational disease, such as in farmer's lung, bagassosis, and in the plastics and paint industry with isocyanate exposure. In Japan, however, the most common exposure to antigen has been associated with the home environment. All susceptible patient populations are at potential risk to develop this disease under appropriate antigen exposure. The clinical course can be acute, subacute, or chronic depending on the nature of the antigen and the circumstances under which exposure occurs. If unrecognized, any stage of disease has the potential to progress to endstage pulmonary fibrosis. Proper antigen identification and avoidance requires that the physician be keenly aware of its existence and the importance of the detailed occupational and home environmental history. Without a high degree of suspicion, this disease can be easily overlooked and misdiagnosed as another type of inflammatory lung disease. Although the immunologic mechanisms mediating this illness are complex and poorly understood, strict avoidance of the provocative antigen is required for optimal long-term outcome.     

The HRCT features of extrinsic allergic alveolitis

Exposure to organic dusts can produce an immune-mediated inflammatory response in sensitized individuals. The pulmonary disease caused by this response has been called extrinsic allergic alveolitis (EAA) or hypersensitivity pneumonitis. The clinical phases associated with this process have been termed acute, subacute, and chronic. There are corresponding imaging findings that are characteristic of each of these phases, although there is some overlap between the phases. The acute phase is characterized by confluent opacities that may mimic infection or edema. The subacute phase is characterized by centrilobular nodules, areas of ground-glass attenuation, a mosaic perfusion pattern, and air trapping on expiratory imaging. The chronic phase is characterized by subpleural irregular linear opacities with associated architectural distortion. Honeycombing may sometimes also be present. In the acute and subacute phases, the disease is predominantly in the lower lungs, whereas in chronic EAA the findings are predominant in the mid to upper lungs. Although the high-resolution computed tomography findings individually are nonspecific, the combination of the findings coupled with the distribution of the findings can often narrow the differential or allow a presumptive diagnosis of EAA to be made.     

Role of tumour necrosis factor-alpha receptor p75 in cigarette smoke-induced pulmonary inflammation and emphysema.

Chronic obstructive pulmonary disease (COPD) is characterised by a local pulmonary inflammatory response to respiratory pollutants and by systemic inflammation. Tumour necrosis factor (TNF)-alpha has been implicated in systemic effects of COPD and operates by binding the p55 (R1) and p75 (R2) TNF-alpha receptors. To investigate the contribution of each TNF-alpha receptor in the pathogenesis of COPD, the present study examined the effects of chronic air or cigarette smoke (CS) exposure in TNF-alpha R1 knockout (KO) mice, TNF-alpha R2 KO mice and wild type (WT) mice. CS was found to significantly increase the protein levels of soluble TNF-alpha R1 (by four-fold) and TNF-alpha R2 (by 10-fold) in the bronchoalveolar lavage of WT mice. After 3 months, CS induced a prominent pulmonary inflammatory cell influx in WT and TNF-alpha R1 KO mice. In TNF-alpha R2 KO mice, CS-induced pulmonary inflammation was clearly attenuated. After 6 months, no emphysema was observed in CS-exposed TNF-alpha R2 KO mice in contrast to WT and TNF-alpha R1 KO mice. CS-exposed WT and TNF-alpha R1 KO mice failed to gain weight, whereas the body mass of TNF-alpha R2 KO mice was not affected. These current findings suggest that both tumour necrosis factor-alpha receptors contribute to the pathogenesis of chronic obstructive pulmonary disease, but tumour necrosis factor-alpha receptor-2 is the most active receptor in the development of inflammation, emphysema and systemic weight loss in this murine model of chronic obstructive pulmonary disease.     

Potential pathogenesis and clinical aspects of pulmonary fibrosis associated with rheumatoid arthritis

Pulmonary fibrosis is an extra-articular disorder that can occur in association with rheumatoid arthritis. The differential diagnosis of this disorder is similar to that of idiopathic pulmonary fibrosis, but specific entities such as atypical pulmonary infections and drug-induced interstitial lung disease must be considered as causes of pulmonary fibrosis in patients with rheumatoid arthritis. Although the cause of lung fibrosis in persons with rheumatoid arthritis is unknown, factors that can potentially contribute to the pathogenesis of this pulmonary disease include genetic susceptibility, development of an altered immunologic response, and/or aberrant host repair processes. The clinical course of patients with pulmonary fibrosis and rheumatoid arthritis is heterogeneous but is generally insidious, chronic, and progressive. These patients respond unpredictably to available empiric therapeutic agents and, overall, their prognosis is poor; limited data suggests that the median survival time can be less than 4 years.     

Clinical approach to chronic beryllium disease and other nonpneumoconiotic interstitial lung diseases

Exposures in the workplace result in a diverse set of diseases ranging from the pneumoconiosis to other interstitial lung diseases to acute lung injury. Physician awareness of the potential disease manifestations associated with specific exposures is important in defining these diseases and in preventing additional disease. Most occupational diseases mimic other forms of lung disease, including pulmonary fibrosis, sarcoidosis, adult respiratory distress syndrome (ARDS), and bronchiolitis. A "sarcoidosis"-like syndrome, usually limited to the lungs, may result from exposure to bioaerosols and a number of metals. Exposure to beryllium in the workplace produces a granulomatous lung disease clinically indistinguishable from sarcoidosis, chronic beryllium disease (CBD). Beryllium's ability to produce a beryllium-specific immune response is used in the beryllium lymphocyte proliferation tests to confirm a diagnosis of CBD and exclude sarcoidosis. Exposure to other metals must also be considered in the differential diagnosis of sarcoidosis. When an individual presents acutely with ARDS or acute lung injury, an acute inhalational exposure must be considered. Exposure to a number of irritant substances at high levels may cause a "chemical pneumonitis" or acute lung injury, depending on the solubility and physicochemical properties of the substance. Some of the most notable agents include nitrogen and sulfur oxides, phosgene, and smoke breakdown products. Ingestion of paraquat may also result in an ARDS syndrome, with pulmonary fibrosis eventually resulting. Bronchiolitis is a rare manifestation of inhalational exposures but must also be considered in the clinical evaluation of inhalational exposure.