Chest
Recent Advances in Chest MedicineRecent Advances in Hypersensitivity Pneumonitis
Section snippets
Definition
Two major groups of international experts have failed to arrive at a consensual definition of HP. The report of the NHLBI/ORD workshop stated that “hypersensitivity pneumonitis, also known as extrinsic allergic alveolitis, is a complex health syndrome of varying intensity, clinical presentation, and natural history. HP is the result of an immunologically induced inflammation of the lung parenchyma in response to inhalation exposure to a large variety of antigens.”1 The HP Study Group defined HP
Etiology
Antigens responsible for HP mostly originate from bacteria (eg, Saccharopolyspora rectivirgula [SR]), molds (eg, Penicillium species), yeasts, or fowl (eg, pigeon proteins). Some chemicals, such as isocyanates, zinc, inks, and dyes, can act as haptens to induce HP (Table 1). Spores of macroscopic fungi can also induce HP.7 The list of environments associated with HP is ever increasing, but most cases are caused by similar antigens in a different setting. Other antigens have recently been
Epidemiology
Data from registries of interstitial lung diseases in three European countries indicated that HP represents 4% to 15% of all interstitial diseases.16 In a population-based study conducted in New Mexico, the estimated annual incidence of interstitial lung disease was 30 per 100,000.17 HP accounted for < 2% of the incident cases. The study was done in a dry environment that is not propitious to the development of many forms of HP. Nevertheless, this figure is consistent with that obtained from a
Genetics of HP
There is no evidence of a clear genetic susceptibility to develop HP. However, recent studies have described cytokine gene polymorphisms in patients with HP. Compared with gene expression in the lung of patients with idiopathic pulmonary fibrosis (IPF), there is a different genetic signature that could help in the differential diagnosis of these two diseases. In IPF, there is an increased expression of CCL24 and genes encoding for IL-1 receptor antagonist, tumor necrosis factor, and complement
Cell Activation Signals
Lung cellular influx and inflammatory responses characteristic of HP are initiated by causing agents via immune cell receptors called toll-like receptors (TLRs). TLRs are expressed on immune cells and recognize most antigens, be they viral, bacterial, or other. In HP, when specific TLRs are activated, they react through an intracellular pathway, known as the MyD88 pathway, to release many proinflammatory cytokines and mediators. Nance et al26 have demonstrated that in mice, exposure to SR, the
Pathology
Several reports have first emphasized that fibrotic or cellular nonspecific interstitial pneumonitis (NSIP), usual interstitial pneumonia, and bronchiolitis obliterans organizing pneumonia may be the sole histologic expression of the disease.35, 36, 37, 38, 39 We agree that all these reports rightly emphasize that HP must be considered in all cases of diffuse lung disease, and a detailed environmental exposure history is mandatory. The difficulty in the interpretation of these reports is in the
Clinical Presentation
Two large cohorts of consecutive patients with HP provide the best clinical picture of the disease (Table 2).4, 41 Overall, the two cohorts had remarkably similar presenting features. The main difference is in the offending antigens. In the Mayo Clinic series, 25% had HP from unknown origin, whereas in the HP Study, this situation occurred in only 1.5% of patients. Referral bias at the Mayo Clinic may account for this difference.
High-Resolution CT Scan
Several pictorial assays illustrating the spectrum of HRCT scan in HP are available.49, 50 Normal HRCT scans may be seen in acute HP. This should be the exception rather than the rule, however. The time interval between the removal from the offending antigen and HRCT scan may be an explanation for normal HRCT scan in HP.51 In the HP study, among the 199 patients with HP who contributed to the analysis, only eight patients (4%) had a normal HRCT scan.4 All were submitted to additional diagnostic
Differential Diagnosis
Lung infection is by far the most frequent differential diagnosis for patients with acute HP. In the chronic form of the disease, the differential diagnosis of HP is particularly wide. In the HP Study, the control group (462 patients without HP) covered the whole spectrum of diffuse parenchymal diseases, with either of the idiopathic interstitial pneumonias (n = 226) and sarcoidosis (n = 52) representing the top two differential diagnoses.4 As granulomatous lung diseases, HP and sarcoidosis
Prevention and Treatment
The obvious best treatment of HP is contact avoidance. When this is possible and rapidly done, the patient will be cured. If, however, the disease has progressed to a point of leaving significant permanent lung damage, such as fibrosis and/or emphysema, it is likely that the disease can progress even after all contacts with the antigen have been eliminated.78 The only current accepted medical treatment is oral or systemic corticosteroids. These are only needed in severe cases or when the
Prognosis and Outcome
The long-term outcome of subjects with HP is highly variable. Factors that are important in determining the outcome include duration, type, and intensity of exposure, lung pathologic changes (fibrosis82, 83 and emphysema56), and possibly genetic background. CT scan findings of parenchymal fibrosis84 as well as pathologic pulmonary fibrosis83 are associated with diminished survival in HP. With appropriate treatment, most cases of HP have a favorable outcome, with improvement or normalization of
New Offending Agents of Special Interest
Two specific forms of HP related to exposure to environmental mycobacteria have recently raised special interest. Hot tub lung and metalworking fluid (MWF) HP illustrate some of the most recent efforts and advances in HP-related research.
Conclusion
In the past decade, we have witnessed the publication of several studies that improved our understanding of HP. As in most of the diffuse parenchymal lung diseases, however, much remains to be learned. The workshop of the NHLBI/ORD identified several areas for future clinical research in HP.1 These include, among others, (1) the need for a better documentation of its incidence and prevalence; (2) the identification of genetic and environmental risk factors that affect its occurrence and natural
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Other contributions: The manuscript was created at the Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval).
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