Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia.pptx

Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia.pptx

1. Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia

2. Hypersensitivity Pneumonitis

3. First described in 1874, hypersensitivity pneumonitis (HP), or extrinsic allergic alveolitis , is an inflammatory disorder of the lung involving alveolar walls and terminal airways that is induced by repeated inhalation of a variety of organic agents in a susceptible host. The expression of HP depends on factors related to the host susceptibility and the inciting agent. The frequency of HP varies with the environmental exposure and the specific antigen involved, which often depends on season, geographic location, or presence of certain industries.

4. Etiology Agents implicated as causes of HP are diverse and include those listed in Table 255-1 . The common name of each disease often reflects the occupational or avocational risk associated with that disease. In the United States, the most common types of HP are Farmer's Lung, Bird Fancier's Lung , and Chemical Worker's Lung.

5. In Farmer's Lung , inhalation of proteins, such as thermophilic bacteria and fungal spores that are present in moldy bedding and feed, are most commonly responsible for the development of HP. These antigens are probably also responsible for the etiology of mushroom worker's disease (moldy composted growth medium), bagassosis (moldy sugar cane), and water-related exposure (molds in air conditioners or humidifiers). Hot tub lung refers to a hypersensitivity reaction to Mycobacterium avium complex , which is present in hot tubs or whirlpools and is differentiated from actual infection.

6. Bird fancier's lung (and the related disorders of duck fever, turkey handler's lung, and dove pillow's lung) is a response to inhalation of proteins from feathers and droppings. Chemical worker's lung is an example of how simple chemicals, such as isocyanates , may also cause immune-mediated diseases. Interestingly , cigarette smoking has been associated with decreased incidence of HP ; however, smoking may lead to a more progressive or severe course of HP once the disease is present.

7. Pathogenesis The finding that precipitating antibodies against extracts of moldy hay were demonstrable in most patients with farmer's lung led to the early conclusion that HP was an immune complex–mediated reaction. Subsequent investigations of HP in human beings and animal models provided evidence for the importance of cell-mediated hypersensitivity. The very early (acute) reaction is characterized by an increase in polymorphonuclear leukocytes in the alveoli and small airways.

8. This early lesion is followed by an influx of mononuclear cells into the lung and the formation of granulomas that appear to be the result of a classic delayed (T cell–mediated) hypersensitivity reaction to repeated inhalation of antigen and adjuvant-active materials. Studies in animal models suggest that the disease is a T H 1-mediated immune response to antigen, with interferon , interleukin (IL)-12, and possibly IL-18 contributing to disease expression.

9. Most likely, multiple cytokines [including also IL-1, transforming growth factor  (TGF-), tumor necrosis factor (TNF-) and others] interact to promote HP; their source includes both alveolar macrophages and T lymphocytes in the lung. Data support a genetic predisposition to the development of HP; certain polymorphisms of the TNF- promoter region and major histocompatibility complex reportedly confer an enhanced susceptibility to pigeon breeder's disease.

10. After inhalation of an antigenic particle, the attraction and accumulation of inflammatory cells in the lung may be due to one or more of the following mechanisms: induction of the adhesion molecules L- selectin and E- selectin , elaboration by dendritic cells of CC chemokine 1 (DC-CK-1/CCL18), or increased expression of CXCR3/CXCL10 by CD4 + and CD8 + lymphocytes. Increased levels of Fas protein and FasL in the lung (which would be expected to suppress inflammation by induction of T cell apoptosis) is counterbalanced by increased expression of the inducible antiapoptotic gene  Bcl-xL , resulting in a lower overall level of pulmonary lymphocyte apoptosis in HP patients.

11. Bronchoalveolar lavage (BAL) in patients with HP consistently demonstrates an increase in T lymphocytes in lavage fluid (a finding that is also observed in patients with other granulomatous lung disorders). Patients with recent or continual exposure to antigen may have an increase in polymorphonuclear leukocytes in lavage fluid, which has been associated with lung fibrosis. A role for oxidant injury has been proposed in HP. Several markers of oxidative stress are reported to be increased during exacerbation of HP and are reduced by treatment with glucocorticoids.

12. Clinical Presentation The clinical picture is that of an interstitial pneumonitis, which varies from patient to patient and seems related to the frequency and intensity of exposure to the causative antigen and, perhaps, other host factors. The presentation can be acute, subacute , or chronic. In the acute form, symptoms such as cough, fever, chills, malaise, and dyspnea may occur 6 to 8 h after exposure to the antigen and usually clear within a few days if there is no further exposure to antigen; it often closely resembles an influenza-like illness.

13. The subacute form often appears insidiously over a period of weeks marked by cough and dyspnea and may progress to cyanosis and severe dyspnea, requiring hospitalization. In some patients, a subacute form of the disease may persist after an acute presentation of the disorder, especially if there is continued exposure to antigen. In most patients with the acute or subacute form of HP, the symptoms, signs, and other manifestations of HP disappear within days, weeks, or months if the causative agent is no longer inhaled. Transformation to a chronic form of the disease may occur, but the frequency of such progression is uncertain.

14. Continuous low-level antigen exposure or repeated episodes can also lead to chronic disease with more subtle symptoms, accounting for delayed or uncertain diagnosis over a long period of time. This may occur without a prior history of acute or subacute manifestations. The chronic form of HP may be clinically indistinguishable from pulmonary fibrosis in its later stages. Symptoms include cough, weight loss, malaise, and gradual increase in dyspnea.

15. Physical examination may reveal inspiratory crackles and digital clubbing. Imaging shows interstitial fibrosis or emphysema. Progressive worsening may result in dependence on supplemental oxygen, pulmonary hypertension, or respiratory failure. Pulmonary fibrosis is the clinical manifestation of HP with the greatest predictive value for mortality. Fibrosis appears most prominent in hypersensitivity pneumonitis associated with birds, while emphysema is often more common in farmer's lung.

16. Diagnosis All forms of the disease may be associated with elevations in erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, lactate dehydrogenase, or serum immunoglobulins . Following acute exposure to an antigen, neutrophilia and lymphopenia are frequently present.

17. Eosinophilia is not a feature . Examination for serum precipitins against suspected antigens, such as those listed in Table 255-1, is an important part of the diagnostic workup and should be performed on any patient with interstitial lung disease, especially if a suggestive exposure history is elicited.

18. The occurrence of precipitins indicates sufficient exposure to the causative agent for generation of an immunologic response and is one of the major diagnostic criteria; however, the diagnosis of HP is not established solely by the presence of precipitins, as they are found in sera of many individuals exposed to appropriate antigens who demonstrate no other evidence of HP. False-negative results may occur because of unreliable testing techniques or an inappropriate choice of antigens. Extraction of antigens from the suspected source may at times be helpful.

19. Chest x-ray shows no specific or distinctive changes in HP. It can be normal even in symptomatic patients. The acute or subacute phases may be associated with poorly defined, patchy, or diffuse infiltrates; with discrete, nodular infiltrates; or with air-space consolidation. In the chronic phase, the chest x-ray usually shows a diffuse reticulonodular infiltrate. Honeycombing may eventually develop as the condition progresses.

20. Apical sparing is common , suggesting that disease severity correlates with inhaled antigen load, but no particular distribution or pattern is classic for HP. Abnormalities rarely seen in HP include pleural effusion or thickening and significant hilar adenopathy .

21. High-resolution chest CT has become the procedure of choice for imaging of HP. Although pathognomonic features have not been identified, acute HP may appear with diffuse "ground-glass" infiltrates, a reticulonodular pattern, or confluent alveolar opacification . In subacute disease, centrilobularnodules and "ground-glass" changes predominate, and expiratory views may demonstrate air trapping or mosaic perfusion (Fig. 255-1) .

22. This pattern is more common in individuals whose exposure to antigen continues rather than in those in whom removal from antigen exposure has occurred. In chronic HP, diffuse changes include patchy emphysema and interstitial fibrosis; subpleural linear opacities and honeycombing are also common. The findings are often similar (but not identical) to idiopathic pulmonary fibrosis.

23. Chest CT scan of a patient with subacute hypersensitivity pneumonitis in which scattered regions of ground-glass infiltrates in a mosaic pattern consistent with air trapping are seen bilaterally. This patient had bird fancier's lung

24. Pulmonary function studies in all forms of HP may show a restrictive or an obstructive pattern with loss of lung volumes, impaired diffusing capacity, and decreased compliance. Resting or exercise-induced hypoxemia may be seen. Bronchospasm and bronchial hyperreactivity are sometimes found in acute HP. With antigen avoidance, the pulmonary function abnormalities are usually reversible in acute and subacute  disease.

25. BAL i s used in some centers to aid in diagnostic evaluation. A marked lymphocytic alveolitis on BAL is almost universal, although not pathognomonic. Lymphocytes are typically activated and show a decreased helper/suppressor ratio, although this ratio can be variable depending on dose and duration of exposure. Alveolar neutrophilia is also prominent acutely, but tends to fade in the absence of recurrent exposure. Bronchoalveolar mastocytosis may correlate with disease activity.

26. Lung biopsy , obtained through flexible bronchoscopy, open-lung procedures, or thoracoscopy , may be diagnostic. Although the histopathology is distinctive, it may not be pathognomonic of HP (Fig. 255-2) . When the biopsy is taken during the active phase of disease, typical findings include an interstitial alveolar infiltrate consisting of plasma cells, lymphocytes, and occasional eosinophils and neutrophils, usually accompanied by loose, noncaseating peribronchial granulomas. Some degree of bronchiolitis is found in about one-half the cases. Rarely, bronchiolitis obliterans with organizing pneumonia (BOOP) (Chap. 261) may be present.

27. In subacute disease , the triad of mononuclear bronchiolitis; interstitial infiltrates of lymphocytes and plasma cells; and single, nonnecrotizing , randomly scattered parenchymal granulomas without mural vascular involvement is consistent with HP. Interstitial fibrosis may be present, but most often is mild in earlier stages of the disease. Chronic HP has variable pathology and may resemble nonspecific interstitial pneumonia, organizing pneumonia, or usual interstitial pneumonia; granulomas may or may not be present. Centrilobular fibrosis, peribronchial inflammation with fibrosis, bridging fibrosis, and emphysema are common.

28. Open-lung biopsy from a patient with subacute hypersensitivity pneumonitis demonstrating a loose, nonnecrotizing granuloma made up of histiocytes and multinucleated giant cells. Peribronchial inflammatory infiltrate made up of lymphocytes and plasma cells is also seen

29. A prediction rule for the clinical diagnosis of HP has been developed by the International HP Study Group. Six significant predictors of HP (exposure to a known antigen, positive predictive antibodies to the antigen, recurrent episodes of symptoms, inspiratory crackles, symptoms developing 4–8 h after exposure, and weight loss) were retrospectively developed then validated in a separate cohort.

30. This diagnostic paradigm has a high predictive value in the diagnosis of HP, without the need for invasive testing. In cases where only a subset of the criteria is fulfilled, the diagnosis is less certain. It is clear, however, that the diagnosis of HP is established by (1) consistent symptoms, physical findings, pulmonary function tests, and radiographic tests; (2) a history of exposure to a recognized antigen; and (3) ideally, identification of an antibody to that antigen. Symptoms upon re-exposure to the suspected antigen also support the diagnosis. In some circumstances, BAL and/or lung biopsy may be needed. The most important tool in diagnosing HP continues to be a high index of suspicion

31. Differential Diagnosis

32. Treatment: Hypersensitivity Pneumonitis

33. Pulmonary Infiltrates with Eosinophilia

34. Pulmonary infiltrates with eosinophilia (PIE, eosinophilic pneumonias ) include distinct individual syndromes characterized by eosinophilic pulmonary infiltrates and, commonly, peripheral blood eosinophilia. Since Loeffler's initial description of a transient, benign syndrome of migratory pulmonary infiltrates and peripheral blood eosinophilia of unknown cause, this group of disorders has been enlarged to include several diseases of both known and unknown etiology (Table 255-2) .

35. These diseases may be considered as immunologically mediated lung diseases, but are not to be confused with HP, in which eosinophilia is not a feature. In differentiating the etiologies of this heterogeneous group of lung disorders, an extensive history and full examination of all organ systems are essential.

36. When an eosinophilic pneumonia is associated with bronchial asthma, it is important to determine if the patient has atopic asthma and has wheal-and-flare skin reactivity to Aspergillus or other relevant fungal antigens. If so, other criteria should be sought for the diagnosis of ABPA (Table 255-3) or other, rarer examples of allergic bronchopulmonary mycosis such as those caused by Penicillium , Candida, Curvularia , or Helminthosporium spp.

37. A. fumigatus is the most common cause of ABPA. The chest roentgenogram in ABPA may show transient, recurrent infiltrates or may suggest the presence of proximal bronchiectasis. High-resolution chest CT is a sensitive, noninvasive technique for the recognition of proximal bronchiectasis . The bronchial asthma of ABPA likely involves an IgE -mediated hypersensitivity, whereas the bronchiectasis associated with this disorder is thought to result from a deposition of immune complexes in proximal airways.

38. Adequate treatment usually requires the long-term use of systemic glucocorticoids. Another eosinophilic process associated with asthma is Churg -Strauss syndrome , or allergic angiitis granulomatosis , which presents with necrotizing eosinophilic vasculitis and eosinophilic infiltration of multiple organs, including the lung.