Chapter 49 Eosinophilic Lung Disease
The eosinophilic lung diseases are characterized by prominent infiltration of the lung structures by eosinophils, leading to several distinct clinical disorders, especially eosinophilic pneumonia. The most important eosinophilic lung diseases other than eosinophilic pneumonia are allergic bronchopulmonary aspergillosis (ABPA) and hypereosinophilic asthma, which primarily affect the airways.
Eosinophils play a major role in immunity against bacteria, viruses, parasites, and tumors and participate in the pathogenesis of allergic diseases. They also take part in the pathogenesis of numerous inflammatory processes and may be the major cause of tissue injury in eosinophilic disorders. Advances have been made recently in elucidation of the complex role of eosinophils in health and disease through the study of several models of genetically engineered murine cell lines deficient in the eosinophil lineage. Approaches that selectively target the eosinophil lineage in vivo are being developed with a therapeutic perspective, such as use of the humanized antiinterleukin (IL)-5 antibody mepolizumab.
The role of the eosinophil leukocyte as a multifunctional cell is now well appreciated in both innate and adaptive immunity. Eosinophils express Toll-like receptors (TLRs) and participate in the nonspecific inflammatory reaction in tissues in response to various ligands; however, they also play a major role by interacting with T cells. Once perceived as a terminal effector cell in parasitic infections and allergy, the eosinophil is now recognized to be able to modulate T cell responses, by presenting the antigen to naive as well as to antigen-primed T cells, thereby inducing T helper cell type 2 (TH2) development, cytokine production, and T cell migration to sites of inflammation. T cells can then secrete TH2-type cytokines (the interleukins IL-4, IL-5, and IL-13), which further enhance the recruitment of eosinophils. Secretion of IL-4 and IL-13 by the eosinophil in turn amplifies the TH2 response in the lung in a positive loop. In addition, eosinophils may present antigens from the airways or the lung tissue to TH0 cells in the draining lymph node in the context of major histocompatibility complex (MHC) class II. Eosinophil precursors differentiate in the bone marrow under the action of several cytokines, including interleukin (IL)-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Eosinophils are recruited in response to diverse stimuli from the circulation into inflammatory foci, including sites in the lung, where they have the potential to modulate immune responses. Recruitment of eosinophils involves cell adhesion and attraction, diapedesis, and chemotaxis by cytokines (mainly IL-5 and eotaxin) and the chemokine receptor CCR3. In tissues, the eosinophils may be triggered through engagement of receptors for cytokines, immunoglobulins, and complement, with ensuing release of active mediators, including proinflammatory cytokines, arachidonic acid–derived mediators, enzymes, reactive oxygen species, complement proteins, chemokines, chemoattractants, metalloproteases, and other toxic granule proteins, especially cationic proteins. Indeed, activation and degranulation of the eosinophil releases specific cationic proteins, including major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), protein eosinophil peroxidase (EPO), and MBP homologue. These proteins released mostly by degranulation have proinflammatory properties, through the upregulation of chemoattraction, expression of adhesion molecules, regulation of vascular permeability, contraction of smooth muscle cells, and direct cytotoxicity. The eosinophils also express receptors for cytokines, complement, immunoglobulins, chemokines, and apoptotic signals; regulate mast cell functions; and interact with basophils, endothelial cells, macrophages, platelets, and fibroblasts. However, histopathologic lesions in eosinophilic pneumonias are largely reversible with treatment, with the possible exception of bronchial wall damage in ABPA.
The diagnosis of eosinophilic pneumonia only exceptionally requires lung biopsy, and histopathologic features were described several decades ago. Eosinophilic pneumonia as exemplified by idiopathic chronic eosinophilic pneumonia (ICEP) is characterized by the prominent infiltration of the lung structures by eosinophils. The lung interstitium is infiltrated by eosinophils, and essentially the alveolar spaces are filled with eosinophils and a fibrinous exudate, with conservation of the global architecture of the lung. Immunohistochemical and electron microscopic studies have demonstrated eosinophil degranulation within involved lung tissue.
Some overlap is common between eosinophilic and organizing pneumonia, with organization of the alveolar inflammatory exudate (less prominent than in cryptogenic organizing pneumonia). In addition, eosinophilic microabscesses and a non-necrotizing vasculitis are common in ICEP and idiopathic acute eosinophilic pneumonia (IAEP). Macrophages and occasional multinucleate giant cells may be present within the infiltrate. The histopathologic pattern in IAEP usually comprises intraalveolar and interstitial eosinophilic infiltrates, diffuse alveolar damage, intraalveolar fibrinous exudates, organizing pneumonia, and non-necrotizing vasculitis.
The diagnosis of eosinophilic pneumonia relies on both characteristic clinical-imaging features and the demonstration of alveolar eosinophilia and/or peripheral blood eosinophilia (Box 49-1). Bronchoalveolar lavage (BAL) is a noninvasive alternative to lung biopsy in this setting. The percentage of eosinophils in BAL fluid is less than 2% in normal control subjects, and a differential cell count for eosinophils of 2% to 25% may be found in nonspecific conditions. Therefore, a cutoff value of 25% eosinophils or more in BAL fluid, and preferably 40% or more, is recommended for the diagnosis of eosinophilic pneumonia. The presence of marked eosinophilia in BAL fluid obviates the need for lung biopsy in this disorder, especially when the eosinophils are the predominant cell population in BAL fluid (macrophages excepted). Markedly elevated peripheral blood eosinophilia (greater than 1000/µL and preferably 1500/µL) together with typical clinical radiologic features are highly suggestive of the diagnosis of eosinophilic pneumonia, and BAL may not be always mandatory in such patients, although other disorders may be associated with pulmonary infiltrates and peripheral eosinophilia (e.g., bacterial pneumonia, parasitic pneumonia, infiltrates related to lymphoma). Peripheral blood eosinophilia may be absent at presentation, especially in IAEP and in patients receiving corticosteroid treatment.
Diagnosis of Eosinophilic Pneumonias
Eosinophilic pneumonia may be separated into that of undetermined origin, which usually may be included within well-individualized syndromes, and that with a definite cause (mainly infection and drug reaction) (Box 49-2). Potential causes must be thoroughly investigated, because identification of a cause may lead to effective therapeutic measures.
Clinical Classification of the Eosinophilic Lung Diseases
Parasite infestation is the main cause of eosinophilic pneumonia worldwide. Clinical manifestations are nonspecific. Tropical pulmonary eosinophilia is a disease of decreasing prevalence caused by the filarial parasites Wuchereria bancrofti and Brugia malayi, deposited in the skin by mosquitoes. The clinical features of tropical eosinophilic pneumonia largely result from an immune response of the host to the antigenic constituents of circulating microfilariae trapped in the lung vasculature (leading to cough that may be associated with fever, weight loss, and anorexia). Patients with tropical pulmonary eosinophilia do not usually have clinical features of lymphatic filariasis. The chest radiograph shows bilateral infiltrative opacities. Blood eosinophilia with counts of more than 2000/µL eosinophils is characteristic of the early stage, occasionally with counts of up to 60,000/µL during the chronic phase of disease. Microfilariae are not detectable in the blood. The diagnosis of filariasis may be established by a strongly positive result on serologic testing in patients residing in an endemic area, with persisting and prominent blood eosinophilia at counts of more than 3000/µL and IgE levels exceeding 10,000 ng/mL. It is further supported by clinical improvement in the weeks after treatment with diethylcarbamazine; the addition of corticosteroids may be beneficial in severe cases.
The nematode Ascaris lumbricoides is the most common helminth infecting humans. The disease is transmitted through consumption of food contaminated by human feces containing parasitic eggs. Löffler syndrome (transient mild eosinophilic pneumonia) may develop during the migration of the larvae through the lung. Signs and symptoms often are limited to cough, wheezing, and transient fever, which resolve within a few days, but blood eosinophilia with counts as high as 20,000/µL may be present and last for several weeks. The diagnosis usually is obtained by the delayed finding of the worm or ova in the stools within 3 months of onset of the pulmonary manifestations; larvae may occasionally be found at an earlier stage in sputum or gastric aspirates.
Visceral larva migrans syndrome caused by Toxocara canis occurs throughout the world. Humans and especially children become infected after ingestion of eggs released in feces of infected dogs (especially in the soil of urban public playgrounds). Fever, seizures, fatigue, and pulmonary manifestations may occur (cough, dyspnea, wheezes, or crackles heard on pulmonary auscultation and pulmonary infiltrates evident on the chest radiograph). Blood eosinophilia may be present initially or may develop only in the following days. The diagnosis of toxocariasis is obtained by serologic methods, especially enzyme-linked immunosorbent assay (ELISA). Symptomatic treatment is recommended; the use of antihelmintics is controversial.
Strongyloides stercoralis is an intestinal nematode, the larvae of which infect humans through the skin by contact with damp soil. Eosinophilia is present in recently infected persons. Strongyloidiasis may cause severe disease, affecting all organs (hyperinfection syndrome), especially in immunocompromised patients, sometimes years after the initial infection, with or without peripheral eosinophilia and bilateral patchy infiltrates on chest radiograph. The diagnosis of strongyloidiasis depends on the demonstration of larvae in the feces or in any secretion or tissue specimen (including sputum and BAL fluid). Immunodiagnostic assays by ELISA methods may be useful for diagnosis and screening. Treatment with thiabendazole is recommended.
ABPA occurs mainly in adults with preexisting asthma (with an estimated prevalence of 1% to 2%) and in patients with cystic fibrosis (with an estimated prevalence of up to 7% to 10%). It results from a complex allergic and immune reaction in the bronchi and the adjacent lung parenchyma in response to antigens from Aspergillus colonizing the airways of patients with asthma. A pattern of allergic bronchopulmonary mycosis similar to that in ABPA has rarely been reported with infections caused by other fungi or yeasts, including Penicillium, Drechslera, Torulopsis, Mucor, Candida, Pseudallescheria, Bipolaris, Curvularia, Fusarium, Cladosporium, and Saccharomyces. The immunologic response to the fungus combines both type I and type III hypersensitivity in an allergic host and is mediated by the immunoglobulins IgG, IgE, and IgA, as well as the helper T cell subset 2 (TH2) CD4+ cells, and by activation and degranulation of mast cells and eosinophils, resulting in progressive damage to the bronchial and surrounding pulmonary tissue. Mucous plugs containing Aspergillus obstruct the airways, with subsequent atelectasis, bronchial wall damage, and proximal bronchiectasis predominating in the upper lobes. Of note, IgE sensitization to Aspergillus in nonasthmatic patients who do not fulfill criteria for ABPA is associated with reduced lung function. ABPA may be associated with allergic Aspergillus sinusitis in a syndrome called sinobronchial allergic aspergillosis. Genetic susceptibility to develop ABPA has been demonstrated, with an increased prevalence of heterozygotic cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in non–cystic fibrosis patients with ABPA, the association of ABPA with a polymorphism within the IL-4 receptor α-chain gene, and association with certain human leukocyte antigen (HLA) DR subtypes.
Early ABPA is characterized by fever, expectoration of mucous plugs, peripheral blood eosinophilia with counts higher than 1000/µL, and pulmonary infiltrates caused by eosinophilic pneumonia, or segmental or lobar atelectasis caused by mucous plugging. Chronic ABPA is characterized by asthma, eosinophilia, and bronchopulmonary manifestations including bronchiectasis (Figures 49-1 and 49-2 and Box 49-3). The presence of bronchiectasis on computed tomography (CT) images in a patient with asthma is therefore highly suggestive of ABPA; however, typical proximal bronchiectasis may be absent, and such cases are designated ABPA-seropositive. Centrilobular nodules and mucoid impaction on CT scan (typically characterized by a V-shaped lesion, with the vertex pointing toward the hilum) also are highly suggestive of ABPA. The expectoration of mucous plugs, the presence of Aspergillus in sputum, and late skin reactivity to Aspergillus antigen also are common at this stage; however, Aspergillus is not reliably identified in sputum or BAL fluid samples of patients with ABPA, and positive cultures are not required for diagnosis. The finding of Aspergillus organisms may reflect colonization and thus is not specific for ABPA. Total serum IgE levels of at least 1000 IU/mL constitute a hallmark of ABPA. Peripheral blood eosinophilia is common but is not a required diagnostic criterion.
Figure 49-1 Bilateral bronchiectasis in a patient with allergic bronchopulmonary aspergillosis. Affected structures (arrows) are well visualized on this computed tomography scan, which also shows some infiltrative opacities.
Figure 49-2 Bronchiectasis (arrows) in another patient with allergic bronchopulmonary aspergillosis. The computed tomography scan also shows ground glass opacities (arrowhead) and centrilobular micronodules.