The Eosinophil Leukocyte

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 (T_H2) development, cytokine production, and T cell migration to sites of inflammation. T cells can then secrete T_H2-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 T_H2 response in the lung in a positive loop. In addition, eosinophils may present antigens from the airways or the lung tissue to T_H0 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.

Histopathologic Features of Eosinophilic Pneumonia

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.

Diagnosis of Eosinophilic Pneumonia

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.

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.

Eosinophilic Pneumonia in Parasitic 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.

Allergic Bronchopulmonary Aspergillosis

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 (T_H2) 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.

Identification of immunologic hypersensitivity to Aspergillus fumigatus in patients with asthma contributes to the diagnosis of ABPA; it may consist in immediate reaction to prick test for Aspergillus antigen, precipitating serum antibodies against A. fumigatus, and/or elevated specific serum IgE against A. fumigatus. Among approximately 40 antigenic components of Aspergillus that can bind with IgE antibodies, specific antibodies to Asp f4 and Asp f6 may be particularly helpful for diagnostic purposes.

Suspicion of ABPA should prompt the measurement of serum total IgE level and skin testing for Aspergillus. Early recognition of ABPA allows treatment of exacerbations of ABPA with corticosteroids (with initiation of prednisone at approximately 0.5 mg/kg per day for 2 to 4 weeks then tapered) to prevent the progression of the disease to the irreversible end-stage. Inhaled corticosteroids may reduce the need for long-term oral corticosteroids. Oral itraconazole used at a dose of 200 mg twice daily for 4 to 6 months is a useful adjunct to corticosteroids, reducing the burden of fungal antigenic stimulation, allowing reduction of the corticosteroid oral dose, reducing the rate of exacerbations, and possibly improving the long-term outcome. The newer antifungal agent voriconazole has been used as a corticosteroid-sparing agent in ABPA only in isolated case reports and currently is not indicated in ABPA. Omalizumab, an anti-IgE recombinant antibody, has been used successfully in some cases; however, clinical experience is limited.

Iatrogenic Eosinophilic Pneumonias Secondary to Drugs, Toxic Agents, and Radiation Therapy

Drugs taken in the weeks preceding clinical onset of eosinophilic pneumonia must be thoroughly investigated, including illicit drugs (cocaine or heroin). Eosinophilic pneumonia has been reported in association with many drugs, but causality has been confidently established for fewer than 20 specific agents (Box 49-4).

Drug-induced eosinophilic pneumonia may develop progressively and manifest as chronic eosinophilic pneumonia, as a syndrome of transient pulmonary infiltrates with eosinophilia (Löffler syndrome), and occasionally as an acute pneumonia sometimes requiring mechanical ventilation. Acute eosinophilic pneumonia may occur in the context of drug rash with eosinophilia and systemic symptoms (DRESS), with frequent reactivation of human herpesvirus type 6, especially that due to anticonvulsant therapy, antibiotics (minocycline), allopurinol, and nonsteroidal antiinflammatory agents.

Corticosteroids often are given concomitantly with drug withdrawal to accelerate clinical improvement. When present, associated cutaneous rash or pleural effusion increases the likelihood of the diagnosis.

As with ICEP, chronic eosinophilic pneumonia has been described after radiation therapy for breast cancer in women. The clinical syndrome is similar to that for radiation-induced organizing pneumonia.

Other Lung Diseases with Associated Eosinophilia

Eosinophilia may be found in other bronchopulmonary disorders in which eosinophilic pneumonia is not prominent. Eosinophilic inflammation of the airways is a pathologic feature defining a phenotype of asthma. Some mild increase in eosinophils in peripheral blood and BAL fluid differential cell count (usually less than 5%) may be found in patients with asthma. Monitoring of the sputum eosinophil count may help in adapting the treatment and reducing asthma exacerbations and hospital admissions. Patients with the eosinophilic phenotype of asthma are considered to have greater airway remodeling and more frequent exacerbations than those without tissue eosinophilia. Mepolizumab, a humanized monoclonal antibody against IL-5, has been demonstrated to reduce the number of severe exacerbations in patients with refractory eosinophilic asthma (as defined by sputum eosinophil percentage of more than 3% on at least one occasion in the previous 2 years despite high-dose inhaled corticosteroid treatment); mepolizumab also improved the quality of life related to asthma and lowered eosinophil counts in blood and sputum. Some sparing of prednisone therapy and reduction in blood and sputum eosinophil counts also were obtained using mepolizumab therapy in patients with sputum eosinophilia (more than 3% eosinophils) and prednisone-dependent asthma. The therapeutic effect of mepolizumab confirms the role of eosinophils as an effector cell in the minority of asthma patients with the eosinophilic phenotype. More important, blood eosinophilia (i.e., counts of more than 1500/µL) may occasionally occur in the absence of any determined cause or context of systemic disease—a condition referred to as hypereosinophilic asthma, which frequently is severe and requires systemic corticosteroid therapy. Hypereosinophilic asthma may evolve to ICEP or overt Churg-Strauss syndrome (CSS), or it may remain solitary, with frequent dependency on oral corticosteroids.

Eosinophilic bronchitis (without asthma) with a high percentage of eosinophils (up to 40%) in sputum is a well-characterized cause of chronic cough responsive to corticosteroid treatment. Bronchial asthma and bronchial hyperreactivity are absent. Patients usually have normal lung function. Eosinophilic bronchitis may exceptionally reveal the myeloid variant of the hypereosinophilic syndrome.

Bronchocentric granulomatosis is a rare condition with nonspecific clinical and radiologic manifestations (fever, cough, and blood eosinophilia with counts generally greater than 1000/µL), diagnosed by lung biopsy. Corticosteroids constitute the mainstay of treatment.

Mildly increased levels of eosinophils may be found on the BAL fluid differential cell count in idiopathic interstitial pneumonias; this finding is associated with a poor prognosis. Focal eosinophilic pneumonia has been reported in cases of usual interstitial pneumonia, nonspecific interstitial pneumonia, and desquamative interstitial pneumonia. The typical clinical and imaging features of cryptogenic organizing pneumonia may closely mimic those of ICEP; some clinical or pathologic overlap between these two diseases is likely, although BAL fluid eosinophilia usually is mild, with differential cell counts less than 20%, in cryptogenic organizing pneumonia. Eosinophilia (usually mild) may be present in pulmonary Langerhans cell histiocytosis and in sarcoidosis.

Idiopathic Chronic Eosinophilic Pneumonia

ICEP is characterized by the progressive development of respiratory and systemic symptoms over several weeks. Cough, dyspnea, and chest pain are often accompanied by prominent fatigue, malaise, fever, and weight loss. Wheezes or crackles are found in one third of patients. Chronic rhinitis or sinusitis is present in approximately 20% of patients.

Most patients are nonsmokers. ICEP predominates in women (2 : 1 female-to-male ratio), with a mean age of 45 years at diagnosis, and a previous history of atopy in approximately half of the patients. Previous asthma is present in up to two thirds of the patients (it may get worse after the occurrence of ICEP), but it also may occur concomitantly with the diagnosis of ICEP or develop after it. Nonrespiratory minor manifestations are possible in ICEP, suggesting some overlap with CSS; however, any nonrespiratory manifestation (and particularly cardiac manifestations) should systematically prompt further evaluation for possible systemic disease, especially CSS.

Imaging features of ICEP (Figure 49-3) characteristically consist of alveolar opacities, with ill-defined margins and variable density, ranging from ground glass to consolidation. Migration of the infiltrates highly suggestive of the diagnosis occurs in approximately a quarter of the cases; however, it also may occur in cryptogenic organizing pneumonia. A peripheral predominance of the lesions (described as the classic pattern of “photographic negative of pulmonary edema”) is seen in approximately one fourth of patients. On high-resolution computed tomography (HRCT), the opacities are almost always bilateral and predominate in the upper lobes, with coexisting peripheral ground glass and consolidation opacities. In addition, septal line thickening, bandlike opacities parallel to the chest, or mediastinal lymph node enlargement may be seen. Small pleural effusions are present in only 10% of cases at HRCT.

Figure 49-3 Bilateral peripheral patchy opacities are evident on this computed tomography scan of the thorax of a patient with idiopathic chronic eosinophilic pneumonia.

High-level peripheral blood eosinophilia is the key to the diagnosis (mean blood eosinophil count of approximately 5500/µL) (Box 49-5). Alveolar eosinophilia, with BAL fluid differential cell count usually more than 40%, is a hallmark of ICEP. Because the BAL eosinophil cell count drops within days after institution of corticosteroid treatment, assessment for alveolar eosinophilia should be undertaken before any corticosteroid intake. Sputum eosinophilia also may be present; however, its diagnostic value has not been evaluated. C-reactive protein levels are elevated. Total blood IgE level is increased in approximately half the cases.

Lung function tests in ICEP show an obstructive ventilatory defect in approximately half and a restrictive ventilatory defect in half the cases. Usually mild hypoxemia is present in most of the patients.

ICEP responds dramatically to corticosteroid treatment. We use an initial dose of 0.5 mg/kg of oral prednisone per day for 2 weeks, followed by 0.25 mg/kg per day for 2 weeks, then corticosteroids are progressively reduced over a total duration of about 6 months and stopped. Improvement of the symptoms occurs within 2 days, and chest radiograph opacities clear within 1 week and eventually disappear without sequelae in almost all patients. Death resulting from ICEP is extremely rare. Relapses occur in more than half the patients while decreasing or after stopping the corticosteroid treatment and respond very well to resumed corticosteroid treatment; a dose of 20 mg per day of prednisone usually is sufficient to treat the relapses. Most patients need corticosteroids for more than 6 months, and often for several years. Relapses of ICEP may be less frequent in asthmatic patients who receive inhaled corticosteroids after stopping maintenance oral corticosteroids.

Idiopathic Acute Eosinophilic Pneumonia

IAEP differs from ICEP not only in its acute onset (less than 1 month) and severity but also in the absence of relapse after recovery. This acute pneumonia develops in previously healthy people, with possible respiratory failure, and may be misdiagnosed as infectious pneumonia or acute respiratory distress syndrome (ARDS). Patients with IAEP often are admitted to the intensive care unit. Blood eosinophilia, often lacking at presentation, contrasts with frank alveolar eosinophilia in BAL fluid. Current diagnostic criteria are listed in Box 49-6.

IAEP occurs mainly in young adults, with a male predominance and no previous asthma history. In several cases, IAEP developed soon after the initiation of tobacco smoking or change in smoking habits. Potential respiratory exposures within the days before onset of disease have been reported (e.g., cave exploration, heavy dust inhalation, inhalation of smoke), suggesting that exposure to inhaled contaminants or any nonspecific injurious agent may trigger the disease.

IAEP manifests with the acute onset of cough, dyspnea, fever, and chest pain, sometimes with abdominal complaints or myalgias. Tachypnea, tachycardia, and crackles are present on examination. The chest radiograph shows bilateral infiltrates (see Figure 49-4), with mixed alveolar interstitial and opacities, especially Kerley lines. Chest CT mainly shows ground glass opacities and air space consolidation, together with poorly defined nodules, interlobular septal thickening, and bilateral pleural effusions (in two thirds of patients)—an imaging pattern very distinct from that of ICEP that may evoke the diagnosis of IAEP.

Figure 49-4 Chest radiograph showing diffuse infiltrative pulmonary opacities in a patient with idiopathic acute eosinophilic pneumonia with respiratory failure.

Blood eosinophilia usually is lacking at presentation, and the diagnosis of eosinophilic lung disease may not be considered on admission. The finding of BAL fluid eosinophilia usually is sufficient, with differential counts greater than 25%, to obviate the need for lung biopsy; bacterial cultures of BAL fluid are sterile. The peripheral blood eosinophil count often rises over a few days during the initial course of disease—an evolution suggestive of the diagnosis. Eosinophilia also may be found in pleural effusion or sputum samples. High levels of IgE may be present as well.

Lung function tests are performed only in the less severe cases and will show a mild restrictive ventilatory defect, reduced carbon monoxide transfer capacity, and increased alveolar-arterial oxygen gradient, measured as PO₂(A−a). Severe hypoxemia may be present, with most patients fulfilling diagnostic criteria for acute lung injury (including a PaO₂/FIO₂ ratio of 300 mm Hg or less) or for ARDS (PaO₂/FIO₂ ratio of 200 mm Hg or less), with mechanical ventilation necessary in most of them. In marked contrast with ARDS, extrapulmonary organ failure or shock is exceptional; however, a few cases of fatal IAEP have been reported.

Lung biopsy generally is not necessary, and the diagnosis is established on clinical, radiologic, and BAL findings. The histopathologic features of IAEP include acute and organizing diffuse alveolar damage together with interstitial alveolar and bronchiolar infiltration by eosinophils, intraalveolar eosinophils, and interstitial edema. Although recovery may occur without corticosteroid treatment, corticosteroid treatment usually is given for 2 to 4 weeks, with a starting dose of oral prednisone or intravenous methylprednisolone of 1 to 2 mg/kg per day. Complete clinical and radiologic recovery occurs rapidly after initiation of corticosteroids, with no relapse (in contrast with ICEP). A careful search for a potential cause of IAEP is mandatory, especially infectious agents, parasites, and drugs, including illicit and over-the-counter drugs.

Churg-Strauss Syndrome

CSS (see also Chapter 59) is included in the group of small-vessel vasculitides and is defined as an eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels; it is associated with asthma and eosinophilia. All of the pathologic lesions—initially described from autopsied cases—are seldom found in a single biopsy specimen, and abnormalities often are limited to an eosinophilic perivascular infiltration of the tissues characteristic of the early (prevasculitic) phase of the disease. CSS is one of the pulmonary vasculitides associated with antineutrophil cytoplasmic antibodies (ANCA), together with granulomatosis with polyangiitis (Wegener) and microscopic polyangiitis, with ANCA found only in about 40% of cases of CSS.

CSS is a very rare disorder, occurring especially in the fourth and fifth decades of life, with no gender predominance. About one third of the patients have evidence of allergy, mostly perennial allergies to dust mites. The natural history of CSS usually incorporates three phases: rhinosinusitis and asthma, blood and tissue eosinophilia, and eventual emergence of systemic vasculitis. Eosinophilic rhinitis, present in three fourths of the cases, often is accompanied by relapsing paranasal sinusitis and nasal polyps; however, septal nasal perforation or saddle nose deformity is rare. Asthma becomes progressively cortico-dependent, usually preceding the onset of vasculitis by 3 to 9 years (however, these conditions may be contemporary). The severity of asthma may worsen before onset of the vasculitis, with attenuation thereafter, and further improvement on remission of the vasculitis.

The chest radiograph may remain normal in appearance throughout the course of the disease. Lung opacities, present in more than half of patients, correspond to eosinophilic pneumonia and consist mainly of ill-defined pulmonary infiltrates, sometimes migratory and transient. Pleural eosinophilic exudate, present in approximately one fourth of patients, must be distinguished from the transudate associated with cardiac failure resulting from cardiac eosinophilic involvement with severe cardiomyopathy. HRCT mainly shows areas of ground glass attenuation or air space consolidation, with peripheral predominance or random distribution (Figure 49-5). Centrilobular nodules, bronchial wall thickening or dilatation, interlobular septal thickening, and hilar or mediastinal lymphadenopathy are less common. These abnormalities are nonspecific and resemble those seen in ICEP, although the subpleural distribution of consolidation is less pronounced, centrilobular nodules within ground glass opacities are more frequent, and traction bronchiectases are less frequent in CSS than in ICEP. Pulmonary cavitary lesions are exceptional.

Figure 49-5 Computed tomography scan of the thorax showing ground glass opacity and consolidation with central predominance in a patient with Churg-Strauss syndrome.

Blood eosinophilia, with cell counts greater than 1500 and often 5000/µL, usually parallels disease activity. It disappears with dramatic rapidity after the initiation of corticosteroid treatment. Eosinophilia also is evident on the BAL fluid differential cell count, which may be more than 60%, and sometimes in the pleural fluid. IgE levels usually are markedly increased. High levels of urinary EDN may represent an indicator of disease activity.

Extrapulmonary manifestations of CSS usually include asthenia, weight loss, fever, arthralgias, and/or myalgias. Neurologic involvement typically consists of mononeuritis multiplex or asymmetric polyneuropathy. Cardiac involvement manifesting as eosinophilic myocarditis (or, more rarely, coronary arteritis) often is of insidious onset and asymptomatic and may lead to dilated cardiomyopathy, although marked clinical improvement may follow corticosteroid treatment. Pericardial effusion is common, but tamponade is rare. Endomyocardial fibrosis is rare, in contrast with the idiopathic hypereosinophilic syndrome. Myocardial involvement is a common finding in systematic studies by echocardiography or magnetic resonance imaging (MRI), and its frequency may have been heretofore underestimated. Digestive tract involvement usually manifests as isolated abdominal pain or diarrhea, but intestinal vasculitis (with ulcerations, perforations, or hemorrhage) and cholecystitis may occur. Cutaneous lesions, seen in approximately half of the patients, consist mainly of palpable purpura (Figure 49-6) on the extremities, subcutaneous nodules, erythematous rashes, and urticaria. Renal involvement, present in a fourth of the cases, usually is mild.

Figure 49-6 Vasculitic palpable purpura on the forearm of a patient with Churg-Strauss syndrome.

Currently used diagnostic criteria for CSS are shown in Box 49-7. ANCA also may be considered a major diagnostic criterion when present. Conversely, absence of ANCA does not exclude the diagnosis of CSS. A histopathologic diagnosis of CSS may be obtained by examination of skin, nerve, or muscle biopsy specimens. Lung biopsy and transbronchial biopsy are not helpful. The diagnosis of CSS may be difficult, especially at an early stage, with mild or limited manifestations corresponding to “formes frustes” of CSS. These may consist of cases in which the disease has been partly controlled by corticosteroids given for asthma.

ANCA are found in only approximately 40% of patients and consist mainly of perinuclear ANCA (p-ANCA), with a specificity for myeloperoxidase on ELISA, whereas other ANCA (especially cytoplasmic ANCA [c-ANCA] with proteinase-3 specificity) are very rare in CSS. Of interest, two phenotypes of CSS can be distinguished on the basis of these antibodies (Table 49-1): Patients with ANCA have a vasculitic phenotype (with more frequent vasculitis on biopsy, renal involvement, peripheral neuropathy, and purpura), whereas patients without ANCA have more frequent cardiac and pulmonary involvement. Therefore, patients with CSS seen in respiratory medicine departments or chest clinics are at high risk for cardiac involvement, which can be subclinical (with especially no chest pain) and should be systematically evaluated with measurement of serum troponin, electrocardiogram, echocardiography, and possibly MRI of the heart, which can identify impaired cardiac function and myocardial involvement. Serum measurement of eotaxin-3 and of CCL17/thymus and activation–related chemokine may reflect disease activity and merits further study as a potential biomarker of disease monitoring.

Table 49-1 Clinical Phenotypes of Churg-Strauss Syndrome

ANCA, antineutrophil cytoplasmic antibodies; p-ANCA, perinuclear ANCA.

A role for triggering or adjuvant factors such as vaccines or desensitization in the development of CSS has been postulated. Drug-induced eosinophilic vasculitis with pulmonary involvement has been occasionally reported. The possible responsibility of leukotriene-receptor antagonists in the development of CSS is still debated, and these agents must be avoided in patients with asthma and eosinophilia or with extrapulmonary manifestations compatible with smoldering CSS.

Corticosteroids are the mainstay of treatment of CSS, starting with 1 mg/kg per day of prednisone, with progressive tapering over several months. Initial intravenous pulses of methylprednisolone (15 mg/kg/day for 1 to 3 days) are useful in the most severe cases. Approximately half of the patients without poor prognostic factors at onset achieve complete remission with corticosteroid treatment alone and do not experience relapse. Relapses of CSS must be distinguished from relapse or persistence of difficult asthma (generally accompanied by less than 500/µL blood eosinophils). Long-term monitoring of lung function is warranted, because a proportion of patients develop fixed airflow obstruction.

Intravenous pulses of cyclophosphamide (usually up to six pulses) in addition to corticosteroids are indicated in patients with poor prognostic factors at onset (proteinuria with greater than 1 g/day protein excretion; renal insufficiency with serum creatinine greater than 15.8 mg/L; gastrointestinal tract involvement; cardiomyopathy; central nervous system involvement). Immunosuppressive treatment using oral azathioprine also is considered in patients who relapse despite more than 20 mg of prednisone daily. Rituximab, intravenous high-dose immunoglobulins, cyclosporine, and subcutaneous interferon-α have been of recognized benefit in patients with treatment-refractory CSS. The anti-IgE agent omalizumab has been used successfully to treat persistent asthma in patients with CSS; it does not control the systemic disease, however, so careful clinical monitoring is warranted. The prognosis for CSS has improved considerably over the years, with more than 90% of patients alive at 5 years according to current data.

Idiopathic Hypereosinophilic Syndromes

The historical definition of the idiopathic hypereosinophilic syndromes (HESs) included a persistent eosinophilia with counts greater than 1500/µL for longer than 6 months, a lack of evidence for a known cause of eosinophilia, and presumptive signs and symptoms of organ involvement. Recent studies have demonstrated that HESs fitting this definition may result especially from clonal proliferation of lymphocytes or of the eosinophil cell lineage itself.

HES, as described in older series, was much more common in men than in women (9 : 1), with an age at onset between 20 and 50 years. The typical clinical presentation includes insidious onset of weakness, fatigue, cough, and dyspnea, with a mean eosinophil count at presentation of up to 20,000/µL. Nonrespiratory manifestations of the HESs mainly target the skin, heart, and nervous system.

Cardiac involvement, present in 60% of patients, manifests mainly as characteristic endomyocardial fibrosis, often associated with development of intracavitary thrombi along the endocardium, and clinically associated with restrictive cardiomyopathy. Echocardiography shows mural thrombus, ventricular apical obliteration, and involvement of the posterior mitral leaflet.

Lung involvement, present in up to 40% of patients, is nonspecific. Cough may be the predominant feature. Asthma, pleural effusion, and pulmonary opacities on the chest CT scan (mostly patchy ground glass attenuation, consolidation, and small nodules) have been reported, and this aspect of HES must be distinguished from pleural effusion secondary to cardiac failure.

The lymphocytic variant of HES, which may account for approximately 30% of the cases, is a T cell disorder resulting from the production of chemokines (especially IL-5) by clonal T_H2 lymphocytes bearing an aberrant antigenic surface phenotype (such as CD3⁻CD4⁺). IgE level typically is elevated as a consequence of IL-4 and IL-13 production by T_H2 lymphocytes. Most patients initially have cutaneous papules or urticarial plaques infiltrated by lymphocytes and eosinophils. Diagnosis is obtained by lymphocyte phenotyping and analysis of the rearrangement of the T cell receptor genes in specialized laboratories.

The myeloproliferative variant of HES, accounting for approximately 20% of cases, is distinguished on the basis of clinical and biologic features in common with those of chronic myeloproliferative syndromes, including hepatomegaly, splenomegaly, anemia, thrombocythemia, increased serum vitamin B₁₂ and leukocyte alkaline phosphatase, and circulating leukocyte precursors. Mucosal ulcerations may be prominent. Severe cardiac manifestations are frequent and may be resistant to corticosteroid treatment. Myeloproliferative HES is attributed to a constitutively activated tyrosine kinase fusion protein (Fip1L1-PDGFRα) due to an interstitial chromosomal deletion in 4q12. Imatinib, a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia, proved to be efficacious in patients with the myeloproliferative variant of HES.

Only approximately half of the patients with HES respond to corticosteroid treatment. Other treatments include chemotherapeutic agents (hydroxyurea, vincristine, etoposide), cyclosporine, interferon-α (particularly for the myeloproliferative variant), and the anti–IL-5 antibody mepolizumab. Imatinib has become the major drug used in patients with the myeloproliferative variant of HES, especially when the FipL1-PDGFRα fusion protein is present. The prognosis with HES has improved markedly, with approximately 70% survival at 1 year.

A large proportion of affected patients have idiopathic HES—no cause can be found despite exhaustive analysis, with neither clonal proliferation of lymphocytes nor fusion protein activity detected. Improvement may be obtained with oral corticosteroids or imatinib. Respiratory manifestations in these patients have not been properly studied but seem to be of generally mild severity.

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