Introduction
The eosinophilic lung diseases are a group of disorders ( Table 68-1 ) characterized by the presence and presumed pathogenetic role of eosinophils in the disease processes. They are mainly represented by the eosinophilic pneumonias, which are defined by a prominent infiltration of the lung parenchyma by eosinophils. The other eosinophilic lung diseases mainly involve the airways, as in the allergic bronchopulmonary mycoses and hypereosinophilic obliterative bronchiolitis. Asthma, in which the eosinophil plays an important role, is not discussed in this chapter.
| EOSINOPHILIC LUNG DISEASE OF UNDETERMINED CAUSE |
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| EOSINOPHILIC LUNG DISEASE OF DETERMINED CAUSE |
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| MISCELLANEOUS LUNG DISEASES WITH POSSIBLE ASSOCIATED EOSINOPHILIA |
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Eosinophil Biology
The role of the eosinophil in homeostasis function, physiology, and pathophysiology has become better appreciated in recent years. Eosinophils are multifunctional leukocytes implicated in innate and adaptive immunity, including numerous inflammatory reactions to parasitic helminth, bacterial, and viral infections. They have been especially credited with a beneficial role in parasitic infestation; however, results from in vivo infection studies have given conflicting results.
The eosinophil matures in the bone marrow under the action of cytokines and especially of interleukin (IL)-5 (involved in the differentiation of eosinophil precursors), IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) and the activation of transcription factors including Δdbl-GATA-1. The eosinophil then circulates in the blood for about 1 day before being attracted into tissues by complex processes including adhesion and attraction, diapedesis, and chemotaxis, where it undergoes apoptosis unless survival factors are present.
Major advances have been made in the understanding of molecular and intracellular pathways regulating eosinophil differentiation, priming, activation, degranulation, and mediator secretion (with especially the role of vesicle-associated membrane proteins in the regulation of granule fusion in eosinophils). The eosinophil contains two types of intracytoplasmic granules. The larger granules, characterized by an electron-dense crystalloid matrix, contain the characteristic cationic proteins, which have direct toxicity to the heart, brain, and bronchial epithelium. The smaller amorphous granules contain arylsulfatase and acid phosphatase. Activation of the eosinophil results in degranulation with the extracellular release of the eosinophil-specific proteins, including major basic protein (MBP), eosinophil cationic protein, eosinophil-derived neurotoxin, and the enzymatic protein eosinophil peroxidase (EPO). The finding of vacuoles in the cytoplasm of the eosinophil and ultrastructural evidence of loss of electron density from the central core of the granules (inversion or disappearance of core density) morphologically characterizes the process of degranulation. Eosinophils also release proinflammatory cytokines, arachidonic acid–derived mediators, enzymes, reactive oxygen species, and matrix metalloproteases. They express a variety of surface proteins, including adhesion molecules, apoptotic signaling molecules, chemokines, complement receptors, chemotactic factor receptors, cytokine receptors, and immunoglobulin receptors. The release of toxic substances in itself contributes to the pathophysiology of eosinophilic disorders.
Many biologic properties of the eosinophil are directed by T helper (Th) lymphocytes, but the eosinophil interacts in many allergic or inflammatory processes with other cells including mast cells and basophils, endothelial cells, macrophages, platelets, and fibroblasts. Eosinophils are capable of regulating mast cell function and histamine release. Activated eosinophils express the major histocompatibility complex II protein human leukocyte antigen, (HLA)-DR, and possess the ability to participate in numerous immune functions, including antigen presentation and secretion of an array of cytokines capable of promoting effector T-cell proliferation. In addition, eosinophils are implicated in the regulation of Th1/Th2 balance, through synthesis of IL-4, promotion of IL-4, IL-5, and IL-13 secretion by CD4 + T cells, as well as the synthesis of indoleamine 2,3-dioxygenase (indirectly promoting Th1 apoptosis). Identification of the immune and multifunction properties of the eosinophil has changed the view on eosinophils, from a terminal effector cell in allergic airway diseases to the current paradigm of eosinophils being involved in the initial stages of disease development. In addition, abnormalities in the T-cell receptor repertoire and T-cell clonotype of bronchoalveolar lavage (BAL) lymphocytes and peripheral blood lymphocytes might contribute to the pathophysiology of eosinophilic lung diseases.
Recruitment of the eosinophil to the lung mostly implicates IL-5 and the eotaxin subfamily of chemokines (itself regulated by the Th2 cell–derived IL-13 cytokine). Release of toxic granule proteins and lipid mediators by eosinophils may contribute to tissue damage and dysfunction. Although histopathologic lesions related to the release of toxic granule proteins and lipid mediators in eosinophilic pneumonias are largely reversible with treatment, tissue damage and remodeling with fibrosis (partly through the release of transforming growth factor-β by eosinophils) associated with eosinophil infiltration can take place, especially in the bronchial mucosa, as in allergic bronchopulmonary aspergillosis (ABPA) and in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (EGPA [CSS]). Corticosteroids are the most effective agents for dramatically reducing eosinophilia in the blood and tissues by shortening the half-life of cytokines such as eotaxins and inhibiting the cytokine-dependent survival of eosinophils.
Major impediments in eosinophil research are the inability of murine eosinophils to degranulate either in vivo or in vitro in contrast with human eosinophils that differentially release their granule proteins after contact with different stimuli and the limits of animal models in mimicking human eosinophilic lung disease. The availability of humanized anti-IL-5 antibody, which lowers eosinophil levels in the blood and in the lung in humans, as well as of genetically engineered mice such as those deficient in IL-5 or in eosinophils, has contributed to a better understanding of the pathogenic role of eosinophils. Recent advances in eosinophil biology and drug design have led to the design of a variety of potential therapeutic agents that target eosinophil-specific molecules and which are the focus of active research in patients with hypereosinophilic diseases. The most promising targets currently being investigated include IL-5 and IL-5R, CD2 binding protein, immunoglobulin E (IgE), and IL-4/IL-13 receptor, with a few agents already evaluated or routinely used clinically.
General Features of Eosinophilic Pneumonias
Historical Perspective
In 1952, Reeder and Goodrich published a series of cases describing pulmonary “infiltration with eosinophilia,” including probable idiopathic chronic eosinophilic pneumonia (ICEP) and EGPA. Crofton and coworkers published in the same year a series of 16 cases of “pulmonary eosinophilia” with a review of 450 cases from the literature and proposed the following classification:
- 1.
Simple pulmonary eosinophilia (Löffler syndrome), defined by mild symptoms and transient opacities.
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Prolonged pulmonary eosinophilia characterized by radiographic shadows persisting for longer than 1 month.
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Tropical eosinophilia.
- 4.
Pulmonary eosinophilia with asthma (a rather heterogeneous category).
- 5.
Polyarteritis nodosa.
The authors mentioned “a continuum from the simple and transient abnormalities of Löffler syndrome to the severe and often fatal manifestations of polyarteritis nodosa.” Churg and Strauss had reported in 1951 the eponym syndrome of “allergic granulomatosis, allergic angiitis, and periarteritis nodosa,” and Carrington and colleagues described in 1969 the syndrome of ICEP. McCarthy and Pepys later reported 27 cases of “cryptogenic pulmonary eosinophilias,” 2 of whom developed systemic vasculitis.
Clinical Presentation
Eosinophilic pneumonia is a pneumonia where the eosinophils are the most prominent inflammatory cells on histopathologic examination. Other inflammatory cells, especially lymphocytes and neutrophils, are often associated, but eosinophils clearly predominate. In clinical practice, the eosinophilic pneumonias may be separated into two main etiologic categories: (1) those in which a definite cause is found or (2) those of undetermined origin, that is, idiopathic (with the eosinophilic pneumonia being either solitary or included in a systemic disorder such as EGPA).
A definite cause must be carefully investigated in any patient with eosinophilic pneumonia because it has practical consequences (e.g., stopping a drug responsible for iatrogenic eosinophilic pneumonia or treating a parasitic infection). When no cause is identified, the eosinophilic pneumonias may usually be included within well-characterized and individualized syndromes.
The eosinophilic pneumonias may manifest by different clinicoradiologic syndromes, namely Löffler syndrome, chronic eosinophilic pneumonia, or acute eosinophilic pneumonia, mostly differing from one another by the pattern of disease onset. Extrapulmonary manifestations accompanying eosinophilic pneumonia are the hallmark of EGPA and, to a lesser extent, hypereosinophilic syndromes (HESs), drug reactions, or infections, especially parasitic infections. The vast majority of cases of eosinophilic pneumonia respond dramatically to corticosteroid treatment and heal without significant sequelae.
Pathology
Histopathologic studies of eosinophilic pneumonia have mainly been done in patients with ICEP, which was initially diagnosed by open-lung biopsy. The pathologic features described in ICEP may be considered as a common denominator of all categories of eosinophilic pneumonias, whatever their origin. Occasionally, pathologic studies in eosinophilic pneumonias of known cause have further shown some specific features, such as a possible distinctive distribution of lesions (e.g., bronchocentric distribution in ABPA) or the presence of causal agents such as parasites or fungal hyphae.
In ICEP, the alveolar spaces are filled with eosinophils ( Fig. 68-1 ). Macrophages are also present with some multinucleated giant cells scattered in the infiltrate; these may contain eosinophilic granules or Charcot-Leyden crystals. An associated interstitial inflammatory cellular infiltrate is invariably present, consisting of eosinophils, lymphocytes, plasma cells, and histiocytes. A proteinaceous and fibrinous exudate accompanies the cellular eosinophilic infiltrate. Some eosinophilic microabscesses may be observed (foci of necrotic intra-alveolar eosinophils surrounded by macrophages or epithelioid cells with palisading arrangement). Morphologic (especially electron microscopic) and immunohistochemical studies have shown eosinophil degranulation within the site of eosinophilic pneumonia. The global architecture of the lung remains intact, without necrosis or fibrosis.
Organization of the alveolar inflammatory exudate is a rather common finding, suggesting some possible overlap between ICEP and organizing pneumonia. However, intraluminal organization in the distal air spaces is only sparse and never prominent in ICEP. Mucus plugs obstructing the small airways may be present in ICEP. A mild non-necrotizing vasculitis involving both small arteries and venules is common, with perivascular cuffing and a few cells infiltrating the arterial media ( Fig. 68-2 ).
The distribution of eosinophilic pneumonia is generally diffuse. However, it may be more focal in some cases, and the lesions may have an angiocentric or bronchiolocentric distribution in some etiologic groups of eosinophilic pneumonia. The hilar lymph nodes associated with ICEP contain many eosinophils, and lymphoid hyperplasia is present.
In idiopathic acute eosinophilic pneumonia (IAEP), the pathologic pattern includes intra-alveolar and interstitial eosinophilic infiltrates, diffuse alveolar damage, intra-alveolar fibrinous exudates, organizing pneumonia, and non-necrotizing vasculitis ( Fig. 68-3 ).
Diagnosis
In clinical practice, the diagnosis of eosinophilic pneumonia is suspected in patients presenting with respiratory symptoms (dyspnea, cough, or wheezing); pulmonary opacities at chest imaging; and the demonstration of eosinophilia in the peripheral blood or, preferably, in the lung. Importantly, blood eosinophilia is defined by an eosinophil blood count greater than 0.5 × 10 9 /L (500/µL) and hypereosinophilia by an eosinophil blood count greater than 1.5 × 10 9 /L (1500/µL) on two examinations at least 1 month apart, and/or tissue hypereosinophilia.
Although pathologic examination of the lung has been the “gold standard” to define eosinophilic pneumonia, surgical lung biopsy is almost abandoned and video-assisted thoracoscopic lung biopsy is seldom necessary. Transbronchial lung biopsy may show characteristic features of eosinophilic pneumonia, but the small size of the specimen usually does not allow morphologic evidence of a possible etiologic process.
BAL has become a widely accepted noninvasive surrogate of lung biopsy for the diagnosis in a patient with high-resolution computed tomography (HRCT) features of eosinophilic pneumonia, although no study has definitely established a correlation between increased eosinophils at differential cell count and the finding of eosinophilic pneumonia at lung pathology. In normal subjects, BAL eosinophilia is lower than 1% of cells at differential count. In contrast, BAL eosinophilia greater than 40% is found mainly in patients with chronic eosinophilic pneumonia, whereas BAL eosinophilia between 3% and 40% (and especially between 3% and 9%) may be found in various conditions, such as idiopathic pulmonary fibrosis, interstitial lung disease associated with connective tissue disorders, hypersensitivity pneumonitis, sarcoidosis, radiation pneumonitis, asthma, pneumoconioses, and infection.
A conservative cutoff of 40% of eosinophils in the BAL has been adopted for the diagnosis of ICEP in clinical studies, and a cutoff of 25% has been proposed for the diagnosis of IAEP. For clinical practice, our recommendation is that a diagnosis of eosinophilic pneumonia is supported by alveolar eosinophilia when the eosinophils (1) are the predominant cell population (macrophages excepted) and (2) represent more than 25% and preferably more than 40% of the differential cell count in the BAL.
Although BAL is usually a safe procedure, it may not always be mandatory in typical cases with both radiographic pulmonary opacities and peripheral blood eosinophilia, although alternative diagnoses can be considered (such as bacterial or parasitic pneumonia, or pulmonary opacities related to Hodgkin disease). However, diagnosing eosinophilic pneumonia on the sole finding of blood eosinophilia and pulmonary opacities requires markedly elevated eosinophilia (>1 × 10 9 /L and preferably 1.5 × 10 9 /L; >1000 and preferably 1500/µL) together with typical clinicoradiologic features, because the finding of peripheral blood eosinophilia does not prove that the observed pulmonary opacities correspond to eosinophilic pneumonia. For example, BAL may occasionally be omitted for the diagnosis of Löffler syndrome (as it is seen in ascariasis), with rather mild and nonspecific cough and wheezes, transient pulmonary opacities at chest radiography, and frank blood eosinophilia. Conversely, peripheral blood eosinophilia may be missing in patients who have already received systemic corticosteroids, and it is often absent at presentation in IAEP. Nevertheless, BAL is recommended to confirm the diagnosis of eosinophilic pneumonia in most cases.
Once the diagnosis of eosinophilic pneumonia has been made, a thorough evaluation is necessary to investigate possible causes, such as parasitic infection or drug or toxic exposure, and to classify the case into one of the possible clinical entities (see Table 68-1 ).
Eosinophilic Lung Disease of Undetermined Cause
ICEP is characterized by a progressive onset of symptoms over a few weeks with cough, increasing dyspnea, malaise, and weight loss, whereas IAEP presents as an acute pneumonia (similar to acute lung injury or acute respiratory distress syndrome [ARDS]) with frequent respiratory failure necessitating mechanical ventilation. Both conditions are idiopathic.
Idiopathic Chronic Eosinophilic Pneumonia
Idiopathic chronic eosinophilic pneumonia (ICEP) was first described in detail by Carrington and colleagues, in a series of nine patients, and further confirmed and detailed by several series and numerous case reports.
Clinical Features
ICEP arises predominantly in women (with a 2:1 female-to-male ratio). Although ICEP may develop in young people, only 6% of patients are younger than 20 years old. The incidence of ICEP peaks in the fourth decade, with a mean age of 45 years at diagnosis. A vast majority of patients with ICEP are nonsmokers, suggesting that smoking might be protective. A prior history of atopy is found in about half of the patients, with allergic rhinitis in 12% to 24%, drug allergy in about 10%, nasal polyps in 5% to 13%, urticaria in 10%, and eczema in 5%.
Prior asthma is present in up to two thirds of the patients. Asthma may also develop concomitantly with the diagnosis of ICEP in 15% of patients or develop after ICEP in 13%. The presentation of ICEP is similar in asthmatic and nonasthmatic patients with the exception of higher total IgE in the former group. ICEP may develop while asthmatic patients are on a desensitization program, but there is no proof that desensitization may contribute to the development of ICEP. Asthma often gets worse after the development of ICEP and requires long-term oral corticosteroid treatment even in the absence of recurrence of the eosinophilic pneumonia.
The onset of ICEP is progressive, with a mean interval between the onset of symptoms and the diagnosis of 4 months in one series. The most common respiratory symptoms are cough, dyspnea, and chest pain. Dyspnea is usually not severe initially, although the necessity for mechanical ventilation after several months of progression of disease has occasionally been reported. Hemoptysis is rare but has been reported in up to 10% of cases. Wheezes at physical examination are found in one third of patients and crackles in 38%. Upper respiratory tract symptoms of chronic rhinitis or sinusitis are present in about 20% of patients.
Systemic symptoms and signs are often prominent, with fever, weight loss (>10 kg in about 10%). Asthenia, malaise, fatigue, anorexia, weakness, and night sweats are also common.
Imaging
The imaging features of ICEP are characteristic, although they may overlap with those found in cryptogenic organizing pneumonia (see Chapter 63 ). Peripheral opacities on chest radiography are present in almost all cases and are migratory in a quarter of the cases. They usually consist of alveolar opacities with ill-defined margins, with a density varying from ground-glass to consolidation ( Fig. 68-4 , eFig. 68-1 ). The classic pattern of “photographic negative or reversal of the shadows usually seen in pulmonary edema,” highly evocative of ICEP, is seen in only one fourth of patients.
Characteristic imaging features of ICEP are better described at HRCT ( Fig. 68-5 ). Whereas the opacities are bilateral in at least 50% of cases at chest radiography, the proportion of bilateral opacities may increase up to 97.5% at HRCT. Characteristic opacities predominate in the upper lobes and are peripheral, with generally coexisting ground-glass and consolidation opacities at HRCT ( 
). Midzone distribution of opacities and centrilobular nodules are present in less than 20% of cases. Consolidation with segmental or lobar atelectasis may be seen. Septal line thickening is common (see ). On corticosteroid treatment, consolidation and ground-glass opacities rapidly show a decrease in size and extent ( eFig. 68-2 ), with possible change from consolidation to ground-glass opacities or inhomogeneous opacities, and later to streaky or bandlike opacities parallel to the chest wall. Cavitary lesions are extremely rare and should lead to reconsideration of the diagnosis. Contrary to organizing pneumonia, the reverse halo or atoll sign (i.e., central ground-glass opacity surrounded by denser consolidation in a crescentic circle or ring) is rare. Compared with IAEP, in which pleural effusions are seen in the majority (see later), small pleural effusions are present in only 10% of cases of ICEP at HRCT and mediastinal lymph node enlargement in 17%.
Laboratory Studies
Peripheral blood eosinophilia over 6% was present in 88% of 111 cases in one literature review, with a mean percentage of blood eosinophils at differential count of 26%. The mean blood eosinophilia was 5.5 × 10 9 /L (5500/µL) in our series, with eosinophils representing a mean of 32% of the total blood leukocyte count. Because peripheral blood eosinophilia is often a diagnostic criterion of ICEP, the proportion of patients with ICEP and possible normal peripheral blood count is unknown.
Erythrocyte sedimentation rate is increased, and C-reactive protein level is elevated. Total blood IgE level is increased in about half of cases and greater than 1000 IU/mL in 15% (normal < 100 IU/mL). Circulating immune complexes have been reported in ICEP in about one third of patients. Antinuclear antibodies may occasionally be present. Urinary eosinophil-derived neurotoxin level indicating active eosinophil degranulation is markedly increased.
Bronchoalveolar Lavage
BAL has replaced lung biopsy for the diagnosis of ICEP. Alveolar eosinophilia is a characteristic and constant feature in ICEP, with a mean of 58% at differential cell count. Alveolar eosinophilia may be associated with an increased percentage of neutrophils, mast cells, and lymphocytes. BAL eosinophil cell count drops within a few days under corticosteroid treatment. Sputum eosinophilia may also be present.
BAL eosinophils of patients with ICEP show activation features such as the release of eosinophil proteins, which are taken up by macrophages. Eosinophil cationic protein and eosinophil-derived neurotoxin are increased in BAL fluid of patients with ICEP. Expression of HLA-DR in a patient with ICEP was present on 86% of alveolar eosinophils in contrast to 7% of blood eosinophils, suggesting compartmentalization of eosinophilic activation within the lung. BAL lymphocytes are characterized by an accumulation of CD4 + T cells that express activation surface antigens of memory T cells (CD45RO + , CD45RA − , CD62L − ), and may present clonal rearrangement of the T-cell receptor repertoire. Recruitment of eosinophils to the lung involves various chemokines, which contribute to suppress Fas-induced apoptosis of eosinophils.
Differential Diagnosis
Although ICEP is not a systemic disease, isolated and moderately severe extrapulmonary manifestations, including arthralgias, repolarization (ST-T) abnormalities on the electrocardiogram, pericarditis, altered liver biologic tests, eosinophilic lesions at liver biopsy, mononeuritis multiplex, diarrhea, skin nodules, immune complex vasculitis in the skin, and eosinophilic enteritis, have been reported occasionally. Such manifestations suggest an overlap between ICEP and EGPA. Eosinophilic pneumonia similar to ICEP may be a presenting feature of EGPA with patients often receiving corticosteroid treatment, which may prevent the development of overt systemic vasculitis. In a series of ICEP with especially high frequency of extrapulmonary signs (30%), some of which were quite evocative of EGPA, none of the patients treated with corticosteroids developed characteristic EGPA or HES on follow-up.
Lung Function Tests
Lung function tests in ICEP show an obstructive ventilatory defect in about half the patients and a restrictive ventilatory defect in half the cases. Hypoxemia defined by an arterial oxygen pressure arterial (P o 2 ) of 75 mm Hg or less was present in 64% of patients in a series ; CO transfer factor (diffusing capacity D l CO ) was less than 80% of predicted in 52%, and transfer coefficient (D l CO per unit alveolar volume) was less than 80% of predicted in only 27%. An increased alveolar-arterial oxygen difference has been reported in 90% of cases. The impaired lung function tests normalize under treatment in most patients. However, a ventilatory obstructive defect may develop over time in some patients, especially those with a markedly increased BAL eosinophilia at initial evaluation.
Treatment and Prognosis
The natural course of untreated ICEP is not well known because most patients receive corticosteroids with a dramatic response. ICEP may spontaneously resolve, and death directly resulting from ICEP is exceedingly rare. Symptoms improve within 1 or 2 weeks of corticosteroid treatment and even within 48 hours in about 80% of cases. Pulmonary opacities on chest radiography clear rapidly ( eFig. 68-3 ). They disappeared within 1 week in 69% of patients in our series of patients treated with a mean initial dose of 1 mg/kg/day, and almost all patients treated with corticosteroids had a normal chest radiograph at their last follow-up visit.
The optimal dose of corticosteroids is not established, but the usual doses vary between 20 and 60 mg/day. Our current recommendation is to start with 0.5 mg/kg/day of prednisone, with slow tapering over 6 to 12 months based on clinical evaluation and blood eosinophil cell count. Most patients require prolonged treatment (i.e., >6 months) because of relapse while decreasing below a daily dose of 10 to 15 mg/day of prednisone, or after stopping the corticosteroid treatment. In one series, 58% of cases relapsed after corticosteroids had been discontinued and 21% while the corticosteroids were being tapered. In our series, half of the patients relapsed after the corticosteroids had been weaned (with a mean delay of 72 weeks) or were being tapered (the mean dose of corticosteroids at the time of relapse was 11 mg/day). Relapses in the same areas of the lungs or in different areas respond well to resumed corticosteroid treatment; a dose of 20 mg/day of prednisone is usually sufficient to treat the relapses.
The clinical series in which follow-up is available clearly show that most patients need very prolonged corticosteroid treatment: in our series with a mean 6.2 years of follow-up, only 31% were weaned at the last control visit. Respiratory symptoms may be due to asthma or to ICEP relapse. Relapses of ICEP are less frequent in patients with asthma, possibly because they often receive inhaled corticosteroids after stopping oral corticosteroids. Inhaled corticosteroids might thus help in reducing the maintenance dose of oral corticosteroids, although they are not sufficient when given as monotherapy. Long-term steroid use may lead to osteoporosis. Omalizumab, a recombinant humanized monoclonal antibody against IgE, has been suggested in case reports to prevent recurrence of ICEP and to spare oral corticosteroids ; however, caution must be exerted given recent reports of omalizumab-associated EGPA. Mepolizumab, a monoclonal antibody against IL-5, has not yet been evaluated in patients with ICEP.
Idiopathic Acute Eosinophilic Pneumonia
Idiopathic acute eosinophilic pneumonia (IAEP) differs from ICEP by its acute onset, the severity of hypoxemia, the usual lack of increased blood eosinophils at presentation contrasting with frank eosinophilic alveolitis at BAL (BAL differential count with ≥ 25% eosinophils or predominance of eosinophils in open lung biopsy), and the absence of relapse after clinical recovery. Because fever and bilateral opacities on chest radiograph are present in all patients, IAEP is often misdiagnosed as infectious pneumonia and its frequency may therefore be underestimated. The absence of hypersensitivity to drugs, historical or laboratory evidence of infection, and other known causes of acute eosinophilic lung disease are additional diagnostic criteria. Current diagnostic criteria of IAEP are listed in Table 68-2 .
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Clinical Features
The average age at presentation is about 30 years, but IAEP may develop in patients age 20 or younger and in older patients. In contrast with ICEP, it is seen almost exclusively in males, and most patients have no prior asthma history.
Importantly, most patients seem to have been exposed to dust or cigarette smoke within the days before onset of disease. Some patients had peculiar outdoor activities, such as cave exploration, plant repotting, wood pile moving, smokehouse cleaning, motocross racing in dusty conditions, indoor renovation work, gasoline tank cleaning, and explosion of a tear gas bomb. One case was also reported in a New York City firefighter exposed to World Trade Center dust.
A causative role of cigarette smoke seems established because IAEP has developed soon after the initiation of smoking (especially when starting with large quantities) in numerous patients, and challenge with cigarette smoking was positive in some of them, but tolerance may develop in patients who resume smoking. Flavoring components of smoked cigars have been suspected. Recent alterations in smoking habits (e.g., beginning to smoke, restarting, or increasing the number of cigarettes smoked daily) especially within 1 month (median delay, 2 weeks) seem to play a major role in the onset of “idiopathic” AEP. Passive smoking has also been reported to cause AEP. It is likely that inhalation of tobacco smoke or of any nonspecific injurious agent may initiate or contribute to the development of IAEP in individuals intrinsically prone to develop eosinophilic reactions to inhaled nonspecific causative agents. Increased levels of β(1→3)-D-glucan (a major component of the cell wall of most fungi and also one of the components of cigarette smoke) have been reported in BAL fluid of patients with IAEP.
IAEP develops acutely in previously healthy individuals, with symptoms at presentation consisting of cough, dyspnea, fever, and chest pain. It may also develop subacutely over a few weeks, with no clinical difference between patients seen in a time interval of less than 7 days or 7 to 31 days from the first symptoms to the diagnosis of IAEP. More than half of patients present with acute respiratory failure. Abdominal complaints and also myalgias have been reported. At physical examination, tachypnea and tachycardia are present, with crackles or, less often, wheezes on auscultation.
Imaging
The chest radiograph shows bilateral opacities, with mixed alveolar or interstitial opacities ( eFig 68-4A-B, G ). In contrast with ICEP, bilateral pleural effusion and Kerley B lines are common. The chest radiograph returns to normal within 3 weeks (see eFig. 68-4L ), with pleural effusions being the last abnormality to disappear.
At chest CT imaging, ground-glass opacities and air space consolidation are the most common patterns of parenchymal lesions, with poorly defined nodules and interlobular septal thickening seen in a majority of patients; pleural effusion is present in at least two thirds of patients and is usually bilateral (see eFig. 68-4C-F, H-K ). We consider that bilateral pleural effusion and interlobular septal thickening are highly characteristic of IAEP in a patient with eosinophilic pneumonia; in addition, they should raise the suspicion of IAEP in a patient considered to have infectious pneumonia.
Laboratory Studies
In contrast with ICEP, the white blood cell count at presentation usually shows an increased leukocyte count with a predominance of neutrophils, with eosinophils only rarely higher than 0.3 × 10 9 /L (300/µL), but the eosinophil count often rises to high values later during the course of disease, a retrospective finding suggestive of IAEP. Eosinophilia is also present in the pleural fluid and sputum.
The IgE level may be elevated in some patients, and serum IgG and especially IgG2 and IgG4 levels may be reduced during the active phase of disease as compared with controls, although with limited diagnostic value. Serum levels of thymus and activation-regulated chemokine (TARC/CCL17), KL6, or exhaled nitric oxide are often increased in IAEP as opposed to other causes of acute lung injury or infectious pneumonia; these biomarkers are not specific for IAEP, however.
Bronchoalveolar Lavage
Given the usual lack of initial blood eosinophilia, BAL is the key to the diagnosis of IAEP, showing an average percentage of 37% to 54% eosinophils on the differential cell count, with sterile bacterial cultures. Lymphocyte and neutrophil counts can be moderately increased. After recovery, eosinophilia in the BAL may persist for several weeks. We consider that the finding of eosinophilia greater than 25% at BAL may obviate the need for lung biopsy for diagnosis, at least in immunocompetent patients.
Lung Function Tests
Hypoxemia may be severe and refractory to breathing 100% oxygen, suggesting right-to-left shunting in some patients. A majority of patients fit the definition of ARDS of various severity (e.g., acute onset of respiratory failure not fully explained by cardiac failure or fluid overload, with objective exclusion of hydrostatic edema); bilateral opacities (not fully explained by effusions, lobar/lung collapse, or nodules); and an arterial P o 2 /F io 2 (fractional inspired oxygen concentration) < 300 mm Hg with positive end-expiratory pressure or continuous positive expiratory pressure greater than or equal to 5 cm H 2 O. Mechanical ventilation, either noninvasive or with intratracheal intubation, was necessary in a majority of patients in earlier series. More recent series have shown that the severity of IAEP is more varied than originally reported. In contrast with ARDS, shock is extremely unusual and extrapulmonary organ failure is not seen. F io 2 may be decreased within a few hours of steroid treatment in many patients initially requiring oxygen.
When performed in less severe cases, lung function tests have shown a mild restrictive ventilatory defect with normal forced expiratory volume in 1 second–to–forced vital capacity (FEV 1 /FVC) ratio and reduced transfer factor (diffusing capacity). Alveolar-arterial oxygen gradient is increased. Lung function tests performed after recovery are normal in most patients, with possible ventilatory restriction in some of them.
Lung Biopsy
Lung biopsy is seldom necessary when BAL is performed. When done, it shows acute and organizing diffuse alveolar damage together with interstitial alveolar and bronchiolar infiltration by eosinophils, intra-alveolar eosinophils, and interstitial edema.
Treatment and Prognosis
Recovery without corticosteroid treatment has been reported, and therefore improvement concomitant with corticosteroid treatment cannot be considered a diagnostic criterion of IAEP. However, when a diagnosis of IAEP is made, corticosteroid treatment is usually started with initially intravenous methylprednisolone and later changed to oral therapy that can be tapered over 2 to 4 weeks. The patient generally responds to corticosteroids within 3 days (see eFig. 68-4L ) and can be rapidly weaned from the ventilator and from oxygen supplementation. The chest radiograph normalizes within 1 week in 85% of patients, but mild pulmonary opacities and pleural effusion may still be present on chest computed tomography (CT) at 2 weeks. One recent study of 137 patients suggested that a treatment duration of 2 weeks may be sufficient, with an initial daily dose of 30 mg of prednisone (or 60 mg of intravenous methylprednisolone every 6 hours in patients with respiratory failure). Recovery is rapid with no significant clinical or imaging sequelae, and with no relapse after stopping corticosteroid treatment, in contrast with ICEP where relapse is common.
Although IAEP often presents clinically like acute lung injury or ARDS, its prognosis is far better. The key to the diagnosis is finding eosinophilia on BAL because blood eosinophilia is usually absent initially. A careful search for a cause of AEP is mandatory, and infectious agents must be sought for in BAL fluid by cultures and appropriate staining. Drug-induced AEP must also be carefully excluded. Identification of causative tobacco or environmental exposures is key to preventing rare recurrences that in most cases are due to resumption of cigarette smoking after smoking cessation.
Eosinophilic Granulomatosis with Polyangiitis
History and Nomenclature
The first reliable case of eosinophilic granulomatosis with polyangiitis (EGPA) was reported by Lamb in 1914. Churg and Strauss described in 1951 the eponymous syndrome, mainly from autopsied cases. They described characteristic pathologic features consisting of granulomatous extravascular lesions, as well as necrotizing, inflammatory, and granulomatous vascular changes, with an inflammatory exudate rich in eosinophils. The most frequent site of inflammation was the heart. In approximately half of the cases, a pneumonic process was found, with an eosinophil-rich exudate mixed with giant cells in the acute stage.
In the 1992 Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis, CSS was included in the group of small vessel vasculitides. In 2012, the nomenclature of the systemic vasculitides was revised at the International Chapel Hill Consensus Conference. The eponym CSS was replaced by the terminology of eosinophilic granulomatosis with polyangiitis to achieve nomenclature symmetry with microscopic polyangiitis and with granulomatosis with polyangiitis (Wegener), which are the pulmonary antineutrophil cytoplasmic antibody (ANCA)−associated vasculitides, together with single-organ, ANCA-associated vasculitis.
EGPA is defined as an eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract and a necrotizing vasculitis predominantly affecting small to medium vessels, associated with asthma and eosinophilia. It is acknowledged that the disease may be confined to a limited number of organs, especially the upper or lower respiratory tract. This terminology reminds us that EGPA is indeed a vasculitis; however, not all patients with EGPA have robust criteria of documented systemic vasculitis or the presence of ANCA. ANCAs are present in approximately 40% of the cases. ANCAs are more frequent when glomerulonephritis is present, and most patients with documented necrotizing glomerulonephritis have ANCAs. Therefore the current revised terminology and classification may require further refinement.
Pathology
Because the diagnosis is now made earlier in the course of disease, lung biopsy is seldom necessary, and patients may receive corticosteroids before overt vasculitis has developed. The pathologic lesions of EGPA currently observed only rarely comprise all the characteristic features on a single biopsy from one organ. When typical features are present, both vasculitis (necrotizing or not, involving mainly the medium-sized pulmonary arteries) and granulomatous eosinophilic infiltration are seen ( Fig. 68-6A-B ). The extravascular granuloma consists of palisading histiocytes and giant cells (see Fig. 68-6C ). Diffuse pulmonary hemorrhage with capillaritis can develop (see Fig. 68-6D ). When present, the eosinophilic pneumonia in EGPA is similar to ICEP. The early (prevasculitic) phase of EGPA is characterized by eosinophilic infiltration of the tissues without vasculitis (perivascular eosinophils are commonly found).
Clinical Features
The clinical features of EGPA have been well defined. It is a rare systemic disease, which presents especially in adults younger than 65 ; it has been occasionally reported in children and adolescents. There is no sex predominance. The mean age of onset of vasculitis ranges from 38 to 49 years.
Asthma, generally severe and becoming rapidly corticosteroid dependent, presents at a mean age of about 35. It usually precedes the onset of vasculitis by 3 years and up to 9 years. The interval between asthma and the onset of vasculitis may be much longer in rare cases, or they may be contemporaneous. The severity of asthma typically increases progressively until the vasculitis develops, but it may attenuate when the vasculitis flourishes and further increase once the vasculitis recedes.
Chronic rhinitis is present in about three quarters of cases of EGPA and is often accompanied by relapsing sinusitis and/or polyposis, with eosinophilic infiltration seen on histopathology. Paranasal sinusitis has been reported in 61% of patients. Crusty rhinitis may be present, but the rhinitis in EGPA is distinctly much less severe than in granulomatosis with polyangiitis, with septal nasal perforation or saddle nose deformation being unusual.
Asthenia, weight loss, fever, arthralgias, and myalgias (all of which are unusual in simple asthma) often herald the development of the extrapulmonary manifestations of vasculitis.
Heart damage, which may be severe and lead to cardiac failure or sudden death, results especially from eosinophilic myocarditis and much less commonly from coronary arteritis. Cardiac involvement is often insidious and asymptomatic and, thus may be recognized only when left ventricular failure and dilated cardiomyopathy have developed. Heart failure may require heart transplantation, but eosinophilic vasculitis may recur in the transplanted heart. However, myocardial impairment and coronary arteritis may markedly improve with corticosteroid treatment, thus necessitating a strict cardiac evaluation in any patient with suspected EGPA, including electrocardiogram, echocardiography, serum level of troponin, and magnetic resonance imaging (MRI) of the heart. The main practical difficulty is the absence of a gold standard to diagnose clinically relevant myocardial involvement. Cardiac MRI can frequently demonstrate late enhancement of the myocardium ; however, it remains difficult to differentiate irreversible lesions representing scarring from active inflammation requiring intense immunosuppression; the combination of cardiac MRI with positron emission tomography may be useful but deserves further study.
Pericarditis with limited effusion at echocardiography is common; tamponade is rare. In contrast with the idiopathic HES, endomyocardial involvement is not a common feature. Patients with EGPA are at greater risk of venous thromboembolic events.
Peripheral neurologic involvement mainly consists of mononeuritis multiplex, present in 77% of patients, or asymmetrical polyneuropathy, with sudden onset of painful, focal or multifocal weakness or sensory loss, generally in the lower extremities. Cranial nerve palsies and central nervous system involvement are rare. Digestive tract involvement is present in 31% of cases and usually manifests as isolated abdominal pain, but intestinal or biliary tract vasculitis may be present. Other digestive manifestations include diarrhea; ulcerative colitis; gastroduodenal ulcerations; perforations (esophageal, gastric, intestinal); digestive hemorrhage; and cholecystitis. Cutaneous lesions, which present in about half of patients, mainly consist of palpable purpura of the extremities, subcutaneous nodules (especially of the scalp and extremities), erythematous rashes, and urticaria. Renal involvement presents in 26% of cases and is usually mild, in contrast with the other ANCA-associated vasculitides.
Imaging
Pulmonary opacities corresponding to eosinophilic pneumonia represent the most typical abnormalities on chest radiograph and have been reported in large series with a frequency of 37% to 72% (see eFig. 60-9A ). The pulmonary opacities are usually noted at presentation, but the chest radiograph remains normal throughout the course of the disease in some patients. The pulmonary opacities usually consist of ill-defined opacities, sometimes migratory, transient, and of varying density. In contrast to granulomatosis with polyangiitis (GPA), pulmonary cavitary lesions are extremely unusual. Pleural effusion (usually mild) and phrenic nerve palsy may be observed.
The pulmonary opacities on thin-section chest CT mainly consist of areas of ground-glass attenuation (see eFig. 60-9B-E ) or air space consolidation, with peripheral predominance or random distribution ( Fig. 68-7 ); centrilobular nodules are more frequent than in patients with ICEP ; less common findings include bronchial wall thickening or dilation, interlobular septal thickening (see eFig. 60-9B-E ), hilar or mediastinal lymphadenopathy, pleural effusion, or pericardial effusion ( Fig. 68-8 ). When present, pleural effusion should lead one to consider both inflammatory eosinophilic exudate and transudate with cardiomyopathy as a possible cause. Because these abnormalities are nonspecific, a correct diagnosis of EGPA was made on CT in only 44% of 111 patients with eosinophilic lung diseases.
Laboratory Studies
Peripheral blood eosinophilia is a major feature of EGPA that usually parallels the activity of the vasculitis. Blood eosinophils are generally between 5 and 20 × 10 9 /L (5000 to 20,000/µL), but they may reach higher values. Blood eosinophilia often disappears dramatically after the initiation of corticosteroid treatment (which may thus cause the absence of eosinophilia if blood tests are not done before starting corticosteroid treatment). Eosinophilia, sometimes greater than 60%, is found on BAL differential cell count and in pleural fluid when present.
The ANCAs reported in about 40% of patients are mainly perinuclear antineutrophil cytoplasmic antibodies (p-ANCAs) with myeloperoxidase specificity (much less often cytoplasmic antineutrophil cytoplasmic antibody [c-ANCA] with proteinase 3 specificity). Serum IgE levels are markedly increased. The erythrocyte sedimentation rate and C-reactive protein level are increased, and anemia is common. High levels of urinary eosinophil-derived neurotoxin have been reported, and these might represent an activity index of disease. Serum IgG4, CCL17/TARC, CCL26/Eotaxin-3 levels are elevated in active disease, but these have not been validated as biomarkers.
Pathogenesis
The pathophysiology of EGPA is not established. EGPA may be considered as an autoimmune process involving T cells, endothelial cells, and eosinophils. Recent studies have identified possible defects in regulatory CD4 + , CD25 + , or CD4 + CD25 − T-cell lymphocytes (producing IL-10 and IL-2) in EGPA (as compared with ICEP), possibly influencing progression and prognosis of disease. Clonal CD8 + /Vβ + T-cell expansions with effector memory phenotype, showing markers of cytotoxic activity and consistent with a hypothesis of persistent antigenic stimulation, were found in peripheral blood lymphocytes by flow cytometry combined to analysis of T-cell antigen receptor (TCR)-γ gene rearrangement. T-cell receptor-C beta gene rearrangement were reported. Some triggering or adjuvant factors (such as vaccines or desensitization) have been suspected to play a role in EGPA. The hypothesis of defective apoptosis pathways in eosinophils has not been confirmed.
Although a family history of atopy and allergic rhinitis is often present, evidence of allergy (demonstration of specific IgE with corresponding clinical history) is present in less than one third of patients; when present, allergy in EGPA mainly consists of perennial allergies, especially to Dermatophagoides, with seasonal allergies less frequent than in asthmatic patients without EGPA. A genetic predisposition to develop EGPA has been demonstrated in patients carrying the major histopathology complex DRB4 allele and perhaps in certain families.
Other possible triggering factors include Aspergillus, allergic bronchopulmonary candidiasis, Ascaris, bird exposure, or smoked cocaine. Drug-induced eosinophilic vasculitis with pulmonary involvement has been reported in the past with sulfonamides used together with antiserum, and later with diflunisal, macrolides, and diphenylhydantoin. EGPA has also been reported in asthmatic patients treated with omalizumab, an anti-IgE antibody.
The possible responsibility of leukotriene-receptor antagonists (montelukast, zafirlukast, pranlukast) in the development of EGPA has generated much debate. Although the association between leukotriene receptor antagonists and EGPA is now established, there is conflicting evidence whether it is the result of confounding by indication or a genuine causal association. Whether the association is coincidental, whether some cases of smoldering EGPA flare because of reducing oral or inhaled corticosteroids and/or adding leukotriene receptor antagonists, or whether these drugs really exert a role on the pathogenesis of the vasculitis is not established. A possible mechanistic link has been proposed. However, EGPA may follow montelukast treatment in the absence of preexisting disease, may recur on rechallenge with leukotriene receptor antagonists, and may remit on withdrawal of this treatment without modifying the corticosteroid and/or immunosuppressive therapy. At least one recent study indicates that a causal relationship cannot be totally dismissed. We therefore consider that leukotriene receptor antagonists should be avoided in any asthma patient with eosinophilia and/or extrapulmonary manifestations compatible with smoldering EGPA.
Diagnosis
The diagnosis of EGPA may be difficult because the clinician nowadays is more often faced with patients presenting with early and mild signs corresponding to the so-called formes frustes of EGPA, which are more or less suppressed by corticosteroid treatment for asthma and which may later be unmasked, especially when treatment is reduced or stopped.
The evolution of EGPA usually follows three stages: asthma and rhinitis; tissue eosinophilia (such as a pulmonary disease resembling ICEP); and extrapulmonary eosinophilic disease with vasculitis. Diagnostic difficulties thus largely depend on the stage of disease at which the patient is seen. Although systemic disease is necessary to consider a diagnosis of EGPA, it is extremely important that the diagnosis be established before severe organ involvement (especially cardiac) is present.
There are currently no established diagnostic criteria for EGPA. Lanham and associates have proposed three diagnostic criteria including (1) asthma, (2) eosinophilia exceeding 1.5 × 10 9 /L (1500/µL), and (3) systemic vasculitis of two or more extrapulmonary organs. According to the classification criteria (which are not diagnostic criteria, however) of the American College of Rheumatology, a sensitivity of 85% and a specificity of 99.7% are obtained if four or more of the six following criteria are present in a patient with proven systemic vasculitis: asthma; eosinophilia greater than 10% on differential blood cell count; mononeuritis (including multiplex) or polyneuropathy; fluctuating opacities on chest radiography; bilateral maxillary sinusal abnormalities; or presence of extravascular eosinophils on a biopsy including a vessel. However, these diagnostic and classification criteria were proposed before ANCAs were available. In the future, the presence of ANCA will probably be considered a major diagnostic criterion when present, and provisional diagnostic criteria have been proposed. A pathologic diagnosis of EGPA is desirable, but not mandatory, in patients with characteristic clinical features and marked eosinophilia. The skin, nerve, and muscle are the most common sites where a pathologic diagnosis of vasculitis may be obtained. Biopsy of the cutaneous lesions is the most common and simple procedure to obtain pathologic evidence of vasculitis. Lung biopsy is seldom done. Transbronchial biopsies usually do not show vasculitis or granulomata.
Differential Diagnosis
The borders separating EGPA from the other ANCA-associated vasculitides and the other eosinophilic syndromes are sometimes difficult to establish. An overlap between ANCA-negative EGPA and unclassified systemic eosinophilic disease is possible. An eosinophilic variant of granulomatosis with polyangiitis has been described. Concurrent EGPA and pulmonary opacities and temporal arteritis (either with or without giant cells, either eosinophilic or not) have been described. Distinguishing between mild EGPA and ICEP with minor extrathoracic symptoms may also be difficult, especially in the absence of typical polyangiitis features. Some mild vasculitis (non-necrotizing) is common on pathologic examination of the lung in patients with ICEP. ICEP may further progress to EGPA. In addition, some cases of “limited” EGPA have been reported, including those solely involving the lung or the heart. Formes frustes of EGPA often consist of cases in which the disease has been controlled to a greater or lesser extent by corticosteroids given for asthma. Other cases are difficult to classify as either EGPA or idiopathic HES. Careful clinical analysis, the presence of ANCA, the finding of a vasculitis and granulomas on biopsy, and molecular biologic analysis (in the cases of idiopathic HES) help in determining the final diagnosis.
Interestingly, recent studies have demonstrated that ANCA status may characterize two distinct clinical phenotypes in EGPA ( Table 68-3 ). Hence patients with ANCA, representing approximately 40% of patients, have a vasculitic phenotype of disease with an increased frequency of extracapillary glomerular lesions, peripheral neuropathy, purpura, and biopsy-proven vasculitis. Conversely, EGPA patients without ANCA have a tissue phenotype of disease with more frequent cardiac and pulmonary involvement (and fever). The latter might conceivably represent a variant of the HES with systemic manifestations. The vasculitic phenotype of EGPA is more frequent in patients carrying the major histopathology complex DRB4 allele. The ANCA-negative EGPA is associated with the IL10 -3575/1082/592 TAC haplotype (part of the ancient haplotype IL-10.2 correlated with increased IL-10 expression). Thus genetic predisposition may affect the phenotype of EGPA.
| Vasculitic Phenotype | Tissular (Tissue) Phenotype | |
|---|---|---|
| Respective frequency | ≈40% | ≈60% |
| ANCA | Present (mostly p-ANCA with anti-MPO specificity) | Absent |
| Predominant clinical features | Glomerular renal disease Peripheral neuropathy | Cardiac involvement (eosinophilic myocarditis) |
| Purpura | Fever | |
| Predominant histopathologic features | Biopsy-proven vasculitis | Eosinophilic pneumonia |
Treatment and Prognosis
Corticosteroids are the mainstay of treatment of EGPA and suffice in a large number of cases. Initial methylprednisolone pulses, for 1 to 3 days, are useful in the most severe cases, then oral treatment is started, usually with 1 mg/kg/day of prednisone. Treatment is prolonged for several months with progressive reduction of doses. Relapses are common, and asthma often persists (or reappears if it had disappeared during high-dose corticosteroid treatment). Distinguishing relapse or persistence of so-called difficult asthma from relapse or persistence of EGPA requires precise evaluation, taking into account the levels of blood eosinophils (generally < 1 × 10 9 but < 1000/µL in asthma without EGPA relapse) and occasionally new systematic manifestations.
Cyclophosphamide therapy should be added to corticosteroids in patients with manifestations that could result in mortality or severe morbidity. A retrospective study of patients with either polyarteritis nodosa or EGPA identified four factors associated with higher mortality: age older than 65, cardiac symptoms (based on easily detectable clinical parameters), gastrointestinal involvement, and renal insufficiency, whereas ear, nose, and throat symptoms were associated with a lower risk of death. Cardiomyopathy is the main predictor of mortality in multivariable analysis, especially in cases of heart failure. Older age at diagnosis is also associated with a poor prognosis. The risk of relapse of the vasculitis is higher in patients with ANCA and lower in patients with baseline eosinophils > 3 × 10 9 /L (>3000/µL).
The combination of immunosuppressors with corticosteroids improved disease control, despite associated infections (which could be decreased by using bolus instead of oral cyclophosphamide administration). Mortality was associated with disease severity, and treatment with cytotoxic agents did not prevent relapses. Although the optimal duration of therapy remains to be determined, 12 cyclophosphamide pulses were better able to control the disease than a 6-pulse regimen in patients with EGPA and at least one poor prognosis factor at onset. Corticosteroid treatment alone for EGPA patients without poor prognostic factors at onset is efficient, with about half of the patients achieving complete remission without relapse. Therefore immunosuppressive therapy (most commonly with intravenous pulses of cyclophosphamide) in addition to corticosteroids is warranted in patients with poor prognostic factors at onset and especially heart failure. Maintenance therapy with oral azathioprine or intramuscular methotrexate in addition to corticosteroids may be useful in patients who relapse when taking less than 20 mg/day or more of prednisone.
Subcutaneous interferon-α was successfully used mainly in EGPA patients with severe disease. High-dose intravenous immunoglobulins, cyclosporin A, and rituximab have been used successfully in case reports or short series. The anti-IgE omalizumab has been used successfully in patients with EGPA to treat persistent asthma ; however, it does not control the systemic disease, and careful clinical monitoring is warranted. Mepolizumab has a glucocorticoid-sparing effect, reduces exacerbations, and improves asthma control in patients with eosinophilic asthma requiring daily oral glucocorticoid therapy. Mepolizumab is under evaluation as a potential therapy in EGPA.
The prognosis of EGPA has improved considerably over time, with almost 80% of patients alive at 5 years and 97% alive at 5 years in one recent series of EGPA without poor prognostic factors. Most deaths during the first year of treatment are due to cardiac involvement. In one series, EGPA did not appear to confer increased mortality, a rather surprising finding. As most patients continue to take oral corticosteroids over the long term, treatment-related side effects cause significant morbidity. In addition, airflow obstruction due to uncontrolled asthma is present despite corticosteroids in many patients during follow-up, and persistent airflow obstruction may develop. Airflow obstruction may not respond to inhaled bronchodilators but may be partly reversible with increased oral corticosteroid treatment.
Hypereosinophilic Syndrome
The definition of the “idiopathic” hypereosinophilic syndrome (HES) proposed by Chusid and coworkers in 1975 included (1) a persistent eosinophilia greater than 1.5 × 10 9 /L (1500/µL) for longer than 6 months, or death before 6 months associated with the signs and symptoms of hypereosinophilic disease; (2) a lack of evidence for parasitic, allergic, or other known causes of eosinophilia; and (3) presumptive signs and symptoms of organ involvement, including hepatosplenomegaly, organic heart murmur, congestive heart failure, diffuse or focal central nervous system abnormalities, pulmonary fibrosis, fever, weight loss, or anemia. The 14 cases they reported included 2 patients with “prolonged benign hypereosinophilia,” 3 with eosinophilic leukemia, and 1 with possible EGPA. The later published cases of the idiopathic HES also proved heterogeneous, although patients with typical chronic disease shared some common complications, especially cardiac involvement. The diagnosis of HES is now considered in patients with blood hypereosinophilia (>1.5 × 10 9 /L [1500/µL]) on at least two occasions in the absence of other etiologies for the eosinophilia.
Pathogenenesis
In contrast with common hypereosinophilia, which is usually a reactive nonclonal process (as in parasitic disorders), several studies demonstrated that HES may result from a clonal proliferation of lymphocytes producing eosinophilopoietic chemokines (“lymphocytic variant” of HES), or from the clonal proliferation of the eosinophil cell lineage itself (“myeloproliferative variant” of HES, also referred to as chronic eosinophilic leukemia ). The term idiopathic should probably be abandoned in the classification of HES and may be appropriate only for the proportion of cases that cannot at present be classified in either category. In such genuinely idiopathic cases, innovative diagnostic tools such as the quantitative assessment of the WTl transcript in peripheral blood may help to differentiate HES from other causes of eosinophilia of determined cause.
The “lymphocytic variant” of HES, which may account for about 30% of patients with HES, results from the production of chemokines (especially IL-5) (which promote the accumulation of eosinophils) by clonal Th2 lymphocytes (as demonstrated by clonal rearrangement of the TCR) bearing an aberrant immunologic phenotype (such as CD3 − CD4 + ). Lymphocyte phenotyping to detect a phenotypically aberrant T-cell subset by flow cytometry and analysis of the rearrangement of the TCR genes in search of T-cell clonality should be performed on the peripheral blood (and bone marrow). The observation of increased IL-5 expression from cultured T cells can also demonstrate that the observed eosinophilia is caused by an expanded population of T cells. Serum levels of IgE are elevated as a consequence of IL-4 and IL-13 production by Th2 lymphocytes. Serum levels of IL-5 and TARC are increased. Most reported patients were recruited from dermatology clinics and had papules or urticarial plaques infiltrated by lymphocytes and eosinophils (and in some of them, a cutaneous T-cell lymphoma or the Sezary syndrome was ultimately present). In such cases, the HES may be considered as a premalignant T-cell disorder.
The “myeloproliferative variant” of HES (or chronic eosinophilic leukemia), accounting for 20% to 30% of cases, is caused by a constitutively activated tyrosine kinase fusion protein created by fusion of FIP1L1–PDGFRA as a consequence of an interstitial chromosomal deletion of a region in the long arm of chromosome 4 (q12) not detectable by karyotype analysis. Hepatomegaly, splenomegaly, mucosal ulcerations, severe cardiac manifestations resistant to corticosteroid treatment, anemia, thrombocythemia, increased serum vitamin B 12 , leukocyte alkaline phosphatase and serum tryptase, and circulating leukocyte precursors are common and suggestive of the diagnosis, whereas cutaneous manifestations are infrequent. A pronounced mastocytosis (lacking KIT mutations) is frequent. The diagnosis is confirmed by chromosomal rearrangement analysis and transcript study of the FIP1L1–PDGFRA fusion gene (or nested polymerase chain reaction analysis), which should be systematically performed in patients with HES. The presence of the FIP1L1–PDGFRA rearrangement is sufficient for the diagnosis of myeloproliferative HES. Presence of the causative deletion can also be demonstrated using FISH probes to the gene CHIC2 encompassed in the deleted sequence. The fusion protein transforms hematopoietic cells and is inhibited by imatinib, a tyrosine kinase inhibitor originally used to treat chronic myelogenous leukemia, other chronic myeloproliferative diseases, and gastrointestinal stromal tumors (also characterized by aberrant constitutively activated tyrosine kinases). Imatinib proved efficient for several months in treating HES in patients refractory to corticosteroids, hydroxyurea, and/or interferon-α. One patient relapsed due to a mutation in PDGFRA conferring resistance to imatinib (thus demonstrating that the FIP1L1-PDGFR- α fusion protein is the target of imatinib). Interestingly, IL-5 overexpression is necessary in mice to induce a condition similar to HES, suggesting that additional mechanisms may cooperate with the FIP1L1–PDGFRA fusion gene in disease etiology.
Clinical Features
The pulmonary involvement in patients with eosinophilia of clonal origin has not been studied extensively and especially has not been examined in cases classified according to the previously discussed two variants. However, lung or pleural involvement, although uncommon, has been mentioned in some cases in patients with clonal lymphoid proliferations. The following data derived from older studies including cases with the two previously mentioned variants of HES may therefore need reevaluation in the future, and the prevalence of pulmonary involvement might be much lower than previously considered.
The HES is more common in men than in women (9:1), and appears between 20 and 50 years. The onset is generally insidious, with eosinophilia discovered incidentally in 12% of the patients. The mean eosinophil count at presentation was 20.1 × 10 9 /L (21,000/µL), with an average highest value of 44.4 × 10 9 /L (44,000/µL) in one series. Extremely high values of eosinophilia, in excess of 100 × 10 9 /L (100,000/µL), are found in some patients.
The main presenting symptoms are weakness and fatigue (26%), cough (24%), and dyspnea (16%). One quarter of the patients may have asthmatic symptoms. Severe coughing attacks were present in 40% of the cases in one series with no other mention of bronchopulmonary disease. In another series, cough was also the predominant feature, with bronchospasm and pulmonary opacities in 11/40 patients each. Cardiovascular involvement, present in 58% of the patients, is a major cause of morbidity and mortality. Fibrotic thickening of the endocardium by collagen-rich connective tissue (endomyocardial fibrosis) is characteristic of cardiac disease in HES, which differs from the cardiac involvement seen in EGPA. Endomyocardial fibrosis is preceded by an initial acute necrotic stage followed by a thrombotic process ( eFig. 68-5 ). Cardiac manifestations include dyspnea, congestive heart failure, mitral regurgitation, and cardiomegaly. Echocardiography demonstrates the classic features of HES consisting of mural thrombus, ventricular apical obliteration, and involvement of the posterior mitral leaflet. The other manifestations of HES include neurologic manifestations (thromboemboli, central nervous system dysfunction, and peripheral neuropathies) and cutaneous manifestations (erythematous pruritic papules and nodules, urticaria, and angioedema).
Imaging
Pulmonary involvement is present in about 40% of patients and includes pleural effusion, pulmonary emboli, and interstitial opacities. Chest CT findings in five patients consisted of small nodules with or without a halo of ground-glass attenuation and focal areas of ground-glass attenuation mainly in the lung periphery. In another series, pulmonary radiologic manifestations varied but most commonly consisted of patchy ground-glass opacities and consolidation. CT findings are therefore poorly specific. Some of the observed pulmonary imaging changes may correspond to pulmonary edema resulting from cardiac involvement rather than genuine eosinophilic lung involvement.
Laboratory Studies
Only mild eosinophilia at BAL contrasting with high levels of eosinophilia in the blood has been reported in patients with the HES, suggesting that eosinophilia may be compartmentalized in some patients with HES. Serum levels of mast cell tryptase may be elevated, and dysplastic mast cells may be found in the bone marrow, with some patients meeting minor criteria for systemic mastocytosis.
Treatment and Prognosis
Imatinib has become the first-line therapy in patients with the myeloproliferative variant of HES, especially (but not exclusively) when the FIP1L1–PDGFRA fusion protein is present. Response to imatinib is more frequentin, yet not restricted to, patients carrying the FIP1L1-PDGFR-α fusion protein. Imatinib can be stopped without relapse in some patients, whereas in others low-dose imatinib is necessary to maintain long-term remission. Corticosteroids may be used, especially in the “lymphocytic variant” of HES (with response in only about half of the patients). The anti-IL-5 antibody mepolizumab has recently been shown to be beneficial as a corticosteroid-sparing agent in HES patients negative for the FIP1L1–PDGFRA fusion gene and requiring 20 to 60 mg/day of prednisone to maintain a stable clinical status and a blood eosinophil count of less than 1 × 10 9 /L (<1000/µL). Other treatments include chemotherapeutic agents (hydroxyurea, vincristine, etoposide); cyclosporin A ; and interferon-α either as monotherapy or in association with hydroxyurea, particularly in the myeloproliferative variant.
Whereas the 3-year survival was only 12% in the first published series, the prognosis has improved markedly in later series with about 70% survival at 10 years, 80% survival at 5 years, and 42% at 10 and 15 years, respectively. It is fascinating that advances in molecular biology may result in direct clinical benefit and provide a better prognosis for patients with an up-to-now almost untreatable disease.
Idiopathic Hypereosinophilic Obliterative Bronchiolitis
A distinct entity coined hypereosinophilic obliterative bronchiolitis has been recently identified and is defined by the following provisional working criteria: (1) blood eosinophil cell count greater than 1 × 10 9 /L (>1000/µL) and/or bronchoalveolar lavage eosinophil count greater than 25%; (2) persistent airflow obstruction despite high-dose inhaled bronchodilators and corticosteroids; and (3) eosinophilic bronchiolitis at lung biopsy and/or direct signs of bronchiolitis (centrilobular nodules and branching opacities) on chest CT ( Fig. 68-9 ). Before this description, biopsy-proven isolated cases of eosinophilic bronchiolitis had been reported. The blood eosinophil cell count is elevated (with a mean of 2.7 × 10 9 /L (2700/µL), and the mean eosinophil differential percentage at BAL was 63% in our series. Airflow obstruction is often severe but reversible with oral corticosteroid therapy in all cases. Whitish tracheal and bronchial granulations or bronchial ulcerative lesions can be present with prominent eosinophilia at bronchial biopsy. Clinical and functional manifestations often recur when oral prednisone is tapered to less than 10 to 15 mg/day. It is hypothesized that unrecognized and/or smoldering hypereosinophilic obliterative bronchiolitis might be a cause of irreversible airflow obstruction in chronic eosinophilic respiratory diseases. In addition to the idiopathic presentation, a similar condition of hypereosinophilic obliterative bronchiolitis can be encountered in patients with asthma, ABPA, or EGPA or may be induced by drugs, especially minocycline.
Eosinophilic Lung Disease of Determined Cause
Eosinophilic Pneumonias of Parasitic Origin
The eosinophilic pneumonias related to parasite infestation probably represent the most common cause of eosinophilic pneumonia in the world. Parasitic eosinophilic pneumonia arises mainly in humans following infection by helminths (large multicellular worms) and especially nematodes (roundworms; see eFig. 39-1 ). The parasites may or may not be found at pathologic examination of the lung when performed (see also Chapter 39 ).
Tropical Eosinophilia
Clinical Features.
Tropical eosinophilia is a syndrome characterized by severe spasmodic bronchitis, leukocytosis, and high blood eosinophilia. The clinical manifestations present mainly in the second and third decades of life, with a male predominance. It has been reported mostly in Indians and occasionally in patients originating from India or Asia and living in North America or in Europe. Tropical pulmonary eosinophilia is one of the most common causes of cough in tropical areas with endemic filariasis. Patients develop a dry, hacking cough exacerbated at night (especially between 1 and 5 am ) and often associated with dyspnea and expiratory wheezing. Associated fever, loss of weight, and anorexia are common. Eosinophils, and sometimes Charcot-Leyden crystals, are present in the sputum. The chest radiograph can reveal patchy bilateral opacities and small nodules (see eFig. 39-2A and B , Fig. 39-2A and B ).
Pathogenesis.
Tropical eosinophilia caused by the filarial nematodes Wuchereria bancrofti and Brugia malayi is endemic in the tropical and subtropical areas of coastal regions of Asia, the southern and western Pacific, and Africa (less commonly in South and Central America). The adult worms reside in the lymphatic vessels, leading to lymphatic obstruction with subsequent elephantiasis. Humans are infected by infective larvae deposited in the skin by mosquitoes, which develop into mature worms within 6 to 12 months. First-stage larvae or microfilariae released from the fecund female’s uterus circulate in the bloodstream from where they are ingested by the mosquitoes.
Patients with tropical pulmonary eosinophilia do not usually have clinical features of lymphatic filariasis. Microfilariae are usually not found in the blood or the lung. The circulating microfilariae are trapped in the lung vasculature where they release their antigenic contents, further triggering the inflammatory pulmonary reaction. The clinical features of tropical pulmonary eosinophilia largely result from an immune response of the host to the parasites.
Although blood eosinophilia is high at the early stage (<2 wk) of pulmonary disease, no prominent eosinophilic infiltration is found in the lung. Eosinophilic pneumonia is seen later (1 to 3 months), with the formation of eosinophilic abscesses and granulomatous lesions characterized by the presence of foreign body giant cells, fibroblasts, and epithelioid cells; prominent eosinophilic infiltration is present at the periphery of the granuloma. Cases left untreated for 5 years or more eventually show pulmonary fibrosis with histiocytic infiltration.
Laboratory Studies.
Blood eosinophilia is prominent, with more than 2 × 10 9 /L (>2000/µL) in all cases and up to 60 × 10 9 /L (>60,000/µL) in some cases. IgE levels are increased. Antifilarial IgG antibodies are increased, as in all patients with filariasis. BAL shows intense alveolitis with a mean percentage of 54% of eosinophils with marked degranulation. High levels of eosinophil-derived neurotoxin are present in the BAL. In patients treated with diethylcarbamazine, BAL eosinophils drop within 2 weeks; blood eosinophils also decrease rapidly upon treatment.
Persisting irregular basilar opacities are present in about two thirds of patients after 1 year. A “reticulonodular pattern” on chest CT is present in a majority of patients, with other features consisting of bronchiectasis, air trapping, and mediastinal lymphadenopathy.
Lung function tests show a restrictive ventilatory defect, with a reversible obstructive ventilatory defect and hypoxemia in about a quarter of the patients.
Because microfilariae are not detectable in the blood, the diagnosis is made in patients with residence for several months in an endemic area by the combination of the clinical, epidemiologic, and laboratory features, including blood eosinophilia persisting for weeks with an absolute eosinophil count in the blood greater than 3 × 10 9 /L (3000/µL), IgE levels exceeding 10,000 ng/µL (4200 IU/mL; normal <100 IU/mL), and markedly increased antifilarial IgG. Diagnosis is further supported by clinical improvement in the weeks following treatment. The diagnostic criteria of tropical pulmonary eosinophilia include cough worse at night; residence in a filarial endemic area; eosinophil count greater than 3300/µL; and clinical and hematologic response to diethylcarbamazine.
Treatment.
Diethylcarbamazine is the only effective drug for tropical pulmonary eosinophilia; corticosteroids in addition to diethylcarbamazine may be beneficial.
Ascaris Pneumonia
Pulmonary opacities with eosinophilia (Löffler syndrome) may develop during the migration of the larvae of the parasite through the lung.
Ascaris lumbricoides is the most common helminth infecting humans, especially children, in the tropical and subtropical areas. Mature females in the human intestine release large numbers of eggs expelled with stools, which may survive for several months or years. The disease is transmitted through food or water contaminated by human feces. The infective larvae formed within eggs develop in the small intestine, penetrate through the intestinal wall, and migrate via the venous circulation to the lungs, where they break out into the alveoli. They then migrate through the bronchi and trachea, are swallowed, and mature into adult worms in the small intestine.
Pulmonary manifestations develop during larval migration to the lungs. Usually, pulmonary symptoms are mild, with cough and wheezing, transient pulmonary opacities (see eFig. 39-1 ), and blood eosinophilia. Transient fever is present in the majority of patients, with possible pruritic eruption at the time of respiratory symptoms. Blood eosinophilia may be as high as 22 × 10 9 /L (22,000/µL). Symptoms spontaneously resolve in a few days, whereas blood eosinophilia may remain elevated for several weeks. The diagnosis may be made by finding larvae in the sputum or gastric aspirates but is more usually made by the delayed finding of the worm or ova in the stool within 3 months of the pulmonary manifestations.
Intestinal ascariasis is treated with oral mebendazole, 100 mg twice a day for 3 days, or albendazole, 400 mg once.
Eosinophilic Pneumonia in Larva Migrans Syndrome
Visceral larva migrans is a zoonotic infection caused in humans by Toxocara canis, a parasite infecting many dogs and other canines. Toxocariasis is found in all temperate and tropical areas of the world. Eggs released by female worms pass in the feces of infected dogs, and the soil of public playgrounds in urban areas is therefore often contaminated with eggs of Toxocara. Children playing in contaminated areas may become infected, especially when they practice geophagia. Ingested eggs hatch in the intestine, migrate through the portal circulation, and invade the liver, lung, and other organs. However, in humans, the development of the parasite is blocked at the larval stage.
Visceral larva migrans presents predominantly in children, the majority of whom remain asymptomatic and undiagnosed. When symptomatic, patients present with fever, pulmonary manifestations, seizures, and fatigue. Pulmonary manifestations in about 80% of cases consist of cough, wheezes, and dyspnea; pulmonary opacities on chest radiography are present in approximately half the patients with pulmonary symptoms. Severe pulmonary involvement, which is seen in about 15% to 20% of cases, may benefit from corticosteroids.
Although uncommon in adults, toxocariasis may be severe and necessitate mechanical ventilation. Patients present with fever, dyspnea, and pulmonary opacities on chest radiography. Wheezes or crackles are present at pulmonary auscultation. Blood eosinophilia may be present initially or may develop only in the following days. Eosinophils are increased in the BAL differential cell count.
The diagnosis of toxocariasis is difficult because a positive serodiagnosis may be caused by residual antibodies that do not have any diagnostic significance. IgM antibodies can be found throughout the course of helminthiasis and are not diagnostic of recent infection.
Visceral larva migrans usually requires only symptomatic treatment, the use of antihelmintics being controversial. Corticosteroids seem beneficial in cases with severe pulmonary involvement.
Strongyloides stercoralis Infection
Strongyloides stercoralis is an intestinal nematode that may cause severe autoinfection in immunocompromised patients. It is widely distributed in the tropics and subtropics. Human infection is acquired through the skin by contact with the soil of beaches or mud. Then larvae pass through the circulation to the lungs, where they break into alveoli, ascend the trachea, are swallowed, and reside in the small intestine where they mature. Females deposit eggs that hatch into larvae that pass with feces. Eosinophilia is usually present in recently infected patients, but it is often absent in disseminated disease. S. stercoralis infection may persist for years and give rise thereafter to severe disseminated strongyloidiasis, which may affect all organs (hyperinfection syndrome), especially with immunosuppression from any cause.
Löffler syndrome develops when larvae migrate through the lungs after acute infection (see eFig. 68-6A ). Peripheral blood eosinophilia, in association with pneumonia, bronchospasm, or bronchitis and abdominal pain or diarrhea, suggests strongyloidiasis in patients living, or having traveled, in endemic areas.
About 20% of hospitalized patients with strongyloidiasis have coexisting chronic lung disease. Patients with chronic obstructive pulmonary disease (COPD) or asthma receiving corticosteroids and immunocompromised patients are at risk of hyperinfection syndrome. Eosinophilia may or may not be present. Cough, wheezing, and dyspnea are associated with bilateral patchy opacities. Rhabditiform larvae may be recovered by BAL or bronchial washing or in the sputum.
Diagnosis of strongyloidiasis depends on the demonstration of larvae in the feces or in sputum and BAL fluid (see Fig. 39-1B-C ). Immunodiagnostic assays by ELISA methods may be useful for diagnosis and screening. Because of the risk of hyperinfection syndrome that persists for years, all infected patients are treated when diagnosed (ivermectin 200 µg daily for 2 days and repeated 2 weeks later).
Eosinophilic Pneumonias in Other Parasitic Infections
The dog hookworm Ancylostoma brasiliense causing cutaneous helminthiasis (creeping eruption) may produce simple pulmonary eosinophilia in 50% of cases. Pulmonary manifestations develop after the seventh day of cutaneous eruption. The human hookworms Ancylostoma duodenale and Necator americanus are other possible causes of Löffler syndrome.
In early acute schistosomiasis (due to infection with either Schistosoma haematobium or S. mansoni ), patients may develop transient, multiple, small pulmonary nodules on chest radiography (best seen on chest CT scan) and eosinophilia (see eFig. 68-6B ). In chronic schistosomiasis, embolization of ova in small arteries in the lungs results in granuloma formation, occlusion and remodeling of pulmonary arteries, and further pulmonary hypertension mediated by portopulmonary hypertension. The granuloma comprises lymphocytes, eosinophils, and giant cells. A posttreatment eosinophilic pneumonitis (also called lung shift, verminous pneumonia, and reactionary Löffler-like pneumonitis) may develop. It could result from parasitic antigen release following treatment.
The filarial parasite of dog Dirofilaria immitis (the pulmonary fluke) may occasionally develop into adult worms in the human lungs after inoculation of infective larvae by mosquitoes ( eFig. 68-6C ). It may manifest by eosinophilic pulmonary opacities on chest imaging studies (see Fig. 39-3 ).
Other parasites causing rare pulmonary manifestations with eosinophilia include Paragonimus westermani (see Fig. 39-4 and eFig. 39-3 ) , Trichomonas tenax, Capillaria aerophila, and Clonorchis sinensis (see eFig. 68-6D ).
Eosinophilic Pneumonias of other Infectious Causes
Pulmonary infection with eosinophilia has been reported with the fungi Coccidioides immitis (see eFig. 37-5 , eFig. 37-6 , eFig. 37-7 , eFig. 37-8 , eFig. 37-9 , eFig. 37-10 , eFig. 37-11 , eFig. 37-12 ), Bipolaris australiensis, Aspergillus niger, and Bipolaris spicifera. BAL eosinophilia has been reported in Pneumocystis jirovecii pneumonitis in patients with acquired immunodeficiency syndrome (see eFig. 90-11 , eFig. 90-12 , eFig. 90-13 , eFig. 90-14 , eFig. 90-15 , eFig. 90-16 , eFig. 90-17 , eFig. 90-18 , eFig. 90-19 , eFig. 90-20 ) . Bacterial or viral pulmonary infection (e.g., tuberculosis, brucellosis, respiratory syncytial virus, influenza infection) may occasionally be a cause of eosinophilic pneumonia.
Allergic Bronchopulmonary Aspergillosis and Related Syndromes
Allergic Bronchopulmonary Aspergillosis
ABPA is distinct from the other pulmonary manifestations due to the fungus Aspergillus such as invasive pulmonary aspergillosis developing in immunocompromised patients, aspergilloma developing in preexistent pulmonary cavities, or Aspergillus fumigatus –associated asthma. However, ABPA may be associated with chronic necrotizing aspergillosis. ABPA is characterized by asthma, eosinophilia, and bronchopulmonary manifestations with bronchiectasis secondary to a complex allergic and immune reaction to the presence of Aspergillus colonizing the airways in susceptible hosts who are unable to clear the respiratory epithelium of inhaled fungal spores. ABPA develops in 1% to 2% of adults with previous asthma present for several years (with a prevalence of 1% to 2%) and also in up to 7% to 10% of patients in large series of cystic fibrosis. ABPA may be associated with allergic Aspergillus sinusitis, which has been considered as a sinus equivalent of ABPA and results in a syndrome called sinobronchial allergic aspergillosis. Recently, cases of ABPA have been reported in patients with COPD ; however, this association seems to be exceedingly rare despite impaired mucociliary clearance in COPD.
Pathogenesis.
ABPA results from an immune and inflammatory reaction in the bronchi and the surrounding parenchyma in response to antigens from Aspergillus growing in mucous plugs in the airways of asthmatics. The immunologic response of the host includes—but is not restricted to—both type I hypersensitivity mediated by IgE antibodies and type III hypersensitivity with the participation of IgG and IgA antibodies and of a Th2 CD4 + T cell–mediated immune response accompanied by sustained IL-17 expression. Over time, the associated inflammatory reaction results in damage to the bronchial epithelium, submucosa, and adjacent pulmonary parenchyma.
ABPA may have an environmental (and especially occupational) dimension, as suggested by a study of workers in the bagasse-containing sites in sugar cane mills, where ABPA was diagnosed in 7% of workers who had chronic respiratory problems.
Interestingly, an increased prevalence of heterozygotic cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations has been reported in non–cystic fibrosis patients with ABPA or sinobronchial allergic mycosis, suggesting that CFTR gene mutations could be involved in the development of these conditions without overt cystic fibrosis. Genetic susceptibility to develop ABPA has also been suggested by association with a polymorphism within the IL-4 receptor α-chain gene and association with HLA-DR subtypes. Infection with nontuberculous mycobacteria may be seen with increased frequency in patients with ABPA. ABPA has been reported after infliximab therapy for sarcoidosis.
Diagnostic Criteria.
The classical diagnostic criteria include asthma, history of pulmonary opacities, proximal bronchiectasis, elevated serum IgE, and immunologic hypersensitivity to A. fumigatus such as immediate reaction to prick test for Aspergillus antigen, precipitating antibodies against A. fumigatus, and elevated specific IgE against A. fumigatus . Other common findings in patients with ABPA include the expectoration of mucous plugs, the presence of Aspergillus in sputum, and late skin reactivity to Aspergillus antigen. In patients with ABPA, typical proximal bronchiectasis may be absent; such cases are designated ABPA seropositive. Revised criteria have recently been proposed to account for some of the components that may be more important than others ( Table 68-4 ). A high index of suspicion should be maintained in patients with particularly severe asthma, and yet those with negative Aspergillus fumigatus –specific IgE are unlikely to have ABPA.
