Eosinophilic Lung Disease
James Allen, M.D.
Objectives
1. Learn the differential diagnosis of eosinophilic lung disease.
2. Learn the diagnosis and management of acute eosinophilic pneumonia.
3. Learn the diagnosis and management of chronic eosinophilic pneumonia.
4. Learn the diagnosis and management of Churg-Strauss syndrome.
5. Learn the causes of drug and parasite-induced eosinophilic lung disease.
6. Learn the diagnosis and management of allergic bronchopulmonary aspergillosis.
Introduction
The eosinophilic lung diseases are a group of pulmonary disorders manifest by an increase in blood or lung eosinophils. The finding of increased eosinophils can be a useful diagnostic finding and can be a marker for disorders that are often either treatable or curable with corticosteroids. In the 1950’s the term “PIE syndromes” (pulmonary infiltrates with [blood] eosinophilia) was popularized. However, it has since become increasingly clear that some lung diseases can have striking eosinophilic infiltration of the lung without significant blood eosinophilia. Thus, eosinophilic lung disease can be suspected based on either the finding of pulmonary disease with blood eosinophilia, pulmonary disease with bronchoalveolar lavage eosinophilia, or pulmonary disease with lung tissue eosinophilia on lung biopsy (1).
The eosinophil is mainly a tissue inflammatory cell with approximately a 1:100 blood:tissue ratio. Production of the eosinophil is largely regulated by T-lymphocytes, and particularly those lymphocytes with a Th2 phenotype. The major T-lymphocyte product that controls eosinophils in the lung is interleukin-5, although eotaxin, interleukin-3 and granulocyte-macrophage colony stimulating factor are also important. Once released into the blood, eosinophils migrate to the lung under the chemotactic effects of interleukin-5 produced by lung lymphocytes and by eotaxin produced by other lung cells.
The eosinophil is endowed with granules containing a number of substances that participate in host defense against pulmonary pathogens such as parasites and fungi. Major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase are all very basic granule contents which can be released by the eosinophil in response to different cytokines and immunoglobulins. In the lung, interleukin-5 and eotaxin are particularly important. Excessive release of these granule contents by eosinophils in the lung can result in direct injury to epithelial and endothelial cells resulting in the development of the clinical abnormalities attendant to the eosinophilic lung diseases (2).
The main eosinophilic lung diseases encountered in clinical practice are:
Simple Pulmonary Eosinophilia
Acute Eosinophilic Pneumonia
Chronic Eosinophilic Pneumonia
Churg-Strauss Syndrome
Idiopathic Hypereosinophilic Syndrome
Allergic Bronchopulmonary Aspergillosis
Parasite-Induced Pulmonary Eosinophilia
Fungal-Induced Pulmonary Eosinophilia
Simple Pulmonary Eosinophilia
Simple pulmonary eosinophilia is often known as Löffler's syndrome for the physician who first identified the condition in the 1930’s. It is characterized by patchy, migratory pulmonary infiltrates on chest radiographs and an increased blood eosinophil count. Patients with this disorder are usually asymptomatic or have relatively mild respiratory symptoms and are often identified because of incidental findings on chest x-rays or an abnormal eosinophilia on a blood count. The condition is frequently due to parasitic infection or drug reaction, however, it can be idiopathic. The self-limited nature of the infiltrates and lack of significant symptoms permits distinction from chronic eosinophilic pneumonia and acute eosinophilic pneumonia. Steroids can hasten resolution of pulmonary infiltrates and blood eosinophilia, although their use is rarely necessary.
In Löffler's original series in 1932 (3), most patients with simple pulmonary eosinophilia likely had Ascaris infection. The finding of simple pulmonary eosinophilia should trigger a careful search for occult parasitic infection and for candidate drugs known to cause pulmonary eosinophilia.
The chest x-ray demonstrates unilateral or bilateral, transient, migratory, non-segmental densities of various sizes which are usually of a combined interstitial and alveolar pattern. They are often peripheral in nature and may appear to be pleural-based.
Acute Eosinophilic Pneumonia
Acute eosinophilic pneumonia was first described in 1989 (4, 5). Patients present with rapid onset of cough, tachypnea, and dyspnea of 1-5 days duration (average = 2.3 days) (4,5). Patients can progress from mild dyspnea to life-threatening respiratory failure in only a few hours. Fever is invariably present and averages 101 degrees F. Chest pain is present in 73% of patients and is usually pleuritic. Myalgias will additionally be present in about half of patients. Crackles are present in 80% of patients with 13% of patients having both wheezing and crackles. The lungs are clear to auscultation in 20% of patients (6). Because of these signs and symptoms, the disease is frequently mis-diagnosed as severe community-acquired pneumonia.
The average age is 29 years but all age groups can be affected. There is no gender preference. Forty percent of patients have a history of smoking cigarettes. Interestingly, there appears to be an association between recent onset of smoking cigarettes and development of acute eosinophilic pneumonia (7,8) and it has been speculated that constituents of tobacco smoke may trigger acute eosinophilic pneumonia in susceptible patients. In a study of acute eosinophilic pneumonia in U.S. military personnel stationed in Iraq, 18 cases occurred among 183,000 personnel for an incidence of 9.1 per 100,000 person-years (8).
The differential diagnosis includes drug reaction and Aspergillus infection. The latter is particularly important to exclude because it requires anti-fungal antibiotics instead of corticosteroids and should be suspected in patients with chronic granulomatous disease or with exposure to composted organic material (9).
Hypoxemia is present in all patients with an average pO2 of 57 mm Hg on presentation. Unlike patients with chronic eosinophilic pneumonia, patients with acute eosinophilic pneumonia generally lack peripheral blood eosinophilia and have an average blood eosinophil count of only 344 (6). The IgE level can be elevated to levels as high as 2,310 kU/L (10). When tested, the pleural fluid is exudative with an increased percentage of eosinophils (6).
Pulmonary function tests are generally not necessary for diagnosis but if performed, can show small airway obstruction, restriction, and a low diffusing capacity. After treatment, pulmonary function studies are normal (4, 8).
Early in the course, chest radiographs show reticular markings with Kerley B-lines and small pleural effusions. Later, radiographs show mixed reticular and alveolar infiltrates which then can progress to densely alveolar as the condition worsens. As patients improve, the parenchymal infiltrates resolve with pleural effusions resolving last (11).
In the proper clinical setting, a high percentage of eosinophils in the bronchoalveolar lavage can provide a tentative diagnosis of acute eosinophilic pneumonia. Because patients otherwise clinically resemble pneumonia or acute respiratory distress syndrome (ARDS), early performance of bronchoalveolar lavage in patients with unexplained diffuse pulmonary infiltrates and respiratory failure is necessary for prompt diagnosis. In most patients, eosinophils will exceed 20% of cells in bronchoalveolar lavage fluid and average 37% (6). As with the alveolar eosinophils in chronic eosinophilic pneumonia, eosinophils in acute eosinophilic pneumonia can be degranulated and possess multiple nuclear lobes that can sometimes make distinction between neutrophils and eosinophils difficult. In addition to eosinophils, the BAL shows an increase in neutrophil and lymphocyte percentages.
Lung biopsy is unnecessary for the diagnosis of acute eosinophilic pneumonia in most cases and its main purpose is to exclude other diseases, which can mimic acute eosinophilic pneumonia such as aspergillus infection (12). Histologic findings include infiltration of eosinophils in the interstitium and in the alveolar spaces with features of diffuse alveolar damage (13).
The treatment of choice is corticosteroids. Most patients will have significant clinical improvement within 24-48 hours and some patients will improve within hours of the first dose of steroids. A commonly used regimen is methylprednisolone 125 mg every six hours until respiratory failure resolves. Thereafter, the patient can be switched to oral prednisone and the steroids can be tapered off over 8 weeks (6). Relapse after steroids are discontinued is extremely rare. Death can occur if the disease is not recognized and treated promptly (8).
Chronic Eosinophilic Pneumonia
Chronic eosinophilic pneumonia was first identified by Christoforidis in 1960(14) and Carrington described the first defining series of patients in 1969 (15). Since then, several large longitudinal series of patients have been described (16,17). It can occur at any age, however, the peak incidence is in the fifth decade and women outnumber men 2:1. Approximately half of patients will have pre-existing asthma or atopic disease. Unlike patients with acute eosinophilic pneumonia, only a very low percentage of patients will have a history of prior cigarette smoking, raising the question of whether smoking could be protective (16). Patients typically present with some combination of cough, dyspnea, fever, and weight loss. The physical examination is most commonly normal, although wheezes, crackles, or both are sometimes heard.
Blood eosinophil counts are elevated in more than 90% of patients. The IgE level is elevated in about half of patients and is usually less than 2,000 kU/L.
Pulmonary function tests are normal in one third of patients, show obstruction in one third of patients, and show restriction in one third of patients. The diffusing capacity will be low in one half of patients. Hypoxemia or an increased A-a gradient is present in nearly all patients (15, 16).
The chest X-ray shows peripheral infiltrates which have been described as being the “photographic negative” of pulmonary edema (18). On occasion, the infiltrates may be patchy or even unilateral. Pleural effusions are uncommon. CT scans show peripheral consolidations, ground glass infiltrates and reticular opacities (19).
The bronchoalveolar lavage shows an isolated increased eosinophil percentage in all patients with an average of 58%. Unlike acute eosinophilic pneumonia, BAL lymphocyte and neutrophil percentages are usually normal or only minimally elevated (16).
Lung biopsy is usually not necessary for the diagnosis of chronic eosinophilic pneumonia. When performed, there is infiltration of the interstitium and alveoli with eosinophils. In contrast to Churg-Strauss syndrome, granulomas and vasculitis are generally absent. Occasionally, areas of bronchiolitis obliterans can be seen.
Corticosteroids remain the mainstay of treatment. The clinical response to steroids is usually dramatic and other than acute eosinophilic pneumonia, no other eosinophilic lung disease responds so completely and so quickly. Most patients will have subjective improvement within 48 hours and radiographic resolution within one week (14, 16). This response to steroids in the proper clinical setting is virtually diagnostic and obviates the need for lung biopsy provided infection and drug reaction have been excluded. Prednisone is usually started at 40-60 mg/day and tapered to a maintenance dose averaging 10 mg/day within the first few weeks. Most patients require long-term treatment. Patients treated for less than 6 months will usually relapse. The average duration of treatment is 82 weeks (16). Many patients will have asthma after the chronic eosinophilic pneumonia resolves and it is important to distinguish respiratory symptoms due to residual asthma from respiratory symptoms due to persistent chronic eosinophilic pneumonia.
Churg-Strauss Syndrome
Churg-Strauss syndrome was first described in 1951 (20). Men and women are equally affected with an average onset at age 38-48 (21). Patients generally have a history of asthma and/or allergic rhinits for 8-10 years before presentation (22). Eosinophilic vasculitis then occurs with striking blood eosinophilia (occasionally as high as 10,000/ml) (23).
Churg-Strauss syndrome can affect many organs. Upper airway findings commonly include sinusitis, rhinitis, and nasal polyps. The skin is affected in 70% of patients and can show nodules, purpura, or urticaria. Peripheral neuropathy is common and central nervous system involvement occurs in 27% (24). Cardiac involvement can include heart failure, pericarditis, and hypertension. In the gastrointestinal tract, abdominal pain, diarrhea, and bleeding can occur. Renal insufficiency occurs in half of patients. Arthralgias or myalgias occur in about one-half of patients. Most patients have fever and weight loss.
Churg-Strauss syndrome has been associated with use of leukotriene antagonists in patients with pre-existing asthma (25). However, it is unclear whether these medications actually cause the syndrome or whether their use permitted reduction of corticosteroids, thus unmasking the syndrome in patients previously mis-diagnosed with simple asthma.
The IgE level is elevated, often to very high levels and appears to correlate with disease activity. Patients can have low titers of rheumatoid factor and anti-nuclear antibodies. The anti-neutrophil cytoplasmic antibody (ANCA) is present in approximately 50% of patients, usually in the perinuclear (P-ANCA) form (26). The BAL typically shows very high percentages of eosinophils, averaging 33%. Pulmonary function tests show obstruction. Chest x-rays and CT scans typically show patchy pulmonary infiltrates but nodules and diffuse interstitial infiltrates can occur. Pleural effusions are present in a third of patients.
The diagnosis can be established by biopsy of an involved organ. In the lung, surgical biopsy is often necessary since transbronchial biopsy generally provides limited vascular material. The earliest or prevasculitic phase is characterized by eosinophilic tissue infiltration without vasculitis. This is followed by a vasculitic phase with eosinophilic vasculitis of the small arteries and veins (27). Interstitial and perivascular granulomas are common.
Most patients respond to steroids alone. Prednisone in doses of 40 - 60 mg/day are required for several weeks for resolution of the vasculitis; mononeuritis multiplex may require even longer treatment. Daily or alternate day low dose prednisone is typically continued for up to a year; relapses thereafter are uncommon. For patients failing to respond to steroids, cyclophosphamide, intravenous IgG, and alpha interferon are alternatives (28,29,30,31).
Idiopathic Hypereosinophilic Syndrome
The idiopathic hypereosinophilic syndrome is diagnosed by blood eosinophilia of greater than 1,500/ml for more than 6 months, absence of parasitic or other cause of secondary eosinophilia, and signs or symptoms of end organ damage related to the increased eosinophils (32). There are two main pathophysiologic mechanisms, a primary eosinophilic myeloproliferative disorder and a T-helper lymphocyte proliferative disorder with secondary eosinophilia (33,34).
Patients usually present in their third or fourth decade and there is a 7:1 male predominance (35). Typical symptoms include night sweats, anorexia, weight loss, pruritis, cough, and fever. Cardiac involvement, including endocardial fibrosis, restrictive cardiomyopathy, valvular damage, and mural thrombus formation is the most serious complication and is the major cause of morbidity and mortality (36). Pulmonary involvement occurs in up to 40% of patients and typically presents as cough, often worse at night. Long-standing disease can result in pulmonary fibrosis. Arterial and venous thromboembolic disease occurs in the majority of patients. Other finding can include peripheral neuropathy, gastrointestinal symptoms, renal insufficiency, arthralgias, and skin rash (37).
The peripheral blood shows profound peripheral eosinophilia, usually greater than 3,000/ml (38). The bronchoalveolar lavage fluid can show very high percentages of eosinophils of up to 73% (39,40). The chest x-ray typically shows interstitial, non-lobar infiltrates and approximately 50% of affected patients have pleural effusions. Chest CT shows small pulmonary nodules and focal areas of ground glass infiltrates, predominately in the lung periphery (41)
About one-half of patients will have a good clinical response to oral corticosteroids alone, with initial doses of prednisone, 60 mg/day (42). Other drugs have been used successfully, including busulfan, hydroxyurea, cyclophosphamide, azathioprine, interferon-a, cyclosporin-A, etoposide, vincristine, and 2-chlorodeoxyadenosine (2-CdA). More recently, patients have been successfully treated with anti-interleukin-5 (mepolizumab) (43, 55) and imatinib mesylate (44).
Allergic Bronchopulmonary Aspergillosis
Allergic bronchopulmonary aspergillosis (ABPA)is caused by colonization of the airway by aspergillus with local airway allergy resulting in refractory asthma. Both genders and all age groups can be affected. The diagnostic criteria for ABPA are listed in table 2 (45). It is a clinical diagnosis as there is no one specific laboratory test that is unique for allergic bronchopulmonary aspergillosis and some patients may not have all of these findings.
Diagnostic Criteria for Allergic Bronchopulmonary Aspergillosis: |
Asthma or cystic fibrosis |
Peripheral blood eosinophilia |
Immediate skin prick test for Aspergillus antigens |
Serum precipitating antibodies against Aspergillus antigens |
Increased serum IgE levels |
Chest x-ray infiltrates |
Bronchiectasis |
Increased Aspergillus-specific IgE and IgG |
ABPA progresses through 5 clinical stages: acute, remission, exacerbation, corticosteroid-dependent asthma, and fibrosis (46). In the acute stage, there is asthma, the IgE level is usually greater than 2500 ng/ml, and there is an immediate skin reaction to aspergillus antigen. Radiographs show pulmonary infiltrates, and proximal bronchiectasis. Corticosteroids can normalize the chest x-ray abnormalities, control the asthma symptoms, and reduce the IgE level. In the second stage, there is remission with no asthma symptoms and with normal chest x-rays and normal IgE levels. The exacerbation stage is clinically similar to the acute stage with recurrence of asthma, a rise in the IgE level, and new chest x-ray infiltrates. The corticosteroid-dependent asthma stage is characterized by persistently elevated IgE levels and asthma that requires oral steroids for control. Patients with long standing disease can develop an irreversible fibrotic stage. Cystic fibrosis is associated with allergic bronchopulmonary aspergillosis with up to 10% of patients with cystic fibrosis having the condition (47).
The IgE level correlates with disease activity and a normal IgE level in a symptomatic patient virtually excludes the diagnosis (48). In most patients, the level exceeds 1,000 ng/ml. In patients with lower total IgE levels, elevated Aspergillus fumigatus-specific IgE or IgG antibody may be present (49).
In early stages, pulmonary function tests show obstruction. In later stages, as bronchiectasis progresses, restriction with a low diffusing capacity also occurs.
Chest radiographs usually show central bronchiectasis involving the upper lobes with signs of mucus impaction. About 15% of patients will present early in the disease before bronchiectasis develops.
Lung biopsy is generally unnecessary but if performed will show a bronchocentric inflammatory infiltrate composed of eosinophils, lymphocytes, plasma cells, and monocytes. Aspergillus hyphae can be identified using fungal stains.
Corticosteroids are the treatment of choice for allergic bronchopulmonary aspergillosis and most patients will require prolonged courses of oral steroids. Maintenance doses of prednisone average 7.5 mg/day. Inhaled steroids (50) and itraconazole (51) can improve overall clinical function and permit a reduction in oral steroid doses.
Parasitic Infection
Many parasites can cause pulmonary infiltrates with blood and/or alveolar eosinophilia (1). The travel history is important because of the regional variation in parasite prevalence rates. In the United States, Strongyloides, Ascaris, Toxocara, and Ancylostoma are the most common parasitic causes of eosinophilic lung disease. Patients infected with one parasite are at risk for multiple parasites. Therefore, failure of pulmonary symptoms or eosinophilia to resolve despite treatment should prompt a search for additional parasites. Strongyloides stercoralis infection deserves special mention as it can be particularly difficult to diagnose and can mimic the idiopathic hypereosinophilic syndrome. The treatment is thiabendazole or ivermectin.
In India and Southeast Asia, tropical pulmonary eosinophilia is caused by the filarial worms, Wuchereria bancrofti and Brugia malayi (52). Other parasites causing pulmonary eosinophilia include Schistosoma, Clonorchis sinesis, Opisthorchiasis, Trichinella spiralis, Paragonimus westermani, the carnivore tapeworm Echinococcus granulosus, and the dog heartworm Dirofilaria immitis.
Stool examination for ova and parasites is commonly ordered but parasites such as Trichinella, Paragonimus, Ancylostoma, Toxocara, and filaria cannot be diagnosed by stool examination. Intestinal parasites (such as Ascaris and Strongyloides) may cause pulmonary eosinophilia weeks before ova first become present in the stool and the stool examinations can be falsely negative even when adult worms are present in the intestine. In many cases (especially with Strongyloides), serologic studies are more sensitive than stool examinations.
Fungal Infection
Eosinophilia is often seen in coccidioidomycosis and aspergillosis but is usually absent in other fungal infections such as histoplasmosis, blastomycosis, candidiasis, and cryptococcosis. A travel history to areas endemic for coccidioidomycosis (the American Southwest) is an important part of the evaluation of any patient presenting eosinophilic lung disease because administration of corticosteroids can result in acceleration of the infection with fatal dissemination. Invasive aspergillosis is unusual in immunocompetent patients but can occur after massive inhalational exposure (for example, after exposure to composted organic material) or in the setting of underlying chronic granulomatous disease (11). Pneumocystis carinii associated with HIV infection can also present with moderately increased BAL eosinophil percentages (53).
Drug Reactions
Many drugs have been associated with pulmonary eosinophilia (54) and a continuously updated list from the University Hospital in Dijon, France is maintained on the internet (www.pneumotox.com). Table 3 lists the drugs most commonly associated with eosinophilic lung disease.
Drugs Commonly Reported To Cause Pulmonary Eosinophilia: |
Amiodarone |
Acetylsalicylic acid |
Bleomycin |
Captopril |
Carbamazepine |
G(M)-CSF |
Gold salts |
Iodine, radiographic contrast media |
L-tryptophan |
Methotrexate |
Minocycline |
Nitrofurantoin |
Nilutamide |
Penicillamine |
Propylthiouracil |
Sulfa-containing antibiotics |
Sulfasalazine |
Patients with drug-induced eosinophilic lung disease can have variable presentations with syndromes resembling simple pulmonary eosinophilia, chronic eosinophilic pneumonia, acute eosinophilic pneumonia, or Churg-Strauss syndrome. Although many patients with drug-induced eosinophilic lung disease will improve by simply discontinuing the medication, in severe or persistent cases corticosteroids may be necessary.
Miscellaneous Lung Diseases Sometimes Associated With Eosinophils
A variety of interstitial lung diseases can have increased BAL or tissue eosinophils as a component of a mixed inflammatory cell infiltration (1). Idiopathic pulmonary fibrosis is frequently associated with increased BAL eosinophils, usually less than 20%. The presence of greater than 5% bronchoalveolar lavage eosinophils is associated with a more rapid deterioration. Similarly, pulmonary fibrosis associated with collagen vascular disease can be associated with mild increases of eosinophils in the BAL fluid in up to 26% of patients.
Bronchocentric granulomatosis presents with dyspnea or wheezing due to airway obstruction. Radiographs show nodules or infiltrates. Lung biopsies show necrotizing granulomatous infiltration of the airways and frequently have eosinophils as a major inflammatory component. The disease is often quite similar to allergic bronchopulmonary aspergillosis but lacks identifiable fungal elements.
Langerhan's cell granulomatosis (eosinophilic granuloma) is associated with an abnormal proliferation of Langerhan's cells in the lung and other organs. An increase in tissue eosinophils is noted on open lung biopsy in most patients; however, an increase in BAL eosinophils is seen in only a small percentage of patients.
An increased BAL eosinophil percentage occurs in about a fourth of patients with bronchiolitis obliterans organizing pneumonia, usually amounting to less than 20% of the total BAL cells. Other interstitial lung diseases which can have mildly elevated eosinophil percentages in the bronchoalveolar lavage include hypersensitivity pneumonitis and sarcoidosis.
Several malignancies can be associated with increased lung eosinophils including non-small cell lung cancer, Hodgkin’s disease, non-Hodgkin’s lymphoma, lymphocytic leukemia, and eosinophilic leukemia. Many malignancies which metastasize to the lungs can be associated with peripheral blood eosinophilia reiterating the importance of a thorough history and physical examination in the initial evaluation of patients.
Clinical Approach
In approaching the patient with eosinophilic lung disease, the history and physical examination is the most important means of determining the specific etiology. Asthma suggests Churg-Strauss syndrome or allergic bronchopulmonary aspergillosis. Travel history may suggest parasitic infection such as tropical pulmonary eosinophilia, Schistosoma, or Paragonimus westermani. Exposure to dogs or cats may suggest Ancylostoma and Toxocara infection. A careful history should be taken for use of prescription, non-prescription, and illicit drugs as well as health food supplements.
Increased BAL eosinophils without blood eosinophilia should raise the possibility of Langerhan's cell granulomatosis, acute eosinophilic pneumonia, P. carinii pneumonia, and some cases of drug-induced lung disease. On the other hand, diseases such as simple pulmonary eosinophilia, chronic eosinophilic pneumonia, parasite infection, some drug-induced lung diseases, ABPA, Churg-Strauss syndrome, fungal infections, and the idiopathic hypereosinophilic syndrome typically have high numbers of blood eosinophils.
Serologic studies alone are rarely diagnostic, however, very high levels of IgE suggests allergic bronchopulmonary aspergillosis and anti-neutrophil cytoplasmic antibodies or anti-myeloperoxidase antibodies suggests Churg-Strauss syndrome.
Bronchoalveolar lavage is useful in the evaluation of the patient with eosinophilic lung disease, not only to verify the presence of increased eosinophils in the lung but also to search for parasitic or fungal infection. Lung biopsy is generally required for the diagnosis of Churg-Strauss syndrome, malignancy, bronchocentric granulomatosis, and some of the interstitial lung diseases.
Most eosinophilic lung diseases are very responsive to appropriate treatment. Corticosteroids are effective in many eosinophilic syndromes and it can be tempting to give an empiric course of steroids in eosinophilic lung disease of unknown cause. In certain diseases, however, steroids can be harmful. Thus parasitic infection, coccidioidomycosis and aspergillosis should be considered in all patients and tested for as indicated by the clinical presentation.
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Last updated March 19, 2008