Pulmonary Infiltrates with Eosinophilia
Internal Medicine Resident Grand Rounds
November 14, 1995
Robert W. West, MD
A. Case Presentation
B. Eosinophils
a. Cell biology
b. Biochemistry
c. Immunology
C. Definition/General Concepts
D. Early descriptions
E. Major etiologies of P.I.E.
Common Uncommon
1. Allergic: Allergic Bronchopulmonary Aspergillosis Allergic Alveolitis
Drug Reactions
Asthma
2. Infectious: Migratory Metazoan Parasites Tuberculosis, PCP
Coccidiomycosis
Chlamydia, Brucella
3. Neoplastic: Hodgkin’s Disease
Lymphoma
Met. carcinoma
4. Rheumatic: Churg-Strauss syndrome Rheumatoid Arthritis
Eos-Myal syndrome Goodpasture’s
5. Unknown cause: CEP, AEP Sarcoid HES
F. Clinical approach
G. Finish case presentation
H. Summary
I. Take home points
J. Bibliography
A. Case Presentation
HPI: A 37 yo previously healthy black male presented to NCBH with a 3 week history of nausea/vomiting, diarrhea (dark green/black in color), night sweats, and lower abdominal pain. He described the abdominal pain as crampy in nature and worse after eating. He also reported subjective fever/chills as well as increasing dyspnea over the past few weeks. He denied cough, hemoptysis, hematemesis, hematochezia, or melena.
The patient was first evaluated in Salisbury, N.C. by his local physician after one week of symptoms. At that time, the physician obtained a chest x-ray and abdominal film. The chest x-ray revealed multiple nodular densities bilaterally. At this point, he was referred to the pulmonary clinic here and evaluated by Dr. Sane. Because he appeared acutely ill and in obvious abdominal pain, he was admitted to the Pulmonary Ward service for further workup.
PMH: Partial splenectomy after MVA SH: Lives with wife and 4 children
Alcohol abuse Works as bulldozer operator
20 pk year history of smoking
MED: Tylenol prn 1/5 whiskey(wknds), marijuana
ALL: None FH: DM, HTN, heart disease
PE: T 101.3 F, P 130, R 38, BP 120/70
Gen: Ill-appearing BM in mod abd pain
Chest: CTA (bil); no wheezing or rales
Abd: BS present, well-healed midline scar, diffusely guarding without rebound
Prostate/GU: Normal testicular exam, normal prostate, heme - stool
Exam otherwise normal
LABS(Adm): WBC 10.1, Hb 17.2, Plts 327K with 42% segs, 1% bands, 15% lymphs, 4% monos, and 37% eos Normal LFT’s and CPK
CXR(outside films): Multiple pulmonary nodules 1/2 - 1 cm in a vascular distribution
HOSP COURSE: Given aggressive IV hydration and kept NPO at least initially. WBC count reached a peak of 24.5 on 11/1/94, and his eosinophil count peaked at 55% on 10/31/94. The patient was seen by several consultants including Surgery, ID, and GI. The patient slowly improved and a repeat chest x-ray on 11/6/95 showed no pulmonary nodules. Since the patient was clinically improved and asking to go home, he was discharged on 11/8/94.
Workup included: Resp isolation, PPD neg, AFB smear neg (3X)
O&P neg (3X), Routine stool Cx neg, C. diff neg
ANA neg, HIV neg, ACE 26, TSH 1.38, B12 nl, Bld Cx neg
Fungal serologies neg, Trichinella neg, Strongyloides neg
CT abd/pelvis - Multiple small 0.5 - 1 cm nodules throughout the lungs, liver, and kidneys.
Upper GI series with SBFT - normal
Liver biopsy - Portal and intralobular inflammation with mixed lymphocytic and eosinophilic infiltration
B. Eosinophils
(adapted from Weller. The Immunobiology of Eosinophils. NEJM Vol 324 (16), p. 1114, 1991)
Central to the understanding of eosinophilic lung diseases is an appreciation of the cell biology, biochemistry, regulation, and overall function of eosinophils. Eosinophils are bone marrow-derived granulocytes which are normal constituents of the lungs. Eosinophils are released into the blood with an emergence time of 60 to 80 hours and enter tissues with site specificity. They disappear from the circulation with a half-life of 8-12 hours and from tissues with a half-life of more than 24 hours. In contrast to other granulocytes, eosinophils are primarily tissue cells with numbers 200 to 400 times greater in tissues than in blood. Eosinophils are most abundant in tissues with an epithelial interface with the environment, such as the respiratory, gastrointestinal, and lower genitourinary tract.
Stimulated T lymphocytes secrete a series of cytokines that are the predominant eosinophilopoietic factors. The sequential actions of interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on eosinophil precursors induce the initial development and commitment to the eosinophil. Following this, interleukin 5 (IL-5) affects the terminal differentiation to mature eosinophils. IL-5 is highly specific to eosinophils, while IL-3 and GM-CSF are not. This dominant role of IL-5 has been confirmed in transgenic mice by the demonstration of high blood eosinophilia in mice overexpressing the IL-5 gene and high levels of IL-5 in patients with a variety of reactive eosinophilic syndromes.
At least three steps are involved in the entry of blood eosinophils into tissues. These include selectin-mediated contact with endothelial cells, vascular adherence and transendothelial migration, and attraction to specific tissues. IL-4, IL-1, and tumor necrosis factor (TNF) are all capable of augmenting eosinophil vascular adherence and transendothelial migration by activating endothelial vascular cell adhesion molecule-1 (VCAM-1) and fascilitating its binding to the very late activation antigen (VLA-4) on the surface of eosinophils.
Eosinophils are unique in that they possess a bilobed nucleus, which lacks a nucleolus, and contain different types of cytoplasmic granules. Some of these include specific granules, primary granules, and smaller granules. Specific granules contain lysosomal hydrolases as well as cationic proteins and are responsible for the tinctorial properties of eosinophils visualized by light microscopy. Primary granules lack a crystalloid core and develop early in eosinophil maturation, while smaller granules contain aryl sulfatase and other enzymes. When stimulated, eosinophils produce a number of potentially injurious substances including major basic protein, eosinophilic cationic protein, eosinophilic-derived neurotoxin, reactive oxygen species, peroxidase, and collagenase. Lysophospholipase forms Charcot-Leyden crystals that are the signature of eosinophils in the sputum, feces, and some tissues. The abundant major basic protein (MBP) and eosinophil cationic protein (ECP) of specific granules are broadly cytotoxic. Eosinophil-derived neurotoxin (EDN) is structurally similar to ECP, and both exhibit neurotoxic activity.
The interactions of eosinophils with other cells including lymphocytes, endothelial and epithelial cells, are mediated by type 1 lymphocyte function-associated (LFA-1) and VLA-4 adhesive proteins. Eosinophils in tissues are exposed to factors that maintain surface expression of CD4 and HLA-DR protein. Expression of HLA-DR provides a mechanism of antigen presentation by activated eosinophils to helper T cells while CD4 permits chemotactic responses to lymphocyte chemoattractant factor.
Although the specific mechanism of eosinophil activation is poorly understood, the principle cytokines of eosinophilopoiesis (IL-3, IL-5, and GM-CSF) as well as interferon gamma, PAF, and some inflammatory factors induce all the characteristics of activated eosinophils. When activated, eosinophils become less dense, lose granule contents, and reveal cytoplasmic vacuoles. Their heightened activity is made obvious by greater expression of complement receptors, mediator generation, and more efficient cytotoxicity.
While eosinophils are capable of phagocytosis and killing bacteria in vitro, they do not have a major role in host defense against microbial pathogens or single-celled parasites. Therefore, they cannot help to defend against bacterial infection when neutrophil function is deficient. Rather, eosinophils primarily defend against large, nonphagocytable organisms such as multicellular helminthic parasites.
The specific effects of eosinophils on lung tissues and function range from transient reversible responses to permanent damage. Both MBP and peroxidase on one end of the spectrum activate pulmonary mast cells and elicit transient broncho-constriction. On the other hand, they are also capable of damaging or destroying respiratory airway cells.
C. Definition / General Concepts
Definition: Eosinophilic lung disease - Infiltration of the lung by eosinophils that may or may not be accompanied by an excess of eosinophils in the peripheral blood.
Eosinophilic lung diseases are a diverse group of pulmonary syndromes linked by the common finding of increased circulating or tissue eosinophils. These syndromes encompass a wide variety of disorders including interstitial lung diseases, infectious diseases, vasculitis, malignancies, drug reactions, obstructive lung diseases, and idiopathic eosinophilic pneumonia. The classification of "eosinophilic lung disease" is to a certain extent a misnomer because of the concomitant existence of inflammatory changes with alveolar macrophages, lymphocytes, and neutrophils. However, the overriding presence of eosinophils is striking and can be of great diagnostic importance as a disease marker.
Except for the presence of eosinophils, the eosinophilic lung diseases bear little clinical correlation to one another. While some are predominantly airways-based, others are parenchymal or a mixture of both. In general, these disorders may be characterized by one of three means. First, peripheral eosinophilia and radiographic infiltrates (pulmonary infiltrates with eosinophilia, or P.I.E. syndrome) can be used to define eosinophilic lung diseases. Although there is a certain degree of variability, normal blood contains between 50 and 250 eosinophils/ul. The absolute blood eosinophil count is preferred to the blood eosinophil percentage. This categorization has two important limitations: eosinophilia in the blood does not prove eosinophilic involvement in the lung, and eosinophil involvement in the lung is not always associated with blood eosinophilia.
The second way of defining eosinophilic lung diseases is bronchoalveolar lavage (BAL). This technique is very useful because it is safe, minimally invasive, and can be repeated at different time points during the course of the disease to assess response to therapy. One limitation of BAL is the inability to distinguish if cells from BAL fluid come from the airways or from the alveoli. Increased percentages of eosinophils in BAL fluid correlates with the presence of tissue eosinophils by lung biopsy.
The third way to characterize eosinophilic lung disease is via lung biopsy. This is a much more direct way of assessing eosinophil involvement in lung disease because the majority of eosinophils migrate from blood to tissues where they reside at a much greater concentration. While open lung biopsy is generally considered the "gold standard" for diagnosis, most clinicians treat these disorders based on clinical criteria. Transbronchial lung biopsy avoids the need for an open procedure, but generally yields only a very small amount of alveolar tissue and usually little or no vascular tissue.
D. Early Descriptions
For over 60 years, scientists and physicians alike have been struggling with different strategies to classify eosinophilic lung diseases. In 1932, Löffler was the first to describe four patients with simple pulmonary eosinophilia ("Löffler’s syndrome"), which is characterized by migratory pulmonary infiltrates accompanied by peripheral blood eosinophilia in mildly infected or asymptomatic patients. In retrospect, the original cases described by Löffler are best explained by Ascaris lumbricoides infection with the pulmonary manifestations and eosinophilia resulting when larvae migrate into the parenchyma during a phase of the helminthic life cycle.
In 1952, J.W. Crofton and his coworkers in London suggested the term "pulmonary eosinophilia." Pulmonary eosinophilia was defined as a condition in which pulmonary infiltration on the radiograph is accompanied by blood eosinophilia. It was their feeling that while pulmonary eosinophilia covers a wide range of diseases from mild and transient to severe and often fatal, they could be classified as follows: (1) simple pulmonary eosinophilia (Löffler’s), (2) prolonged pulmonary eosinophilia, (3) tropical eosinophilia (Weingarten’s), (4) pulmonary eosinophilia with asthma, and (5) pulmonary eosinophilia with periarteritis nodosa.
In the same year, Reeder and Goodrich in Detroit, Michigan indicated a preference for the descriptive phrase "pulmonary infiltration with eosinophilia" (P.I.E.) to identify these disorders and coined the term P.I.E. syndrome. It was their feeling that use of this term allowed inclusion of cases not logically called Löffler’s syndrome or tropical eosinophilia.
In 1969, Liebow and Carrington presented the term "eosinophilic pneumonia" to designate pulmonary infiltration by eosinophils that may or may not be accompanied by an excess of these in the peripheral blood. This effectively broadened the P.I.E. syndrome of Reeder and Goodrich to include a new group of diseases that had histologic evidence of increased lung eosinophils but not necessarily blood eosinophils. Eosinophilic pneumonia was divided into four categories: (1) acute, which is associated with helminthic infections, drug-induced, and idiopathic; (2) chronic, which is allergic bronchopulmonary aspergillosis, associated with asthma, and idiopathic: (3) tropical eosinophilia; and (4) allergic granulomatosis and angiitis. Later, Carrington and others reported nine cases of chronic eosinophilic pneumonia characterized by severe dyspnea, weight loss, and fever lasting months or years with atypical radiographs showing peripheral pulmonary infiltrates.
Finally, others have offered simpler schemes of classification including McCarthy and Pepys who divided these disorders into either allergic bronchopulmonary aspergillosis or "cryptogenic pulmonary eosinophilia." Schatz and colleagues also proposed a classification based on pulmonary infiltrates with eosinophilia.
E. Major Etiologies of P.I.E.
1. Allergic
a. Allergic Bronchopulmonary Aspergillosis
Allergic Bronchopulmonary Aspergillosis (ABPA) is an asthma syndrome first described by Hinson and colleagues in 1952. This disorder is the most common cause of pulmonary eosinophilia in temperate climates and is probably the most common cause worldwide. Although all age groups can be affected, it is more common in adults. While primarily associated with asthma, ABPA also occurs in approximately 10% of patients with cystic fibrosis. The diagnostic criteria generally used in the U.S. include asthma, peripheral blood eosinophilia, immediate pinprick test for Aspergillus antigens, serum precipitating antibodies against Aspergillus antigens, increased serum IgE levels, and chest x-ray infiltrates. Also, Aspergillus organisms in the sputum, history of coughing up brown mucous plugs, and positive type III (Arthus) reaction for Aspergillus are frequent findings. Central bronchiectasis is present in 85% of patients at the time of diagnosis and has been used in the diagnostic criteria by some authors. Bronchiectasis associated with this disorder is thought to result from deposition of immune complexes in proximal airways. Antibodies to Aspergillus antigens can be identified in both serum and BAL fluid. The IgE level is probably the most useful test in ABPA as it correlates well with disease activity.
Generally, the spores of A. fumigatus are inhaled and deposited in secretions of the bronchial tree of susceptible persons. There, the fungus proliferates and produces hyphae which provokes an antibody reaction with the production of specific IgE and IgG antibodies. Blood eosinophilia is usually moderate in the range of 500 to 2,000 mm3, but occasionally higher counts are seen. The pulmonary pathologic lesions in patients with ABPA are of two types: marked eosinophilic infiltration of the lung with features of eosinophilic pneumonia, and mucous plugging of the airways. ABPA progresses through five clinical stages: acute, remission, exacerbation, corticosteroid-dependent asthma, and fibrosis. Many studies have shown that long term corticosteroids in patients with the earlier stages of ABPA may prevent development of the fibrotic stage and ultimately lessen permanent lung damage.
The radiographic features of ABPA are well-described. These include "tramline shadows" caused by thickening of the walls of dilated bronchi, "ring shadows" due to dilated bronchi themselves, "gloved-finger" shadows due to trapped distal secretions within dilated bronchi, and finally "toothpaste shadows" caused by mucoid impaction within bronchi.
The cornerstone of therapy is oral prednisone. A typical regimen might consist of prednisone, 0.5 mg/kg/d for 2 weeks followed by every other day dosing for 3 months. Others treat at a high dose until a clinical response is obtained. Response is usually assessed in terms of radiographic clearing and resolution of blood eosinophilia or monitoring serum IgE levels. While some physicians continue their patients on a low dose of prednisone in hopes of avoiding reoccurrences, it is generally the practice in North America to stop steroids between attacks and monitor IgE levels. Antifungals including ketoconazole and inhaled Amphotericin B have not been proven to be beneficial. However, a uncontrolled study of six patients suggested that itraconazole may have steroid-sparing effects. The ultimate goal of therapy in ABPA is to prevent development of bronchiectasis, irreversible airway obstruction, and development of aspergilloma.
b. Drug Reactions
Drug reactions are one of the most commonly reported causes of pulmonary infiltrates with blood and/or alveolar eosinophilia. One problem with this literature is that most of it is in the form of single case reports. A number of drugs with no chemical similarity have been implicated, and essentially all drugs are candidates for this syndrome. Typically, the patient develops low-grade fever and varying degrees of pulmonary symptoms ranging from none to severe dyspnea with or without wheeze and cough. The mechanisms underlying these reactions remain largely unknown although certainly immune complexes may be important.
Reactions may begin within hours of taking the drug; however, clinical manifestations are more common after several days of therapy. Fever, dry cough, and dyspnea are common symptoms presented by patients with acute pulmonary eosinophilia caused by drugs. In one study, two-thirds of the patients had crackles on physical examination, and all had a decline in diffusion capacity on pulmonary function testing. Also, none had reversible drug-related airways obstruction or restriction.
A few drugs warrant special mention. Nitrofurantoin is well-recognized (over 3,000 cases) as causative of acute reactions, subacute reactions lasting longer than one month, and chronic reactions lasting more than six months. Eosinophilia can be massive in the acute variety (60,000 mm3) and is generally lower in the chronic variety. Nitrofurantoin may stimulate an impressive inflammatory response associated with fever, malaise, dyspnea, and cough. Examination reveals cyanosis, bibasilar rales, hypoxemia, a lung diffusion defect, and eosinophilia. The mechanism is thought to be due to oxygen radicals. In one study of 335 cases of nitrofurantoin-associated P.I.E., 56% had infiltrates, 19% infiltrates and effusions, 3% effusions only, and 21% had a normal chest x-ray. Nitrofurantoin has also been known to cause a lupus-like syndrome with obstructive pulmonary vasculitis, granulomatous interstitial inflammation, and fibrosis.
Also, there have been a large number of reports of sulfasalazine causing pulmonary infiltrates with blood and/or BAL eosinophilia. As you know, this drug is composed of sulfapyridine and 5-ASA and is a mainstay in the treatment of inflammatory bowel disease. It appears that the sulfapyridine moiety is largely responsible for the pulmonary toxicity.
Inorganic chemical exposure may also result in transient pulmonary infiltrates with eosinophilia. Several cases of nickel-induced Löffler’s syndrome have been described, either after the inhalation of nickel carbonyl fumes in an industrial setting or in association with ingestion of a nickel-containing coin.
In general, blood eosinophilia and radiologically diffuse pulmonary infiltration are found in all these disorders. As a general rule, many patients improve simply by discontinuing the medication. However, in severe or persistent cases, short courses of corticosteroids appear to hasten recovery.
Drugs Causing Eosinophilic Disease
Ampicillin Febarbamate Methotrexate Phenytoin
Beclomethasone (inhaled) Fenbufen Methylphenidate (Ritalin) Pyrimethamine
Carbamazepine Glafenine Minocycline Rapeseed oil
Chlorpromazine GM-CSF Naproxen Sulfadimethoxine
Clofibrate Ibuprofen Nickel Sulfadoxine
Cocaine (inhaled) IL-2, IL-3 Nitrofurantoin Sulfasalazine
Cromolyn (inhaled) Iodinated contrast dye Para-aminosalicylic acid Sulindac
Desipramine L-tryptophan Penicillin Tamoxifen
Diclofenac Mephenesin carbamate Pentamidine (inhaled) Tetracycline
Tolazamide
(adapted from Allen and Davis. Eosinophilic Lung Diseases. Am J Respir Crit Care Med Vol 150. Vaginal cream
p. 1431, 1994)
c. Asthma
While asthma does not directly cause pulmonary infiltrates, it is always included as a cause of pulmonary eosinophilia. However, complete discussion of this classic eosinophilic lung disease is beyond the scope of this review. It is safe to say that although many cells are involved in the pathogenesis of asthma, the eosinophil is the most characteristic inflammatory cell, leading to descriptions of asthma as "chronic eosinophilic bronchitis." The increased production, localization, and degranulation of the eosinophil in respiratory tissues appears to be an important component of airway inflammation and hyperreactivity in asthma. It has been shown that peripheral blood and BAL eosinophil counts correlate with the degree of airway obstruction.
Most patients with asthma can be differentiated from patients with other eosinophilic lung diseases based on a history of wheezing or cough accompanied by reversible airway obstruction. Although the chest radiograph is often without evidence of infiltrates, some patients with asthma can develop atelectasis or lobar collapse due to airway mucous plugging.
2. Infections
a. Migratory Metazoan Parasites
Several parasites have been identified as causing pulmonary infiltrates with blood and/or alveolar eosinophilia. As with other microbial diseases, familiarity with the common parasites in one’s geographic area of practice is the key to diagnosis. In the United States, Strongyloides, Ascaris, Toxocara, and Ancyclostoma are frequent causes of infection with pulmonary eosinophilia. It must be emphasized that patients need to be evaluated at multiple time points because infection with one parasite indicates risk for other parasites. Also, knowledge of the life cycle of the parasite is important, since stool ova may not be detected for 4-6 weeks after a P.I.E. syndrome.
Strongyloides stercoralis can be associated with peripheral blood eosinophilia, rash, and transient pulmonary infiltrates. Larvae of this nematode enter through exposed skin, migrate to the lung, crawl up the airway, become swallowed, and develop into adult worms in the intestinal tract. Infiltrates usually occur before adults develop and therefore before ova can be found in the stool. An ELISA is now available which may help improve detection in difficult cases. As opposed to other nematodes, Strongyloides is capable of perpetuating its life cycle in humans indefinitely. A hyperinfection syndrome can develop in patients with deficiency in cell-mediated immunity which manifests itself as diffuse pulmonary infiltrates, gram-negative sepsis, respiratory failure, and an overall high mortality rate. This is due to massive numbers of newly hatched larvae penetrating the intestinal wall to migrate to the lungs, often carrying gram-negative bacteria with them. The treatment of strongyloidiasis is thiabendazole, 25mg/kg bid for 2 days, but treatment should be continued for 2 weeks with the hyperinfection syndrome.
Simple pulmonary eosinophilia, which was first described by Löffler in 1932 as a transient illness associated with blood eosinophilia and radiographic shadowing, is usually associated with infection with ascaris worms, either Ascaris suum or Ascaris lumbricoides. Generally, patients have transient cough and low-grade fever, but physical examination of the chest is usually unremarkable. The absence or minimal nature of symptoms in Löffler’s syndrome usually heralds complete resolution with or without therapy; however, in severe episodes corticosteroids are highly effective. Other parasites that may cause Löffler’s syndrome include Necator americanus and Strongyloides stercoralis.
With regard to Ascaris infection, the life cycle is similar to that of Strongyloides in that there is a migratory phase through the lungs. In this case eggs of Ascaris are ingested, and larvae hatch in the small intestine. Fever, nonproductive cough, chest pain, and rash are common. Radiographs reveal bilateral discrete densities often including the perihilar regions. Pulmonary function tests show restriction with occasional mild obstruction. Because the pulmonary syndrome occurs before the adult worms mature, stool examination for ova is usually negative for up to 8 weeks after the onset of respiratory symptoms. Although pulmonary symptoms resolve spontaneously over 7 to 10 days, the intestinal infection should be treated with oral mebendazole 100 mg bid for 3 days.
Toxocara canis ( the dog roundworm) causes visceral larvae migrans. This term applies to a clinical syndrome consisting of eosinophilia, hepatomegaly, and pneumonitis that results from prolonged migration through human viscera by nematode larvae. Ingested eggs hatch in the intestine and migrate through the blood to the liver, lungs, and other organs. Mature worms do not develop in humans (therefore, stool for ova is always negative). Pulmonary involvement is found in 80% of patients and is manifest by coughing or wheezing. Patients may have crackles on examination of the chest and infiltrates on chest x-rays. There are generally increased numbers of eosinophils and elevated levels of IgE in the peripheral blood as well as BAL eosinophil percentage, which can be profoundly elevated. Diagnosis is made serologically and thiabendazole or mebendazole may relieve symptoms. In severe cases, brief courses of corticosteroids appear to be beneficial.
Ancyclostoma brasiliense ( the dog hookworm) causes "creeping eruption." This term applies to a clinical syndrome consisting of pulmonary infiltrates accompanied by peripheral blood eosinophilia and a serpiginous rash. The filariform larvae in soil infect humans by skin contact. As the larvae burrow under the skin, the rash extends from the original site over a period of several days. Approximately 50% of patients will develop patchy, migratory infiltrates which appear about 1 week after the onset of the rash and persist for several weeks. In some cases, sputum eosinophilia has been reported to correlate with pulmonary infiltrates; however, it can also occur in the absence of infiltrates. Humans represent a "dead-end" host, and therefore diagnosis is based on the clinical presentation. Thiabendazole 25 mg/kg bid for 2 days is usually effective treatment.
Tropical pulmonary eosinophilia is caused by the filarial worms, Wuchereria bancrofti and Brugia malayi. Weingarten in 1943 first described the association of cough, wheeze, blood eosinophilia, and response to arsenicals typical of tropical pulmonary eosinophilia. The filaria are transmitted to humans by mosquitos, and the adult worms eventually reside in the lymphatics. It is there that they release microfilariae which subsequently travel to the lung and create an intense inflammatory reaction. Patients generally present with symptoms of nocturnal cough, dyspnea, wheezing, fever, weight loss, and malaise. Serum and BAL fluid contain high levels of IgE and IgG, which correlate with disease activity. Blood eosinophilia is usually in the range of 5,000 to 60,000 mm3, and BAL eosinophils average 50%. Although pulmonary function tests generally show a restrictive defect, 20 to 30% of patients have an accompanying obstructive ventilatory defect. Severe or longstanding disease can result in a reduced diffusing capacity. Laboratory features include high levels of IgE and filaria specific for IgG and IgE antibodies. Radiological features include fluffy reticulonodular shadowing more marked in the midlung zones and bases. Histologically, there is an influx of histiocytes into alveolar spaces followed by invasion of eosinophils into alveolar and interstitial spaces. The diagnosis is based on presentation and biopsy is generally unnecessary. Treatment consists of diethylcarbamazine 6-12 mg/kg/d in three divided doses for 1 to 3 weeks. However, cough, wheezing, dyspnea, chest x-ray abnormalities, peripheral blood eosinophilia can persist after treatment of TPE, consistent with development of chronic interstitial lung disease.
Many other parasites have been witnessed to cause eosinophilia accompanied by pulmonary symptoms or chest x-ray infiltrates including schistosoma infection, flukes (Clonorchis and Opisthorchiasis), Trichinella spiralis, Paragonimus westermani (lung fluke), Dirofilaria immitis (dog heartworm), and Echinococcus.
In addition to parasites, other infections found to be associated with the P.I.E. syndrome include tuberculosis, coccidiomycosis, RSV, chlamydial pneumonia of infancy, and Pneumocystis carinii in AIDS. With regard to P. carinii, there has been documented an increase in BAL (not blood) eosinophil percentages in 15% of patients with AIDS-associated P. carinii pneumonia. While pulmonary eosinophilia has been associated with bacterial infections, there is usually a eosinopenia (and not eosinophilia) found in the case of pyogenic bacterial infection.
Parasites Causing Eosinophilic Lung Disease
Ancyclostoma sp. Opisthorchiasis sp.
Ascaris sp. Paragonimus westermani
Brugia malayi Schistosoma sp.
Clonorchis sinesis Strongyloides steratocolis
Dirofilaria immitis Toxocara sp.
Echinococcus sp. Trichinella spiralis
Wuchereria bancrofti
(adapted from Allen and Davis. Eosinophilic Lung Diseases. Am J Respir Crit Care Med Vol 150. p. 1430, 1994)
3. Neoplastic
Although not as common as infections or allergy, several neoplasms have been found to have an association with pulmonary eosinophilia. For example, non-small cell carcinoma can be accompanied by peripheral blood eosinophilia. While an increase in BAL eosinophils is not common in patients with bronchogenic carcinoma, histologic sections show tumor and interstitial tissue infiltration by eosinophils in up to 50% of patients. The mechanism of eosinophilia in bronchogenic carcinoma may be related to tumor-derived eosinophilopoietic factors such as high levels of GM-CSF (a known stimulus for eosinophil production, chemotaxis, and activation.) Because of the importance of early diagnosis of non-small cell lung cancer, this is an important diagnosis to remember with unexplained chest x-ray findings and blood eosinophilia.
Tissue eosinophils usually can be found as a component of the mixed inflammatory infiltrate in Hodgkin’s disease. In addition an increase in both BAL and blood eosinophilia has been reported. However, it can sometimes be difficult to tell if the eosinophilia is due to Hodgkin’s disease or due to chemotherapy.
Both non-Hodgkin’s lymphoma and lymphocytic leukemia can be associated with pulmonary infiltrates and peripheral blood eosinophilia. Lung disease can present before the diagnosis of malignancy, and lung histology can resemble chronic eosinophilic pneumonia. The peripheral and pulmonary eosinophilia respond well to chemotherapy. Although the cause of this association is poorly understood, lymphocyte-derived eosinophilopoietic factor production has been proposed.
Eosinophilic leukemia can occur in a subset of patients with myeloblastic leukemia. The lungs can become infiltrated with eosinophils and myeloblasts, causing dyspnea and radiographic infiltrates. This must be primarily differentiated from hypereosinophilic syndrome.
Finally, many malignancies that metastasize to the lungs can be associated with peripheral blood eosinophilia. This further underscores the importance of a thorough clinical evaluation in patients with unexplained pulmonary infiltrates and peripheral blood eosinophilia.
4. Rheumatic
a. Churg-Strauss syndrome
In 1951, Churg and Strauss were the first to describe a clinical syndrome consisting of asthma, history of allergic disease (allergic rhinitis), peripheral blood eosinophilia, and a granulomatous inflammatory response with vascular necrosis, primarily involving the lungs, but also at times involving the heart, skin, nervous system, and kidney. Most patients have a history of allergic disease for 8 to 10 years before presentation, and all have asthma or history of asthma. Patients can develop marked eosinophilia (occasionally up to 10,000/ul) and infiltration of a variety of tissues with eosinophils. It is not until months or years later that systemic vasculitis develops. Interestingly, asthma symptoms may diminish as vasculitis symptoms become more prominent.
The clinical manifestations in this entity include a history of asthma or allergic rhinitis, and complaints of fever, malaise, weight loss, and dyspnea. Upper airway findings include sinusitis, rhinitis, and nasal polyps. Skin findings are found in 70% of patients and may include nodules, purpura, or urticaria. Mononeuritis multiplex (altered sensation in one of the extremities) occurs in 66% of patients. Gastrointestinal symptoms, renal insufficiency, and arthralgias/myalgias are common. Common cardiac findings include heart failure in 47%, pericarditis in 32%, and hypertension in 29%. Cardiac lesions cause death in approximately half of all cases.
Chest x-rays show pulmonary infiltrates in the majority of patients. Radiographic findings can vary from bilateral infiltrates to diffuse interstitial lung disease. Pleural effusions occur in one-third of patients, and hilar adenopathy has occasionally been noted. Pulmonary function tests generally show obstructive defects.
The IgE level is elevated often to very high levels and appears to correlate with disease activity. Most patients have anemia and an increased erythrocyte sedimentation rate. The BAL typically shows very high percentages of eosinophils (average of 33% in one study.)
Open lung biopsy is the "gold standard" for diagnosis. Histology generally demonstrates necrotizing giant cell vasculitis predominantly in the small arteries, but veins also may be affected. Interstitial and perivascular granulomas are common, and eosinophils have been noted to accumulate in blood vessels, interstitial tissue, and alveolar structures. Because of the minimal vascular tissue obtained, transbronchial biopsy is usually insufficient for diagnosis.
Corticosteroids are the treatment of choice in Churg-Strauss vasculitis. Untreated, approximately 50% die within 3 months of the onset of vasculitis. However, the mean survival is 9 years in patients treated with steroids. In general, prednisone at a dose of 40-100 mg/d (at least 1 mg/kg) is required for several weeks for resolution of the vasculitis. Daily or alternate day low-dose prednisone is typically continued for one year. In patients who fail to respond or develop significant corticosteroid toxicity, high dose "pulse" methylprednisolone, azathiaprine, or cyclophosphamide may be effective.
b. Eosinophilic-Myalgia syndrome
Eosinophilia-Myalgia syndrome is a multiorgan disorder caused by contaminants found in batches of L-tryptophan made by one manufacturer in the late 1980’s. Severe myalgias accompanied by acute peripheral blood eosinophilia were seen in approximately half the persons ingesting the contaminated drug. Respiratory symptoms were also reported in over 50% of affected patients, and pulmonary findings include chest x-ray infiltrates, pleural effusions, dyspnea, cough, pulmonary hypertension, and respiratory muscle weakness. Pulmonary function tests usually revealed a reduced diffusion capacity often with a restrictive ventilatory defect. Lung histology demonstrates interstitial infiltrates by lymphocytes and eosinophils, alveolar eosinophils, and small to medium vessel vasculitis.
5. Unknown
a. Chronic Eosinophilic Pneumonia
Chronic Eosinophilic Pneumonia (CEP), as opposed to simple eosinophilic pneumonia, can be a serious disease that requires a specific treatment. The first two cases were described by Christoforidis and Molnar in 1960; however, Carrington and his colleagues are generally credited with the first large series of patients. They were the first to coin the term "chronic eosinophilic pneumonia" to describe a condition in which there was coexistence of peripheral eosinophilia with pulmonary eosinophilic infiltration without an identifiable precipitant. The initially described cases were all in women who ranged in age from 18 to 77 years. However, we have since learned that although reported in children, the peak incidence occurs in the fifth decade, and females predominate 2:1.
In general, the onset is insidious, with as average symptom duration of 7.7 months before diagnosis. Cough with mucoid or no sputum, fever, dyspnea, and weight loss are the main initial symptoms. Symptoms reported in a smaller group of patients include malaise, wheezing, and night sweats. Asthma may accompany or precede the onset of symptoms and has been noted in approximately 50% of cases. Also, respiratory failure has been reported in accelerated cases and cases in which diagnosis has been delayed.
Peripheral blood eosinophilia, defined as greater than 6% of the total white count, remains a hallmark in this syndrome and occurred in 88% of patients in one study. However, because eosinophilia is absent in up to one-third of cases, diagnosis may be delayed. In general, eosinophilia is usually mild to moderate. Eosinophils can be found in the sputum in about half of patients. Laboratory values associated with, but not specific for, chronic eosinophilic pneumonia include an elevated sedimentation rate that may exceed 100 mm/hr and thrombocytosis. Also, serum IgE levels are increased in two-thirds of patients, and rheumatoid or immune complexes may be found.
Pulmonary function tests can be normal in mild cases but usually show restrictive defects with a reduced diffusing capacity. Obstructive defects have been noted, but their presence probably represents concurrent asthma. Essentially all patients will have hypoxemia or an increased A-a gradient.
Chest radiographic findings have been extensively described in CEP. The classical radiographic features are of dense peripheral infiltrates that are often referred to as reverse pulmonary edema or the photographic negative of pulmonary edema. However, a recent study indicated that the classical radiographic features are found in only one-fourth of the cases. Less frequent radiographic findings include nodular infiltrates, consolidation, cavitations, atelectasis, and pleural effusions.
Computerized tomography (CT) may demonstrate the peripheral predominance of airspace consolidation more frequently than the chest radiograph does. Also, half of patients will have mediastinal adenopathy on CT scans which are not apparent on plain chest x-rays. One study of CT findings illustrated the evolution of changes in chronic eosinophilic pneumonia. When the initial CT was performed within 1 month of the onset, the main abnormality was dense confluent consolidation in contact with the pleura accompanied by ground-glass opacities. If the CT was obtained 1-2 months after the onset, the main lesions were either inhomogeneous irregular consolidation and nodules or only ground-glass opacities. Finally when the initial CT was performed >2 months after the onset, the findings were band-like opacities or streaky shadows that were not in contact with the pleura and severe atelectasis.
Histologically, CEP manifests itself as eosinophilia noted in the interstitial tissue and alveoli. The mixed inflammatory cell infiltrate is notable in that the multinucleated histiocytes may contain eosinophilic granules and Charcot-Leyden crystals. Eosinophilic abscesses may be seen and noncaseating granulomas occur in a minority of patients.
When the clinical presentation and chest x-ray are highly typical, the diagnosis can be made quickly. Debate continues over the role of BAL, transbronchial biopsy, and open lung biopsy in the diagnosis of CEP. BAL demonstrates a high percentage of eosinophils (usually >25%) in the acute stage of CEP with normalization of eosinophil percentages after treatment with corticosteroids. In fact, the finding of an increased percentage of BAL eosinophils may be the first clue to a diagnosis of CEP in patients with interstitial lung disease. Open lung biopsy, which is rarely required except for more difficult cases, shows eosinophils in alveolar walls and spaces.
The etiology of chronic eosinophilic pneumonia is unknown. The disease may represent a hypersensitivity response to unknown antigens or may be an idiopathic immunologic activation. In general, treatment with prednisone in doses of 30-60 mg/day will result in prompt resolution of symptoms within 24 to 48 hours and of chest x-ray abnormalities within 10 days. The dosage can be gradually decreased, but this must be done with caution. The most striking feature of long term follow-up in CEP was the occurrence of relapses when corticosteroid therapy was discontinued or the dose was tapered. Such relapses can be prevented by doses of prednisone ranging from 5 to 20 mg every other day. Once steroid therapy has been reinstituted in those patients, they responded in the same dramatic fashion with rapid resolution of their systemic symptoms. In some patients low-dose alternate day steroid therapy is required for at least 1 year. Most patients will be able to discontinue corticosteroids without further relapse; however, a minority will require steroids indefinitely. Overall, the long term prognosis for patients with CEP is excellent.
b. Acute Eosinophilic Pneumonia
Acute Eosinophilic Pneumonia was simultaneously described by Badesch et al and Allen et al in 1989 as a clinical entity distinct from chronic eosinophilic pneumonia. In general, these patients may be of any age and either gender. Classically, they present with an acute febrile illness of 1 to 5 days duration, hypoxemia, and diffuse alveolar or mixed alveolar-interstitial chest x-ray infiltrates. Many have hypoxemic respiratory failure requiring mechanical ventilation. Also, a majority of patients have not had previous or subsequent asthma; however, some have reported a history of allergic rhinitis. Physical examination is notable for high fever, respiratory distress, and basilar or diffuse crackles on pulmonary auscultation. While wheezing is not heard during spontaneous breathing, transient wheezing and rhonchi have been reported.
Early radiographic findings include a subtle interstitial infiltrate and commonly Kerley B lines. Within several hours to a few days this is followed by a mixed alveolar and interstitial infiltrate involving all lobes. In sharp contrast to the infiltrates seen in CEP, chest x-rays and chest CT in AEP rarely show peripherally-based infiltrates at presentation. Instead, CT usually shows diffuse alveolar infiltrates, pleural effusions, pronounced septal markings, and normal lymph nodes.
Small to moderate-sized pleural effusions are frequent and often bilateral. Also, they usually demonstrate a high percentage of eosinophils with a high pH consistent with release of basic eosinophil granule contents. In striking contrast to blood eosinophil percentages (which are usually normal), a very high percentage of BAL eosinophils is characteristic with an average of 42% in one series. Leukocytosis is usually present, and serum IgE levels have been elevated in some but not all patients. Pulmonary function tests generally show a low diffusing capacity and a restrictive pattern which largely normalize after treatment. Obstructive defects have not been reported thus far.
When the clinical findings and bronchoalveolar lavage findings are characteristic, lung biopsy is not needed to make the diagnosis. However, lung biopsy has been required in some cases to exclude acute infections such as P. carinii and Aspergillus pneumonias. Lung biopsies generally demonstrate eosinophils and edema within the alveolar space, the bronchial walls, and interstitial space. Eosinophilic infiltration into the bronchobronchiolar mucosa might temporarily cause inflammatory small airway dysfunction to account for the transient wheeze and forced expiratory rhonchi that has been reported.
Patients generally respond rapidly and dramatically to corticosteroid therapy, usually within 24 to 48 hours. Commonly used dosages range from 60 to 125 mg of methylprednisolone every 6 hours until the respiratory failure resolves ( usually within 1 to 3 days). At that point the dosage is decreased to 40 to 60 mg/d for 2 to 4 weeks followed by a taper over the next 2 to 4 weeks. In contrast to patients with CEP, patients with AEP do not relapse after discontinuation of steroids. In fact, some patients have been known to improve spontaneously.
The exact etiology of AEP is unknown. However, it has been suggested that this syndrome is the result of an acute hypersensitivity response to an unidentified inhaled antigen in an otherwise healthy individual. It is critical to remember that AEP is a diagnosis of exclusion, and an infectious etiology must be continuously sought even after corticosteroids are begun. In other words, failure to respond rapidly to corticosteroids should prompt an extensive search for other diagnoses including lung biopsy if necessary.
c. Hypereosinophilic Syndrome
The idiopathic hypereosinophilic syndrome (HES) is a rare heterogeneous group of disorders characterized by prolonged blood eosinophilia greater than 1,500/ul (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. Virtually any organ system can be involved including the heart, lungs, central nervous system, skin, gastrointestinal tract, and other organs. Although formerly called "eosinophilic leukemia" and "disseminated eosinophilic collagen disease," the term hypereosinophilic syndrome is now preferred.
The cause of HES remains unknown; however, the profound eosinophilia may be lymphocyte-dependent based on the finding of abnormal clonal proliferation of T-helper lymphocytes in patients with HES. Onset of the disease in the majority of patients is between 20 and 50 years of age, and there is a 7:1 male predominance. Common presenting symptoms include night sweats, weight loss, pruritus, cough, and fever. The most striking finding is profound peripheral eosinophilia, usually 30 to 70% with a total white count of greater than 10,000/ul. Eosinophils are found in large quantities in the bone marrow. Also, serum levels of soluble interleukin-2 receptors correlate with disease activity and severity.
The heart is involved in approximately 60% of cases and remains the major cause of mortality and morbidity. Cardiac involvement, including cardiomyopathy, valvular insufficiency, and mural thrombus formation is perhaps the most important complication of HES. Myocardial biopsies reveal early damage to the endothelial cell and not the myocardial cell. Endothelial cell damage may serve as an initiator of thrombosis, with recurrent episodes resulting in tissue damage and fibrous thickening of the endocardium. Untreated, some patients may develop congestive heart failure.
Pulmonary involvement occurs in approximately 40% of patients, and nocturnal cough or dyspnea is a prominent feature. Chest x-rays reveal interstitial, nonlobar infiltrates (in about 25% of patients) as well as pleural effusions (in approximately 50% of patients). BAL fluid generally shows a very high percentage of eosinophils of up to 73%. Longstanding HES can result in pulmonary fibrosis. Autopsy studies reveal interstitial eosinophilic infiltrates and less commonly, areas of necrosis postulated to be secondary to pulmonary thromboemboli.
Thromboembolic disease occurs in two-thirds of patients and is more frequently arterial than venous. The most common manifestation is splinter hemorrhages but other evidence of thromboemboli can be seen such as splenic infarcts, deep venous thrombosis, cerebrovascular accident, or femoral artery embolism. Generalized intellectual deterioration as well as peripheral neuropathy occurs with advanced disease. Abdominal pain, polyarthropathy, muscular weakness, and skin rashes are among the non-specific presentations.
Historically, survival in HES has been poor with a reported three-year survival of 12 %. Poor prognostic indicators have included high peripheral leukocyte counts (90,000 to 100,000), blast forms in the peripheral blood, and the appearance of congestive failure. Approximately one-half of patients will have a good response to corticosteroids alone. Improvement with steroid therapy is particularly common in patients with pulmonary eosinophilia, cardiac failure, purpura, and raised serum IgE levels. One treatment regimen that has been suggested consists of prednisone 60 mg/d for 1 month, then 60 mg every other day for 3 months. Anticoagulants should be used in those with thromboembolic disease. If the disease progresses while the patient is taking prednisone, hydroxyurea, 0.5 to 1.5 g/d, may be added with the goal of maintaining the leukocyte count at less than 10,000. Other drugs have been used successfully including busulfan, cyclophosphamide, azathioprine, interferon- , cyclosporin-A, etoposide, and vincristine.
d. Sarcoid
Sarcoidosis is usually accompanied by a prominent T-helper lymphocyte alveolitis. However, in approximately 15% of cases more than 5% BAL eosinophils have been observed. There have been a few cases of sarcoidosis masquerading as eosinophilic pneumonia. Because radiographically the differentiation can be difficult, absence of adenopathy or a nodular quality of peripheral infiltrates may not mitigate against the diagnosis of sarcoidosis in favor of CEP. On occasion, sarcoidosis has been found in patients having CEP who did not respond to corticosteroids.
e. Miscellaneous
Other lung diseases sometimes associated with eosinophils include idiopathic pulmonary fibrosis, Langerhan’s cell granulomatosis (eosinophilic granuloma), hypersensitivity pneumonitis, BOOP, primary coccidiomycosis, Pneumocystis carinii, tuberculosis, RSV infection, and pertussoid eosinophilic pneumonia. Also, eosinophilic lung diseases can accompany both ulcerative colitis and eosinophilic gastroenteritis.
F. Clinical Approach
Patients may first be recognized as having an eosinophilic lung disease because of pulmonary symptoms and/or chest x-ray abnormalities accompanied by increased numbers of blood, BAL, or tissue eosinophils. Certainly, the patient’s clinical presentation and geographic location would impact on the clinical approach. Although the content and order of individual work-ups would be diverse, certain aspects should be common to all.
As with most medical diseases, the importance of a thorough history and physical examination cannot be overemphasized. The duration and severity of symptoms is of vital importance. With regard to eosinophilic lung disease, history of asthma, contact with pets, HIV risk factors, symptoms of systemic disease, travel history, and a complete drug history are essential. History of asthma may make certain diseases more likely including Churg-Strauss syndrome, ABPA, or bronchocentric granulomatosis. Travel abroad may suggest parasitic infection and raise the possibility of such diseases as TPE, schistosoma, or Paragonimus westermani. Even remote travel should be elicited as certain parasites (Strongyloides stercoralis and Clonorchis sinesis) can persist for as long as 50 years before clinical presentation. Close contact with cats or dogs might suggest Ancyclostoma and Toxocara infection. Symptoms of underlying systemic diseases such as collagen vascular disease, vasculitis, or malignancy should be sought. Finally, a careful history of all prescription, over-the-counter, and illicit drugs is of paramount importance.
A white count and differential is an important component of the evaluation. Some diagnoses may have an increase in pulmonary eosinophils without an increase in blood eosinophilia such as eosinophilic granuloma, AEP, P. carinii pneumonia, and some drug-induced disease. On the other hand, diseases such as simple pulmonary eosinophilia, CEP, parasite infection, ABPA, some drug-induced lung diseases, Churg-Strauss syndrome, fungal infections, and HES typically have high numbers of blood eosinophils.
Stool should be examined multiple times for evidence of parasitic infection. However, some parasites cannot be diagnosed by stool examination (such as Trichinella, Paragonimus, Ancyclostoma, Toxocara). Other parasites (such as Ascaris) may cause pulmonary eosinophilia weeks before ova are present in the stool.
Serologic tests can be helpful in certain situations such as ABPA and Cryptococcosis. Also, Toxocara, Trichinella, and filariasis can be diagnosed with the aid of serologic studies. When Strongyloides is suspected but can’t be identified in the stool, serology may be useful.
Pulmonary function tests can often be useful in the initial evaluation of patients with eosinophilic lung disease as well as following the course of patients with an established diagnosis. Those that typically show a restrictive pattern include AEP,CEP, interstitial lung disease, and TPE. Conversely, those primarily associated with an obstructive pattern include asthma, bronchiolitis obliterans, ABPA, and Churg-Strauss syndrome.
For some disorders not accompanied by peripheral eosinophilia, BAL may provide the first indication of eosinophilic lung disease. Higher percentages of eosinophils (>20%) may suggest such etiologies as AEP, CEP, HES, Churg-Strauss syndrome, drug reactions, and parasitic infections. On the other hand, lower percentages of eosinophils (<20%) may suggest interstitial lung disease and certain drug reactions. BAL and specific cultures may also aid in identifying certain fungal, bacterial, parasitic, or protozoan infections. Finally, cytology from BAL may aid in detecting carcinoma or lymphoma cells.
In general, open lung biopsy should be reserved for difficult cases and those patients who aren’t responding to standard therapy including corticosteroids. This may confirm disease such as Churg-Strauss syndrome, malignancy, interstitial lung diseases, and bronchocentric granulomatosis. Biopsy is generally not required for the diagnosis of ABPA, HES, drug reaction, or parasitic infections. Biopsy remains the "gold standard" in CEP but rarely must be utilized in order to make the diagnosis. Similarly, AEP doesn’t require biopsy for confirmation unless the history suggests fungal infection or a contraindication to a trial of corticosteroids exists.
G. Finish case presentation
H. Summary (adapted from Allen and Davis. Eosinophilic Lung Diseases. Am J Respir Crit Care Med Vol 150. p. 1434,1994)
As you can see, significant strides have been made in our understanding of the group of disease characterized by pulmonary infiltrates and peripheral eosinophilia. The eosinophil plays a central role in the pathophysiology of these disorders and serves as a marker for disorders that are often treatable or curable with corticosteroids.
Despite our present understanding, several syndromes can only be defined clinically, and significant overlap persists between these syndromes. Although many classifications schemes have been proposed, no one is perfect, and the diagnostic criteria for individual disorders should not be so rigid as to exclude patients with less than "classic" presentations.
There is still a great deal of work to be done with regard to better understanding of the determinants of eosinophil growth, chemotaxis, adhesion, and activation. Also, an ideal classification scheme will ultimately require identification of the specific etiologies of the eosinophilic pneumonias. Only by continuing research in this area coupled with thoughtful clinical practice may we learn more about this intriguing group of diseases.
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Special Thanks to Dr. David Bass for his guidance and support.