AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Pulmonary diseases associated with tissue and/or blood eosinophilia are a heterogeneous group of disorders. Various nosologies have been offered, but this article classifies these syndromes as extrinsic or intrinsic in origin. Some syndromes overlap, but this approach is convenient from the diagnostic standpoint.

Inhaled or ingested extrinsic factors, including medications and infectious agents (eg, parasites, fungi, mycobacteria), may trigger an eosinophilic immune response. This may be mild and self-limited, as in Loeffler syndrome.

Intrinsic pulmonary eosinophilic syndromes are generally idiopathic in nature. They include a diverse group of autoimmune and idiopathic syndromes ranging from blood dyscrasias to vasculitis. This group includes acute eosinophilic pneumonia (AEP), chronic eosinophilic pneumonia (CEP), idiopathic hypereosinophilic syndrome (IHES), Churg-Strauss syndrome (CSS), and eosinophilic granuloma (EG; pulmonary histiocytosis X or Langerhans cell granulomatosis).

Eosinophilia and pulmonary infiltrates have been reported in patients with AIDS, lymphoma, a variety of inflammatory lung diseases, and collagen vascular diseases (see Causes).

Asthma may manifest with marked eosinophilia, with or without infiltrates.

For additional information, see the following:

• Asthma
• Churg-Strauss Syndrome
• Pneumonia, Bacterial
• Pneumonia, Fungal
• Pneumonia, Viral
• Medscape's Pneumonia Resource Center

Pathophysiology

Tissue pathology is largely related to the release of toxic eosinophil products. These products include major basic protein, eosinophil cationic protein, and eosinophil-derived neurotoxin, which damage the respiratory epithelium, induce ciliastasis, and influence mucus production. Tissue injury may also be caused by the release of reactive oxygen species. The release of platelet-activating factor and leukotrienes contributes to bronchospasm. In some syndromes, such as tropical pulmonary eosinophilia (TPE) and CEP, interstitial fibrosis may result from chronic inflammation. Commonly, lung parenchyma is affected, but in certain extrinsic and intrinsic syndromes, other organs may be affected.

Extrinsic eosinophilic syndromes

• Loeffler syndrome: The pathogenesis of Loeffler syndrome is unknown but presumably reflects a hypersensitivity response to an ingested or inhaled antigen from food, medication, or an infectious agent. Many of the original cases of Loeffler syndrome were thought to be related to Ascaris infection.
• Parasitic infections: Migrating parasites traversing the lungs may cause bronchospasm, dyspnea, and pulmonary infiltrates. Embolization of microfilariae or eggs, which degenerate and expose antigens to the local immune system, leads to granuloma formation. Local elaboration of chemokines and cytokines plays a role in T-cell recruitment and granuloma formation. Persistent inflammation may lead to parenchymal necrosis and fibrosis.
• Schistosomiasis: The most common pulmonary complication is pulmonary hypertension from chronic embolization of ova.
• TPE: These patients have marked immune responses to filariae, while other individuals infected with Wuchereria bancrofti or Brugia malayi have suppressed parasite-specific immune responses. Patients with TPE rarely have signs of lymphatic filariasis. Elevated immunoglobulin E (IgE) and immunoglobulin G (IgG) levels in patients with TPE reflect polyclonal B-cell activation.
• Strongyloidiasis: Patients who are immunocompromised, including those recently prescribed systemic corticosteroids, may develop hyperinfection syndrome, in which large numbers of recently released larvae burrow through the intestine and migrate to the lungs. Sepsis and respiratory failure may result from accompanying enteric bacteremia.
• Fungal causes: Allergic bronchopulmonary aspergillosis (ABPA) is an immunologic response to Aspergillus antigens in the airways of individuals with obstructive lung disease. Both IgE-mediated and immune complex–mediated hypersensitivity responses are active. Chemokines recruit CD4+ T helper 2 antigen-specific cells to the lung. The inflammatory responses lead to airway reactivity, mucus hypersecretion, epithelial damage, bronchiectasis, eosinophilic pneumonia, and parenchymal injury and fibrosis. Aspergillus proteases likely also contribute to airway damage. Other fungi have also been found to cause a similar disorder, prompting some to suggest renaming this disorder allergic bronchopulmonary mycosis.
• Bronchocentric granulomatosis: This idiopathic condition, in which the mucosal epithelium is supplanted by epithelioid histiocytes and then by granuloma formation, is often associated with ABPA.

Intrinsic eosinophilic syndromes

• AEP: This is not associated with any history of medication usage or infection. Many patients have engaged in dusty outdoor activities, suggesting a hypersensitivity response to inhaled antigens. Eosinophilic alveolitis may be extensive, and profound hypoxemia with respiratory failure may result.
• CEP: The pathogenesis is unknown. CEP may occur in isolation and/or in association with polyarteritis nodosa, rheumatoid arthritis, scleroderma, ulcerative colitis, breast carcinoma,¹ and histiocytic lymphoma. Most patients have evidence of asthma and atopy. Although not a prominent feature, microgranulomata are occasionally seen on biopsy specimens, suggesting that an antigen-driven, T-cell–mediated process is active.
• IHES: Some patients display overproduction of chemokines,² proeosinophilic factors, including interleukin (IL)–4 and IL-5 by clonally expanded differentiation clusters 3 and 4 (CD3⁺ and CD4⁺) and Th2-like lymphocytes. These patients also have evidence of polyclonal hypergammaglobulinemia. Other patients have increased numbers of stem cells committed to the eosinophil lineage. Pulmonary involvement is manifested as wheezing, coughing, pulmonary edema, and pleural effusions. Pulmonary emboli result from a hypercoagulable state. Multiple organ systems may be affected, resulting in gastrointestinal tract dysfunction, skeletal muscle weakness (which may lead to respiratory failure), endomyocardial fibrosis, myocarditis, congestive heart failure, and/or valvular disease.
• CSS: The pathogenesis is unknown. Inhaled or ingested antigens have been proposed as causative agents in susceptible individuals. Recent reports linking the syndrome with the leukotriene inhibitors zafirlukast and montelukast in the setting of steroid withdrawal suggest these agents unmask preexisting CSS rather than suggesting that CSS is a direct causal effect of these agents. Vasculitis may affect the sinuses, central and peripheral nervous systems, gastrointestinal tract, kidneys, and heart.
• EG: The cause is unknown, but the reactive histiocytic proliferation suggests a reactive process, perhaps to an unknown antigen. Patients develop reticulonodular interstitial and cystic disease. EG is strongly associated with cigarette smoking. This may affect the lungs, bones (including the skull, resulting in diabetes insipidus), and other organs. Tissue and peripheral eosinophilia are generally not prominent features of this condition.

Frequency

United States

Intrinsic syndromes are uncommon. Regarding extrinsic syndromes, medication- or food-related syndromes are sporadic. Occasionally, outbreaks are related to contaminated food or medication, eg, L-tryptophan and toxic oil syndrome.

• Strongyloidiasis is the most common infection in the United States and is usually observed in individuals from the south, southeast, and Caribbean areas.
• Schistosoma mansoni infection is observed in the Caribbean.
• Toxocariasis (visceral larva migrans) is usually found in the southeast region of the country.
• Ascariasis, because it is prevalent worldwide, is likely to be observed in the United States.
• Among the hookworms, Necator americanus is endemic to the southeastern United States.
• Occasionally, international visitors or recent immigrants may present with other parasitic infections such as TPE and paragonimiasis.
• For fungal causes, ABPA is relatively common, with some estimates indicating that 5-10% of people who are steroid-dependent and have asthma meet the criteria. Of persons with cystic fibrosis, 10% have ABPA. Coccidioidomycosis is found predominantly in the southwestern part of the United States or among individuals with a relevant travel history.

International

Intrinsic syndromes are uncommon. Regarding extrinsic syndromes, in much of the world, parasitic infections are endemic.

• Ascaris is likely the most prevalent nematode infecting humans worldwide but tends to occur in tropical or subtropical areas.
• Ancylostoma duodenale is commonly found in the Eastern Hemisphere.
• Visceral larva migrans is found throughout the world.
• Strongyloidiasis, which usually occurs in warmer climates, has a worldwide prevalence of approximately 50-100 million individuals.
• Schistosomiasis is common in Africa, Asia, Latin America, and South America. Paragonimiasis and clonorchiasis are common in Asia.
• TPE is often observed in southern Asia, Southeast Asia, and South America. Most reported cases have occurred in ethnic Indians, while it is uncommon in Chinese persons. TPE is actually observed in a minority of patients infected with the causative filariae.

Mortality/Morbidity

• With the exception of Loeffler syndrome and drug-induced disease, these syndromes may be associated with significant morbidity. While most are responsive to corticosteroids, recognition of infection and institution of an appropriate therapy are important in preventing chronicity of symptoms and, in some cases, respiratory failure.
• Patients with IHES may develop congestive heart failure, pulmonary emboli, and multiorgan-system dysfunction. Mortality in cases of IHES has been improving with increasing therapeutic options; now, 80% of patients are surviving at 5 years and 40% are surviving at 10-15 years.
• The mortality rate in cases of CSS has been decreasing, with approximately 75% of patients surviving 5 years.

Race

• No clearly defined racial predispositions have been identified in these syndromes.
• Parasitic infections are endemic in many geographic areas, but they reflect public health conditions rather than racial predispositions.

Sex

• No sexual predilection has been noted for extrinsic eosinophilic syndromes, with the exception of TPE, which has been reported to have a male predominance at a male-to-female ratio of 4:1.
• Among the intrinsic syndromes, differences are noted. AEP is more common in men than in women, unlike CEP. CEP is twice as common in women as in men, but this sexual disparity declines with increasing age. For IHES, approximately 90% of cases are found in men and 10% are found in women. For CSS, no sexual predisposition has been reported. For EG, no sexual predominance is described. The older literature suggests a male predominance, but more recent data suggest equal distribution between sexes, possibly reflecting the changing demographics of cigarette smoking, which is thought to be etiologic.

Age

• Extrinsic syndromes tend to affect adults, but exceptions exist. Toxocariasis tends to occur in children and is often associated with geophagia. Ascariasis tends to occur in children. ABPA usually occurs in adults but may occur in children, including some patients with cystic fibrosis.
• Intrinsic syndromes generally affect adults. AEP usually occurs in persons in their third decade of life. CEP peak incidence is in the fourth decade of life. IHES usually occurs in people aged 20-50 years; however, it has also been infrequently reported in children. Most cases of CSS have been reported in adults. EG may affect individuals ranging in age from infancy to old age, but it most frequently affects patients in their second to third decade of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Methodical history taking, to exclude infections, foods, medications, or other precipitants, is important before labeling a pulmonary eosinophilic syndrome as intrinsic or idiopathic. The duration of symptoms and the presence of concomitant medical illnesses, such as collagen vascular disease, may be relevant.

• Query patients about the usage of all medications, including dietary supplements, and illicit drugs.
• Loeffler syndrome is precipitated by food, medications, or infections. It is self-limited (usually <1 mo duration). Symptoms are mild, and the syndrome is characterized by blood eosinophilia and fleeting pulmonary infiltrates, with or without dyspnea.
• Obtaining a careful travel history is important for assessing the risk of fungal or parasitic infection. Travel to or from areas endemic for parasites (eg, Asia, Africa, Latin America, South America, southeast region of the United States) is of particular relevance to parasitic infection. Parasitic infections tend to cause fever, weight loss, fatigue, dyspnea, dry cough, wheezing, chest discomfort, and, occasionally, hemoptysis. Relevant historical elements for parasitic infections are provided below.
• • Strongyloidiasis: Patients may report skin contact with sand or soil, abdominal pain or distension, and/or diarrhea, with or without immunocompromise. Marked wheezing and/or respiratory distress may occur.
  • Ascariasis: Mild pulmonary symptoms are accompanied by pruritic dermatitis.
  • Schistosomiasis: Patients may report contact with contaminated water and the presence of skin lesions. Symptoms of early infection are mild, but the manifestations of chronic infection include chronic dyspnea. Other symptoms are bladder and gastrointestinal dysfunction, cirrhosis, and, commonly, pulmonary hypertension.
  • Clonorchis sinensis infection: Patients may relate a history of ingestion of inadequately cooked or pickled fish, abdominal pain, nausea, vomiting, and/or diarrhea.
  • Paragonimiasis: Ingestion of inadequately cooked or pickled crustaceans, abdominal pain, nausea, vomiting, diarrhea, testicular pain, and/or CNS manifestations are reported findings. Patients may develop significant hemoptysis or extensive infiltration.
  • Toxocariasis: Findings include skin or oral contact with soil contaminated by canine feces, contact with puppies, and/or seizures. This condition can lead to significant wheezing and, occasionally, respiratory distress. Patients with toxocariasis may also be asymptomatic.
• Fungal infections associated with pulmonary infiltrates and eosinophilia include Aspergillus infections, Coccidioides immitis infections, and other less common infections.
• • Aspergillus infections: Although Aspergillus species are ubiquitous, ask about contact with soil or contaminated water sources.
  • ABPA: Although technically not an infection because it is the host response to colonization by Aspergillus that is etiologic, it is considered here. Wheezing may be severe, and patients eventually develop prominent central bronchiectasis. The mildest form of ABPA is serologically positive (ABPA-S), the moderate form has central bronchiectasis (ABPA-CB), and the severe form includes both central bronchiectasis and other radiologic features (ABPA-CB-ORF). Early treatment has been suggested to prevent progression to more severe parenchymal disease.³ 
  • C immitis infection: Inquire about recent travel to the southwestern United States.
  • The clinical course of coccidioidomycosis is highly variable, with more than 60% of patients being asymptomatic, while most of the remainder have mild symptoms.
• For intrinsic syndromes, seek the historical elements described below.
• • AEP: Acute onset of rapidly progressing dyspnea, often accompanied by abdominal complaints and myalgias, usually occurs within 1 week of presentation. Commonly, recent antecedent outdoor activity with considerable dust exposure has occurred. Marked acute hypoxemia, often progressing to respiratory distress, is typical. AEP is distinguished from CEP by its rapid progression, the presence of fever and severe hypoxemia, and no associated history of hypersensitivity to drugs.
  • CEP: Gradual onset of cough, fever, dyspnea, constitutional symptoms, and weight loss occurs. Wheezing, night sweats, chest pain, and, occasionally, hemoptysis may be reported. Respiratory failure is occasionally reported. Half the patients with CEP have a history of asthma.
  • IHES: Patients may complain of constitutional symptoms, dyspnea, cough, wheezing or angioedema (occasionally), and symptoms related to multiple affected organs, particularly those in the cardiovascular, gastrointestinal, and musculoskeletal systems. Symptoms related to arterial and venous thromboembolic disease may be present (eg, pulmonary emboli, vascular insufficiency, cerebrovascular accident).
  • CSS: Patients often have antecedent rhinitis, sinusitis, and nasal polyps, followed by the development of asthma symptoms. Symptoms related to vasculitis occur years later and include mononeuritis multiplex, abdominal pain, gastrointestinal bleeding, symptoms of heart failure, arthralgias, myalgias, urticaria, purpura, and nodular skin lesions.
  • EG: Approximately one fourth of patients are asymptomatic. Most have a cough, dyspnea, fever, and chest discomfort. Wheezing may be reported. Patients may develop symptoms related to the pneumothorax, bony lesions, and diabetes insipidus. Cigarette smoking is nearly universal in these patients and is considered etiologic. The course of EG is highly variable. Patients at age extremes, those with multiorgan or skin involvement, and those with pneumothoraces tend to have a poor prognosis.

Physical

A complete physical examination of these patients is necessary. For this heterogeneous group of diseases, clues to establishing a diagnosis are found in virtually every portion of the examination.

• Skin examination
• • A pruritic rash, which may be raised or serpiginous, is often seen.
  • Medication-related syndromes may result in skin manifestations.
  • Parasitic infection, commonly with Strongyloides, Ascaris, Toxocara, Ancylostoma, Necator, and Trichinella species, may cause skin symptoms.
  • Disseminated coccidioidomycosis is related to patients' skin symptoms.
  • A rash associated with IHES may be due to skin infiltration by eosinophils. Splinter hemorrhages and evidence of vascular occlusion may be seen.
• Head, eyes, ears, nose, and throat examination
• • Evidence of rhinitis/sinusitis may be observed in persons with CSS and CEP.
  • Vascular occlusion may be observed during the eye examinations of patients with IHES.
  • Proptosis may be seen in patients with CSS.
• Chest examination
• • All the syndromes discussed can cause rales and wheezing.
  • Physical signs of cardiac decompensation (eg, valvular insufficiency, S₃, rales, jugular venous distension [JVD], peripheral edema) may be present in patients with IHES and CSS.
  • Patients with chronic schistosomiasis may present with signs of pulmonary hypertension (eg, loud P₂, JVD, peripheral edema, right-sided S₃).
• Abdominal examination
• • Patients with chronic schistosomiasis may present with signs of cirrhosis (eg, distended abdomen, shifting dullness, peripheral edema, telangiectasias, icterus).
  • Nonspecific abdominal tenderness is common in patients with parasitic diseases and intrinsic diseases.
• Neurologic examination
• • Neuropathy may be observed in patients with IHES and CSS.
  • Evidence of CNS deficits due to cerebrovascular accident may be observed in patients with IHES.

Causes

• Extrinsic syndromes and the eosinophilic immune response can be triggered by inhaled or ingested substances, including medications, drugs (eg, cocaine), food (eg, contaminated cooking oil), dietary supplements (eg, L-tryptophan), and infections (eg, parasites, fungi, mycobacteria).
• • Medications that have been implicated include the following:
  • • Antibiotics (among the most common offending agents)
    • Nonsteroidal anti-inflammatory drugs (among the most common offending agents)
    • Antidepressants
    • Contraceptives
    • Antihypertensives
    • Leukotriene inhibitors
    • Anticonvulsants
    • L-tryptophan
    • Cocaine
  • Parasitic infections due to nematodes, filariae, and helminths may cause pulmonary infiltrates and eosinophilia. Such infections include strongyloidiasis, ascariasis, paragonimiasis, schistosomiasis, dirofilariasis, ancylostomiasis, trichomoniasis, clonorchiasis, and visceral larva migrans.
  • Fungal processes, such as ABPA and coccidioidomycosis, may also cause pulmonary eosinophilia. Bronchocentric granulomatosis is most commonly related to Aspergillus infection.
  • Other infections may include tuberculosis and Pneumocystis carinii pneumonia.
• Intrinsic syndromes (ie, AEP, CEP, IHES, CSS, EG) are idiopathic.
• Asthma can cause pulmonary eosinophilia.
• Occasionally, eosinophilia and pulmonary infiltrates have been associated with AIDS, bronchiolitis obliterans organizing pneumonia (BOOP), hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, sarcoidosis, Hodgkin disease, rheumatoid lung disease, and other collagen vascular diseases.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Eosinophilic leukemia
Paragonimiasis
Clonorchiasis
Visceral larva migrans
Bronchiolitis obliterans organizing pneumonia
Collagen vascular diseases

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The workup should start with the history and physical examination. Pertinent history of travel, evidence of collagen vascular disease, status of the immune system, usage of medications, duration of symptoms, and evidence of airway obstruction are essential elements to consider. The final diagnosis always rests with the response to treatment, even with infectious syndromes.
• • Rule out infectious etiologies based on the travel history, regardless of how remote.
  • Initially, examine stool for ova and parasites.
  • Individualize additional studies.
  • Intrinsic eosinophilic syndromes, including AEP, CEP, and IHES, become more likely in the differential diagnosis once extrinsic etiologies have been excluded.
• Blood leukocyte count with differential is necessary.
• • Leukocytosis is common in all of these syndromes. The eosinophil percentage is less sensitive than the absolute eosinophil count (AEC). Normal blood AEC is as high as 250/µL.
  • CBC count and AEC should be monitored to assess the course of illness and response to treatment when appropriate.
  • Bronchoalveolar lavage (BAL) fluid cell count and differential are often valuable diagnostically (see Procedures).
  • Blood and pulmonary eosinophilia are generally present together in persons with Loeffler syndrome, parasitic and fungal infections, CEP, ABPA, CSS, and IHES.
  • Isolated pulmonary eosinophilia may be observed in persons with AEP, medication-related syndromes, P carinii pneumonia, BOOP, tuberculosis, and EG (Langerhans cell).
• Microbiologic studies, rarely, may show evidence of infection with Mycobacterium tuberculosis, P carinii, or fungi. Make additional efforts to exclude parasitic or other fungal co-infection.
• • Parasitic infections may be detected by examining stool, urine, and sputum or BAL fluid.
  • • Stool specimens sent for ova and parasite evaluation may be unrevealing if intestinal infection is not established. Multiple specimens should be sent and examined by experienced laboratory personnel. Stool or gastric aspirate examination is generally useful for detecting Strongyloides species, Schistosoma species, and C sinensis; is often less useful for detecting Paragonimus, Ancylostoma, Necator, and Ascaris infection; and is usually not helpful for detecting Toxocara, Trichinella, and Echinococcus species and TPE-associated filariae.
    • Urine examination may be useful in cases of schistosomiasis.
    • Sputum or BAL fluid examination may be useful for detecting Paragonimus, Ascaris, Strongyloides, and, rarely, Schistosoma infections.
  • Fungal infection may be detected by examining respiratory secretions.
  • • ABPA is supported by growth of Aspergillus species from respiratory secretions.
    • Coccidioides species may be cultured from respiratory secretions.
• Immunologic studies, ie, serologic testing, may be useful in persons with ABPA, parasitic infection, and CSS. Serologic testing may obviate the need for invasive testing in the case of parasitic infections. Use a targeted approach to serologic testing, bolstered by clinical information.
• • Total IgE values are often elevated in persons with these syndromes, and this finding has no specific diagnostic value. Some general trends may be noted.
  • • Levels of less than 1000 ng/mL are usually observed in association with asthma and low-intensity infections.
    • ABPA and parasitic infections are typically associated with high levels, often greater than 2000 ng/mL.
  • The diagnosis of ABPA is supported by an elevated IgE level, an elevated Aspergillus-specific IgE level, a positive result for Aspergillus precipitins, and an immediate skin hypersensitivity response to Aspergillus.
  • • Levels correlate with the activity of ABPA.
    • If levels are within the reference range in a patient with respiratory symptoms, ABPA can usually be excluded.
  • Some parasitic infections may be diagnosed based on serological results. These include TPE-associated filarial infection (eg, B malayi, W bancrofti); echinococcal infection (serology results are positive in 60-90% of cases); and toxocariasis, with best results obtained by enzyme-linked immunosorbent assay (ELISA).
  • A variety of sensitive and specific serologic tests, including complement fixation, ELISA, and immunoblot, have been developed to detect Paragonimus infection.
  • Tests with limited value are available for Strongyloides and Ascaris infections.
• In CSS, perinuclear antineutrophil cytoplasmic antibody results are positive in at least 60% of cases.
• In CEP, check antinuclear antibody or rheumatoid factor levels because CEP may be associated with connective tissue diseases.

Imaging Studies

• Chest radiography of extrinsic syndromes
• • Loeffler syndrome: Fleeting interstitial infiltrates may be evident.
  • Parasitic infections: These typically manifest as interstitial or indistinct nodular densities, usually in the middle and/or basilar lung fields. Infiltrates may be migratory. Chest x-ray films may yield normal findings in many individuals.
  • TPE: Fibrosis may be evident in persons with chronic disease.
  • Echinococcus infection: This manifests as large, smooth-edged, masslike densities, with or without calcification.
  • Chronic schistosomiasis: Patients with chronic schistosomiasis may have hilar enlargement and right ventricular enlargement as a consequence of pulmonary hypertension.
  • ABPA: Fleeting infiltrates, atelectasis, pneumonitis, and bronchiectasis may be evident.
• Chest radiography of intrinsic syndromes
• • AEP: Interstitial infiltrates progress to alveolar-filling infiltrates. Small pleural effusions and Kerley B lines may be present.
  • CEP: Peripheral alveolar infiltrates may be migratory, and they have the classic appearance of the photographic negative of pulmonary edema in one fourth of cases.
  • IHES: Interstitial infiltrates, pleural effusions, pulmonary edema, pulmonary infarct, and fibrosis may be present.
  • CSS: Interstitial infiltrates, alveolar infiltrates, and nodular opacities may be present. Cavitary, small, patchy irregularities are not usually present.
  • EG: Reticulonodular infiltrates, increased lung volumes, cystic changes, coalescing nodules, and pneumothorax may be seen.
• Chest CT scan: CT scan of the chest helps define the extent and distribution of the disease; helps distinguish between predominantly interstitial or alveolar infiltrates; helps detect lymphadenopathy, fibrosis, and bronchiectasis; may be helpful in distinguishing between malignancy and other etiologies; and may be needed if biopsy is contemplated. High-resolution CT scan is preferred to enhance the evaluation of the pulmonary parenchyma.
• • ABPA: Fleeting infiltrates, atelectasis, pneumonitis, and bronchiectasis may be evident. High attenuation mucoid impaction is associated with higher IgE levels, eosinophilia, Aspergillus-specific titers, and a greater probability of relapse.⁴
  • Parasitic diseases: CT scan images provide finer detail of nodules and interstitial infiltrates. In schistosomiasis and echinococcal diseases, additional cysts may be seen in the liver.
  • AEP: Ground-glass infiltrates are commonly seen, but dense consolidation, nodules, and septal thickening may also be revealed.
  • CEP: Alveolar ground-glass infiltrates in a peripheral distribution are highly characteristic of CEP.
  • IHES: Nodules and effusions may be seen.
  • CSS: In addition to abnormalities seen on plain radiographs, irregular pulmonary arteries may be seen.
  • BOOP: Peripheral triangular-shaped infiltrates are classic, but alveolar filling may be evident.
  • EG: Cystic changes, nodules, and fibrosis are seen.
  • Idiopathic pulmonary fibrosis: Interstitial infiltrates, a ground-glass alveolar pattern, nodules, and fibrosis are seen.
• Echocardiography
• • Establishing an estimation of right ventricular, left ventricular, and valvular function is indicated in individuals with certain intrinsic syndromes (eg, CSS, IHES) or in individuals with sustained high-level eosinophilia in which cardiac complications are relatively common.
  • Establishing an estimation of pulmonary systolic pressure and right ventricle function is indicated in persons with chronic schistosomiasis because pulmonary hypertension is common.

Other Tests

• Pulmonary function testing
• • This testing may be useful in the initial evaluation to help narrow the differential diagnosis. It is helpful as an initial test to distinguish between obstructive and restrictive diseases.
  • An obstructive pattern may be seen in persons with asthma, ABPA, bronchocentric granulomatosis, EG, BOOP, CSS, and, occasionally, IHES.
  • A restrictive pattern may be seen in persons with TPE, intrinsic eosinophilic syndromes, and interstitial lung diseases.
  • This type of testing helps assesses the severity of airway obstruction or parenchymal restriction.
• Ventilation/perfusion scanning
• • This scan may be useful in some patients with IHES in the appropriate clinical setting who have a propensity to develop pulmonary emboli.
  • Schistosomiasis and other parasitic diseases may result in matched and unmatched defects.
• Skin testing
• • Prick testing and intradermal testing can be performed for an immediate hypersensitivity response to Aspergillus infection.
  • Avoid skin testing if the patient has significant wheezing.

Procedures

• Fiberoptic bronchoscopy with BAL
• • BAL is often necessary to obtain adequate specimens to help rule out infection, particularly in the instance of CEP and other intrinsic syndromes.
  • BAL fluid leukocyte and differential cell counts may provide the presenting or only sign of eosinophilic pulmonary syndrome. Normally, few eosinophils are obtained from BAL fluid. The presence of more than 20% suggests Loeffler syndrome, AEP, CEP, or IHES.
  • Pulmonary eosinophilia alone may be present in persons with AEP, medication-related syndromes, P carinii pneumonia, BOOP, tuberculosis, and EG (Langerhans cell).
  • BAL examination may be useful for detecting Paragonimus, Ascaris, Strongyloides, and, rarely, Schistosoma infections.
  • BAL fluid cytology findings may be useful for excluding malignancy.
  • BAL cytology findings may also be useful for detecting EG, for which immunohistochemical staining for the S-100 antigen or electron microscopy (demonstrating the pentilaminar Birbeck granule) can be diagnostic.
• Transbronchial biopsy
• • Transbronchial biopsy may be performed to help determine if an invasive fungal infection is present.
  • The size of the tissue specimens obtained is generally insufficient to reliably provide the histopathologic information for the syndromes discussed.
• Transthoracic needle aspiration/biopsy
• • This may occasionally may be used to help distinguish infection from malignancy when the results of other, less-invasive studies have been unrevealing.
  • Dirofilariasis, which is difficult to diagnose with noninvasive methods, has been diagnosed based on findings from this method.
  • Avoid aspiration of echinococcal cysts because of the risk posed by dissemination, resulting in a massive hypersensitivity reaction.
• Open lung biopsy
• • Open lung biopsy is rarely necessary, but it is usually performed if CSS, interstitial lung disease, or malignancy is suggested.
  • For AEP and CEP, BAL is usually performed. Once infection is excluded, the rapid response to therapy contributes to a clinical diagnosis.
• Other biopsies
• • Liver biopsy is performed for chronic schistosomiasis with cor pulmonale. It rarely is performed for TPE (which is usually confirmed based on serology findings) and toxocariasis.
  • Lymph node biopsy is occasionally used in cases of TPE.
  • Skin biopsy is performed for trichinosis, and it is occasionally performed for toxocariasis or when skin manifestations of other diseases are prominent.
  • Rectal biopsy is occasionally pursued in persons with schistosomiasis.
  • Muscle biopsy findings may indicate trichinosis.

Histologic Findings

• Parasitic diseases: Findings include increased histiocytes, eosinophilic and lymphocytic infiltration of airspaces, eosinophilic abscesses, granulomas, and areas of fibrosis.
• ABPA: Findings include eosinophilic, lymphocytic, plasmacytic, and monocytic infiltration around bronchi; granulomas; fibrosis; microabscesses; and bronchiectasis.
• AEP: Findings include eosinophilic infiltration of airspaces and airway walls and edema, but not vasculitis.
• CEP: Findings include eosinophilic and lymphocytic accumulation in alveoli, eosinophilic abscess formation, bronchiolitis, and fibrosis. Granulomas are not seen. Occasionally, mild vasculitis is seen.
• CSS: Eosinophilic necrotizing vasculitis of small vessels and granulomas are common.
• IHES: Findings include eosinophilic infiltration of interstitium and airways and intravascular thrombi.
• EG: Findings include Langerhans cell proliferation and granulomas, lymphocytic and monocytic infiltration, desquamative interstitial pneumonitis, granulomatous vasculitis, lymphoid follicles, S-100 antigen staining of Langerhans cells, and, with electron microscopy, the Birbeck (X-body) within cytoplasm of Langerhans cells.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Give general supportive care by treating hypoxemia with supplemental oxygen. Treat bronchospasm with inhaled or nebulized bronchodilators. Inhaled corticosteroids may also be used when appropriate for persistent wheezing. Administer systemic steroids judiciously because they may worsen some infections.

• Extrinsic syndromes
• • Medication-induced syndromes: These respond to the withdrawal of the offending agents, with few, if any, residual effects.
  • Loeffler syndrome: Remove any potentially offending medications or ingested substances. Loeffler syndrome is mild and self-limited. Patients rarely require systemic corticosteroids.
  • Parasitic infections: Once a diagnosis of parasitic infection is established, initiate therapy with appropriate antibiotics. Patients who are immunocompromised or patients taking systemic steroids with strongyloidiasis may develop hyperinfection syndrome,⁵ often associated with gram-negative septicemia and adult respiratory distress syndrome. They may require empiric antibiotic coverage and respiratory and hemodynamic support.
  • Fungal causes: For ABPA, administer systemic steroids and inhaled bronchodilators. Short-term itraconazole may be used in the treatment of ABPA, as data suggest that it causes reductions in inflammatory markers and may have steroid-sparing effects. For coccidioidomycosis, the use of steroids early in infection may result in dissemination and death.
• Intrinsic syndromes
• • AEP: Patients with AEP respond rapidly to high doses of systemic corticosteroids and do not tend to relapse.
  • CEP: Patients with CEP respond rapidly to prednisone at a dose of 30-40 mg/d, with significant symptom improvement occurring within 48 hours and radiographic clearing occurring within 10 days. Relapse is common if steroids are discontinued in the first 6 months of therapy. Continue therapy with lower doses of prednisone for several additional months. Patients rarely require permanent steroid therapy.
  • IHES: Half the patients respond to corticosteroids, but others require more aggressive therapy with busulfan, cyclophosphamide, cyclosporin-A, etoposide, azathioprine, hydroxyurea, vincristine, or interferon alfa. Imatinib is used in myeloproliferative IHES.
  • CSS: Prednisone administered at a dose of 40-60 mg/d for several weeks, followed by lower-dose therapy for a total of 1 year, generally provides efficacious therapy. High doses of intravenous methylprednisolone, cyclophosphamide, and azathioprine have been used to treat patients whose conditions are refractory. In refractory cases, high-dose intravenous immunoglobulin has been reported to be helpful.⁶ Interferon-alpha and tumor necrosis factor inhibitors, such as infliximab and etanercept, have also been used.⁷
  • EG: Smoking cessation is essential. Corticosteroids are generally not beneficial.

Surgical Care

Surgical intervention is rarely necessary for patients with these syndromes. The need for open lung biopsy is rare (see Procedures).

• Parasitic diseases
• • Echinococcal cystectomy or lung resection is the preferred treatment for this disease. Right hepatic echinococcal cysts may be removed during the echinococcal cystectomy. Often, adjuvant medical therapy is administered.
  • Dirofilariasis may be difficult to distinguish from malignancy and may require transthoracic needle aspiration or resection.
• Malignancy
• • Lung resection may be necessary if a solitary pulmonary nodule is present or if malignancy is in the forefront diagnostically.
  • Mediastinoscopy may be necessary if lymphadenopathy, possibly representing lymphoma, is significant.
• Pneumothorax with obstructive lung disease
• • This may require tube thoracostomy.
  • If recurrent, such as with EG, pleurodesis may be required.

Consultations

Often, the complexity of these patients' presentations and treatment warrants subspecialty consultation. This may facilitate diagnosis and treatment.

• Pulmonologists provide expertise in the diagnostic approach, optimize the management of respiratory symptoms, may perform flexible bronchoscopy when indicated, and assist in the long-term management of the disease.
• Infectious disease specialists provide diagnostic and therapeutic expertise and assistance, especially with unusual pathogens.
• Radiologists who have good knowledge of chest radiography and tomography findings can be invaluable. A radiologist may be needed in the rare instance that a radiologically guided biopsy is warranted.
• Consult a thoracic surgeon when an open lung biopsy is indicated.
• Consult a hematologist for management of IHES.

Diet

Patients who have ingested food, supplements, or medication to which the syndrome is attributed should subsequently avoid reexposure.

• Chemically related medications should be avoided.
• Measures should be taken to avoid ingestion of contaminated water or food.
• Patients should avoid incompletely cooked seafood and crustaceans.
• Patients should avoid incompletely cooked pork.

Activity

Discourage the patient from engaging in activities linked to the syndrome or encourage the patient to take measures to avoid recurrence of the syndrome.

• Patients should avoid contaminated water or soil known to harbor parasites or fungi.
• Patients should avoid close contact with animals known to harbor parasites until these animals have been decontaminated.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

For extrinsic diseases, remove any offending agent. Treat parasitic infections with the appropriate antibiotics. ABPA and other diseases with prominent wheezing are managed with bronchodilators, inhaled corticosteroids, and, for exacerbations, systemic corticosteroids. Use systemic corticosteroids judiciously in individuals with parasitic infection.

Intrinsic diseases are generally managed with oral or intravenous corticosteroids. CSS is also occasionally treated with cyclophosphamide or azathioprine. IHES is usually initially treated with systemic corticosteroids, with half the patients responding. Other treatments for IHES include cyclophosphamide, azathioprine, busulfan, and others.

Take care to establish a diagnosis or to at least rule out parasitic or cryptococcal infection before treating the patient with steroids because of the risk of dissemination.

Drug Category: Corticosteroids

Eosinophils are exquisitely sensitive to steroids. These medications inhibit eosinophil egress from the vascular compartment, inhibit their chemotaxis, and decrease eosinophil survival.

Drug Category: Bronchodilators

Provide symptomatic relief of dyspnea from bronchospasm. Do not use as sole management of these diseases.

Drug Category: Antifungals

Most of the fungal diseases discussed do not require specific antifungal treatment. For disseminated, severe, or invasive fungal infection, amphotericin B is administered IV. Short-term itraconazole can improve symptoms in ABPA and may have a steroid-sparing effect. Itraconazole is generally reserved for steroid-refractory cases.⁸ Fluconazole and other azoles have been used in the treatment of patients who are stabilized with progressive or disseminated coccidioidomycosis. Various agents are available for treatment of P carinii pneumonia.
Coccidioidomycosis does not usually require treatment, but treatment is required for immunocompromise or progressive or disseminated disease (see Coccidioidomycosis (Infectious Diseases). Itraconazole can be used for mild-to-moderate disease, and it is also used for treatment of blastomycosis.

Drug Category: Antiparasitic agents

Several of the azoles inhibit microtubule assembly and, in some instances, glucose uptake. Albendazole is a preferred agent because of the low incidence of adverse effects, in contrast to thiabendazole.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• With extrinsic diseases, the priority is to establish the diagnosis, assure adequate oxygenation, and provide bronchodilator therapy, with or without steroids as indicated.
• • Fungal infections: For ABPA, assure clinical improvement. For coccidioidomycosis, patients who are immunocompromised may develop disseminated infection if steroids are administered.
  • Parasitic diseases: Patients may develop a Mazzotti reaction, in which the death of parasites releases new antigens, with resultant fever, urticaria, pruritus, bronchospasm, and associated gastrointestinal symptoms. Patients who are immunocompromised and have strongyloidiasis may develop hyperinfection syndrome with use of steroids (see Medication).
• With intrinsic syndromes, make aggressive attempts to exclude infections.
• • AEP: Patients may deteriorate rapidly to respiratory failure and require mechanical ventilation, but they generally respond well to high-dose steroids.
  • CEP: CT scan and bronchoscopy are generally performed. If no infection is present, the patient is treated with prednisone. Rapid clinical and radiologic improvement occurs within 24-72 hours.
  • CSS: If significant end organ damage results from vasculitis and if the damage is rapidly advancing, the urgency of treatment may be increased.
  • IHES: Patients tend to respond slowly, and only 50% respond to steroids. Patients may develop deep venous thrombosis and pulmonary emboli.

Further Outpatient Care

• For extrinsic diseases, maintain clinical and radiologic follow-up with patients. Monitor oxygen saturation.
• • ABPA: Patients tend to relapse after treatment. Monitor symptoms, peak flow, spirometry, IgE levels, and oxygen saturation. Patients may develop complications of bronchiectasis (ie, infections, hemoptysis, aspergilloma).
  • Parasitic diseases: Occasionally, repeated treatment courses may be needed. For TPE, provide symptomatic relief with bronchodilators and systemic and/or inhaled steroids. Patients often develop fibrosis. Monitor spirometry and lung volumes. For schistosomiasis, patients may develop pulmonary hypertension and cor pulmonale, requiring supplemental oxygen, diuretics, and supportive measures.
• Intrinsic diseases are marked by a tendency to recur. Monitor oxygenation at rest and with exertion, perform pulmonary function tests as necessary, and perform radiologic evaluations.
• • CEP: This tends to recur if treatment is stopped early. Initially, determining if the syndrome is CEP alone or an early manifestation of IHES is difficult.
  • CSS: Long-term treatment is necessary. If end organ damage is progressive from vasculitis, patients may require additional treatment beyond systemic corticosteroids.
  • IHES: Various agents have been used to treat those with disease that is unresponsive to steroids (see Medication). Allogeneic bone marrow transplant has been used.
  • EG: These patients may develop symptoms of diabetes insipidus from infiltration of the pituitary gland. Smoking cessation is essential.

In/Out Patient Meds

• Extrinsic diseases
• • Fungal diseases
  • • ABPA: Albuterol and/or other bronchodilators, inhaled corticosteroids, and systemic steroids, when needed, may be administered. If the patient is unresponsive to these medications, see Asthma for further options.
    • Coccidioidomycosis: Treatment is usually not necessary. For patients with progressive or disseminated disease, use amphotericin B intravenously, followed by fluconazole.
  • Parasitic diseases: If the patient has significant bronchospasm, provide bronchodilators and inhaled or systemic steroids judiciously.
  • • Ascaris infections - Albendazole or mebendazole
    • Hookworms (Necator species, Ancylostoma species) - Albendazole
    • TPE - Ivermectin or diethylcarbamazine
    • Strongyloides infections - Ivermectin or thiabendazole
    • Toxocariasis (visceral larva migrans) - Ivermectin or albendazole
    • Trichinella infections - Albendazole or mebendazole, may need steroids
    • C sinensis infections – Praziquantel
    • Paragonimus infections - Praziquantel
    • Schistosoma infections – Praziquantel
    • Echinococcus infections - Surgery and/or albendazole
• Intrinsic diseases
• • AEP: Administer intravenous methylprednisolone in an inpatient setting, followed by taper to oral form.
  • CEP: Administer prednisone, as described above (see Medication).
  • CSS: Administer prednisone. Other agents include azathioprine and cyclophosphamide.
  • IHES: The initial treatment should be with prednisone in both inpatient and outpatient settings. Assess the response to therapy over weeks to months, unless the disease is rapidly progressive (see Medical Care and Medication).

Transfer

• Rapidly progressive disease
• • Severe respiratory failure may require aggressive ventilatory management.
  • Treatment may be imperative while the diagnostic workup is in progress.
• Diagnostic expertise of specialists
• • These individuals may help with diagnostic reasoning and can provide knowledge from experience.
  • They can also provide procedural support.

Deterrence/Prevention

• Extrinsic diseases
• • Fungal diseases: Avoid contact/inhalation of contaminated soil, dust, or water.
  • Parasitic diseases: Avoid contact with contaminated soil, sand, water, and animals. Avoid ingestion of undercooked meat or fish.
  • Medications: Avoid ingestion/inhalation of same or same class of medications.
• Intrinsic diseases: Use recommended treatment courses. Closely monitor patients for relapse.

Complications

• Extrinsic diseases
• • Fungal diseases
  • • ABPA: Complications may include respiratory failure, bronchiectasis, hemoptysis, aspergilloma, and/or complications of steroids.
    • Coccidioidomycosis: Respiratory failure may occur in patients with progressive or disseminated disease. Patients who are immunocompromised may present with disseminated disease or persistent primary coccidioidomycosis; both are associated with significant morbidity and mortality. Patients who are older may develop a chronic illness resembling reactivation tuberculosis.
  • Parasitic diseases - Respiratory failure, hemoptysis, and/or pneumonia
  • • TPE: If TPE is left untreated for more than 6 months, it commonly leads to interstitial pulmonary fibrosis and restrictive defects.
    • Strongyloidiasis: Severe disseminated infection (hyperinfection) may occur in individuals who are immunocompromised because this nematode can replicate within humans.
    • Schistosomiasis: This results in eosinophilia and pulmonary nodules in early infection because the schistosomulas migrate through the lung. Later, granuloma formation and pulmonary arterial occlusion with chronic pulmonary hypertension are caused by embolization of ova.
• Intrinsic diseases
• • AEP: Respiratory failure may occur.
  • CEP: Fibrosis may develop if patients are left untreated or if the disease is extensive. If CEP is left unrecognized and untreated, it can progress, resulting in significant gas exchange abnormalities.
  • IHES: Patients with IHES may develop congestive heart failure, pulmonary emboli, and multiorgan system dysfunction.
  • CSS: Renal failure, pulmonary fibrosis, and neuropathy may develop. The mortality rate in cases of CSS has been decreasing, with approximately 75% of patients surviving 5 years.
  • EG: The course of EG is highly variable. Patients at age extremes, those with multiorgan or skin involvement, and those with pneumothoraces tend to have a poor prognosis. Diabetes insipidus may develop from pituitary involvement, and pneumothorax may develop from cystic lung