eMedicine Specialties > Pulmonology > Eosinophilic Lung Diseases

Pulmonary Eosinophilia

Author: Jussi J Saukkonen, MD, Associate Professor, Department of Internal Medicine, Division of Pulmonary/Critical Care Medicine, Boston University School of Medicine, Boston Medical Center
Contributor Information and Disclosures

Updated: Nov 20, 2009

Introduction

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 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.

The airway inflammation of chronic obstructive pulmonary disease (COPD) is largely neutrophilic, but 20-40% of induced sputum samples from individuals with stable COPD have eosinophilic airway inflammation, associated with elevated levels of sputum interleukin (IL)–5.¹
 
Eosinophilic bronchitis without asthma (EBWA) is characterized by cough for at least 2 months, a sputum eosinophil count greater than 3%, and no evidence of airway obstruction. Affected patients are usually middle-aged, are nonatopic, and have no history of smoking. Activation and eosinophilic infiltration of the superficial airway occurs, rather than of airway smooth muscle.²

Eosinophilia may often be seen in the bronchoalveolar lavage fluid in patients with desquamative interstitial pneumonitis.³

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.
• DRESS syndrome: The Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a severe drug hypersensitivity reaction, notable for skin rash, fever, lymphadenopathy, and involvement of various tissues, such as hepatitis, pneumonitis, or myositis. So far, numerous drugs, such as sulfonamides, phenobarbital, sulfasalazine, carbamazepine, and phenytoin, have been reported to cause the DRESS syndrome.⁴
• 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. The Brugia malayi larval gamma-glutaryl transpeptidase has similarities with that found on human pulmonary epithelium, suggesting a pathogenetic role for this transpeptidase.⁵
• 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.
• AEP: Increasing evidence suggests an association with inhaled exposures and, in some cases, infections.⁶ An association between AEP and new-onset cigarette smoking has been reported.⁷ Many patients have engaged in dusty outdoor activities, suggesting a hypersensitivity response to inhaled antigens. AEP has also been reported following allogeneic hematopoietic stem cell transplantation, coexisting with graft versus host disease.⁸ 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,⁹ 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,¹⁰ 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. The frequency of T regulatory cells that produce IL-10 and transforming growth factor (TGF)–beta (Treg1) has been reported to be decreased in active CSS, in comparison with asthma, EP, and inactive CSS.¹¹ 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. Similarly, omalizumab treatment allowing weaning of corticosteroids or their initiation has been reported to unmask CSS.¹² 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, but it can be found worldwide.
• 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

• TPE has been reported to have a male predominance, at a male-to-female ratio of 4:1. AEP is more common in men than in women, unlike CEP.
• Among the intrinsic syndromes, 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. AEP usually occurs in persons in their third decade of life.
• Intrinsic syndromes generally affect adults. 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

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.
• AEP: An 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.
• 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.¹³  
  • 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.
  • 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 inhibitors¹⁴
    • 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.¹⁵
  • 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, 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.

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