Pulmonary Eosinophilia

Updated: Dec 10, 2020
  • Author: Jussi J Saukkonen, MD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Overview

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. [1]

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), hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA, formerly called Churg-Strauss syndrome), 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 Etiology).

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. [2]

Nonasthmatic eosinophilic bronchitis (NAEB) 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. [3]

Eosinophilia may often be seen in the bronchoalveolar lavage fluid in patients with desquamative interstitial pneumonitis. [4]

For patient education resources, see Bronchoscopy.

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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 chronic eosinophilic pneumonia (CEP), interstitial fibrosis may result from chronic inflammation. [1] 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. Numerous drugs, such as sulfonamides, phenobarbital, sulfasalazine, carbamazepine, and phenytoin, have been reported to cause the DRESS syndrome. [5] Among antimicrobials, DRESS syndrome can be caused by vancomycin, sulfonamides, tetracyclines, β-lactams, and flouroquinolones. [6]

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.

Tropical pulmonay eosinophilia (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. [7]

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.

Acute eosinophilic pneumonia (AEP)

Increasing evidence suggests an association with inhaled exposures and, in some cases, infections. [8] An association between AEP and new-onset cigarette smoking has been reported. [9] 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. [10] Eosinophilic alveolitis may be extensive, and profound hypoxemia with respiratory failure may result.

Intrinsic eosinophilic syndromes

Chronic eosinophilic pneumonia (CEP)

The pathogenesis is unknown. CEP may occur in isolation and/or in association with polyarteritis nodosa, rheumatoid arthritis, scleroderma, ulcerative colitis, breast carcinoma, [11] 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.

Hypereosinophilic syndrome (HES)

HES is a myeloproliferative disorder (MPD). Some patients display overproduction of chemokines, [12] 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.

Eosinophilic granulomatosis with polyangiitis (EGPA)

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 EGPA, in comparison with asthma, EP, and inactive EGPA. [13] Reports linking the syndrome with the leukotriene inhibitors zafirlukast and montelukast in the setting of steroid withdrawal suggest these agents unmask preexisting EGPA rather than suggesting that EGPA is a direct causal effect of these agents. Similarly, omalizumab treatment allowing weaning of corticosteroids or their initiation has been reported to unmask EGPA. [14] Vasculitis may affect the sinuses, central and peripheral nervous systems, gastrointestinal tract, kidneys, and heart.

Eosinophilic granuloma (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.

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Etiology

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 [15]

  • 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. [16]

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.

Although AEP was initially described as an idiopathic acute respiratory illness, multiple identifiable causes have been identified, including smoking, environmental/occupational inhalational exposures, use of recreational inhalant drugs, and connective tissues diseases. [17]

Intrinsic syndromes (ie, CEP, HES, EGPA, 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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Epidemiology

United States data

The most common cause of eosinophilia in the United States is an allergic reaction or allergic disease. Intrinsic syndromes are uncommon. The incidence and prevalence of hypereosinophilic syndrome (HES) and eosinophilic granuloma (EG) are not well characterized. The incidence of eosinophilic granulomatosis with polyangiitis (EGPA) in the United States is 1-3 cases per 100,000 adults per year. [18] The international incidence of EGPA is approximately 2.5 cases per 100,000 adults per year. Note the following:

  • 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 tropical pulmonary eosinophilia (TPE) and paragonimiasis.

  • For fungal causes, allergic bronchopulmonary aspergillosis (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.

  • Occasionally, outbreaks are related to contaminated food or medication, eg, L-tryptophan and toxic oil syndrome.

International data

Worldwide, the most common cause of eosinophilia is parasitosis. [19] Intrinsic syndromes are uncommon. Regarding extrinsic syndromes, in much of the world, parasitic infections are endemic. Note the following:

  • 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.

Race-, sex-, and age-related demographics

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.

TPE has been reported to have a male predominance, at a male-to-female ratio of 4:1. Acute eosinophilic pneumonia (AEP) is more common in men than in women. Among the intrinsic syndromes, chronic eosinophilic pneumonia (CEP) is twice as common in women as in men, but this sexual disparity declines with increasing age. For HES, approximately 90% of cases are found in men and 10% are found in women. For EGPA and EG, no sexual predisposition has been reported.

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. HES usually occurs in people aged 20-50 years; however, it has also been infrequently reported in children. Most cases of EGPA 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.

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Prognosis

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.

Extrinsic diseases

Acute eosinophilic pneumonia (AEP)

Patients with AEP often develop respiratory failure, but, with treatment and supportive measures, they generally survive.

Medication-induced and Loeffler syndrome

Removal of the offending agent usually results in a resolution of symptoms.

Schistosomiasis

Schistosomiasis 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.

Parasitic diseases

Parasitic diseases are usually successfully treated but may require a repeated course of therapy.

Strongyloidiasis

Patients with strongyloidiasis may be critically ill with sepsis and respiratory failure. Severe disseminated infection (hyperinfection) may occur in individuals who are immunocompromised because this nematode can replicate within humans.

Tropical pulmonary eosinophilia (TPE)

If left untreated for more than 6 months, TPE commonly leads to interstitial pulmonary fibrosis and restrictive defects.

Allergic bronchopulmonary aspergillosis (ABPA)

Patients with ABPA usually have lifelong symptoms with intermittent exacerbations. Complications may include respiratory failure, bronchiectasis, hemoptysis, aspergilloma, and/or complications of steroids.

Coccidioidomycosis

Coccidioidomycosis usually resolves spontaneously. 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.

Intrinsic diseases

Chronic eosinophilic pneumonia (CEP)

Patients with CEP have a rapid response to therapy but may develop relapse within 6 months. Some patients who initially present with only pulmonary involvement actually have HES. 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.

Hypereosinophilic syndrome (HES)

Half of the patients with HES respond to steroids, while patients who do not respond go on to have significant disease requiring increasingly complex regimens. Now, 80% of patients survive 5 years, and 40% survive 10-15 years. The most serious complication of hypereosinophilic syndrome is cardiac involvement, which can result in myocardial fibrosis, chronic heart failure (CHF), and death.

Eosinophilic granulomatosis with polyangiitis (EGPA)

Patients with EGPA generally respond well to steroids, but they require lifelong therapy. Renal failure, pulmonary fibrosis, and neuropathy may develop. Development of eosinophilic myocarditis is a poor prognostic indicator. [20] The mortality rate in cases of EGPA has been decreasing, with approximately 75% of patients surviving 5 years. Novel treatments, including immunomodulatory drugs and targeted biotherapies show promise for improving the prognosis for patients with refractory/relapsing disease. [21, 22]

Eosinophilic granuloma (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 disease.

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