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.
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.
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.
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.
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:
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.
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:
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:
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.
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.
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.
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.
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.
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. Query patients about the usage of all medications, including dietary supplements, and illicit drugs.
An acute onset of rapidly progressing dyspnea, often accompanied by abdominal complaints and myalgias, usually occurs within 1 week of presentation of acute eosinophilic pneumonia (AEP). 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 chronic eosinophilic pneumonia (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 include the following:
Fungal infections associated with pulmonary infiltrates and eosinophilia include Aspergillus infections, Coccidioides immitis infections, and other less common infections. Note the following:
For intrinsic syndromes, seek the following historical elements:
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. All of the syndromes discussed can cause rales and wheezing.
Skin examination may include the following:
Head, eyes, ears, nose, and throat examination: Evidence of rhinitis/sinusitis may be observed in persons with EGPA and CEP. Vascular occlusion may be observed during the eye examinations of patients with HES. Proptosis may be seen in patients with EGPA.
Chest examination: Physical signs of cardiac decompensation (eg, valvular insufficiency, S3, rales, jugular venous distension [JVD], peripheral edema) may be present in patients with HES and EGPA. 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 HES and EGPA. Evidence of CNS deficits due to cerebrovascular accident may be observed in patients with HES.
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.
Pulmonary function testing may be useful in the initial evaluation to help narrow the differential diagnosis. Note the following:
Skin 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.
Initially, examine stool for ova and parasites. Specimens may be negative 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 tropical pulmonary eosinophilia (TPE)–associated filariae.
Blood leukocyte count with differential is necessary. Leukocytosis is common in all of these syndromes.
The upper limit of normal for the range of eosinophils in the peripheral blood is 3%-5% with a corresponding absolute eosinophil count (AEC) of 350–500/µL. The severity of eosinophilia has been arbitrarily divided into mild (AEC from the upper limit of normal to 1500/µL), moderate (AEC 1500–5000/µL) and severe (AEC >5000/µL) The eosinophil percentage is less sensitive than the absolute eosinophil count (AEC).[24] CBC count and AEC should be monitored to assess the course of illness and response to treatment when appropriate.
Blood and pulmonary eosinophilia are generally present together in persons with Loeffler syndrome, parasitic and fungal infections, CEP, allergic bronchopulmonary aspergillosis (ABPA), EGPA, and HES.
Isolated pulmonary eosinophilia may be observed in persons with AEP, medication-related syndromes, P carinii pneumonia, BOOP, tuberculosis, and eosinophilic granuloma (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. 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 EGPA. 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. The following general trends may be noted:
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 EGPA, 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.
In 2009, Velthove et al report on possible biomarkers (neutrophilia, eosinophilia) for inflammation in obstructive lung disease. Based on the results of their case-control study, they suggested both neutrophil counts and eosinophil counts may be useful biomarkers for exacerbations in obstructive lung disease.[25] Additionally, Hillas et al suggest eosinophil counts are the future direction of focus for a noninvasive method of assessing airway inflammation in clinical practice and not just research settings.[26]
Extrinsic syndromes
The following findings may be noted on chest radiography studies in patients with extrinsic syndromes:
Intrinsic syndromes
The following findings may be noted on chest radiography studies in patients with intrinsic syndromes:
Computed tomography (CT) scanning 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 scanning is preferred to enhance the evaluation of the pulmonary parenchyma. Note the following:
Patients with pulmonary eosinophilia have been reported to have F-18 fluorodeoxyglucose (FDG)–avid uptake on positron emission scans.[28]
Establishing an estimation of right ventricular, left ventricular, and valvular function is indicated in individuals with certain intrinsic syndromes (eg, EGPA, HES) 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.
This scan may be useful in some patients with HES 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.
Bronchoalveolar lavage (BAL) is often necessary to obtain adequate specimens to help rule out infection, particularly in the instance of CEP and other intrinsic syndromes. Note the following:
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 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 is rarely necessary, but it is usually performed if EGPA, 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 are indicated based on clinical presentation as follows:
Histologic findings may include the following:
With extrinsic diseases, the priority is to establish the diagnosis, assure adequate oxygenation, and provide bronchodilator therapy, with or without steroids as indicated. Note the following:
With intrinsic syndromes, make aggressive attempts to exclude infections. Note the following:
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.
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.
Acute eosinophilic pneumonia (AEP): Patients with AEP respond rapidly to high doses of systemic corticosteroids and do not tend to relapse.
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,[29] 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 allergic bronchopulmonary aspergillosis (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.
Chronic eosinophilic pneumonia (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.
Hypereosinophilic syndrome (HES): Half the patients respond to corticosteroids. Other agents for treatment of HES include hydroxyurea, interferon α, and imatinib.[24] Numerous additional agents, including chlorambucil, vincristine, etoposide, cladribine, cytarabine, methotrexate, cyclosporine, alemtuzumab, and cyclophosphamide, have been used to treat steroid-unresponsive patients with varied success and may be appropriate in some situations.[30]
Eosinophilic granulomatosis with polyangiitis (EGPA): 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.[31] Interferon-alpha and tumor necrosis factor inhibitors, such as infliximab and etanercept, have also been used.[32]
Eosinophilic granuloma (EG): Smoking cessation is essential. Corticosteroids are generally not beneficial.
Surgical intervention is rarely indicated in the treatment of pulmonary eosinophilia. Note the following:
Often, the complexity of these patients' presentations and treatment warrants consultation. For example, severe respiratory failure may require aggressive ventilatory management and treatment may be imperative while the diagnostic workup is in progress. The following specialists can provide assistance with diagnostic reasoning as well as procedural support:
Encourage the patient to take measures to minimize risk of exposure linked to the syndrome. Patients who have ingested food, supplements, or medication to which the syndrome is attributed should subsequently avoid reexposure. Note the following:
For extrinsic diseases, maintain clinical and radiologic follow-up with patients. Monitor oxygen saturation. Note the following:
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. Note the following:
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.
For extrinsic diseases, remove any offending agent. Treat parasitic infections with the appropriate antibiotics. Diseases with prominent wheezing are managed with bronchodilators, inhaled corticosteroids, and, for exacerbations, systemic corticosteroids. Use systemic corticosteroids judiciously in individuals with parasitic infection. Note the following:
Intrinsic diseases are generally managed with oral or intravenous corticosteroids. Eosinophilic granulomatosis with polyangiitis (EGPA) is also occasionally treated with cyclophosphamide or azathioprine. Hypereosinophilic syndrome (HES) is usually initially treated with systemic corticosteroids, with half the patients responding. Other treatments for HES include cyclophosphamide, azathioprine, busulfan, and others.
Clinical Context: May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. May be used in both extrinsic diseases (eg, ABPA, trichinosis, TPE, toxocariasis) and intrinsic diseases. Doses vary depending on disease and severity. Low-dose suppression may be needed in some cases.
Clinical Context: Decreases inflammation by suppressing migration of PMN leukocytes and reversing increased capillary permeability. Administered IV for severe disease. Doses vary depending on disease and severity.
Eosinophils are exquisitely sensitive to steroids. These medications inhibit eosinophil egress from the vascular compartment, inhibit their chemotaxis, and decrease eosinophil survival.
Clinical Context: Relaxes bronchial smooth muscle by action on beta-2 receptors, with little effect on cardiac muscle contractility.
Provide symptomatic relief of dyspnea from bronchospasm. Do not use as sole management of these diseases.
Clinical Context: Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes. Used anecdotally, with steroid-sparing effects, in several patients with ABPA or aspergilloma, but benefit has not been proven.
Available as tab, PO, and IV solutions. Duration of therapy depends on disease and clinical response, but is generally months.
If patient has invasive Aspergillus infection, is eating well, has good GI function, and is not on medication that reduces gastric acidity or induces cytochrome P-450, can use as alternative to amphotericin B.
Highly protein–bound with poor CSF penetration. Should not be used to treat primary meningitis.
Clinical Context: Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation. Used as first-line treatment of progressive or disseminated coccidioidomycosis or in host who is immunocompromised.
Also used in candidal and cryptococcal infections.
Dosage, dose intervals, and duration of therapy vary with age and illness.
Clinical Context: Produced by a strain of Streptomyces nodosus. Can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak, with subsequent fungal cell death.
Used for severe or life-threatening fungal infections (eg, invasive aspergillosis, blastomycosis, candidiasis, disseminated histoplasmosis, zygomycoses, penicilliosis, sporotrichosis, progressive or disseminated coccidioidomycosis).
No benefit demonstrated in aspergilloma.
Available as nonlipid form, which is less expensive. Also available as lipid, liposomal, or cholesteryl complexes, which achieve higher tissue levels, are cleared more rapidly, and have larger volumes of distribution. The latter forms are used in individuals intolerant of or refractory to nonlipid therapy. Liposomal form is used in patients who are refractory, those with renal insufficiency, or those intolerant of nonlipid form. Lipid forms have less toxicity than nonlipid form.
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.[33] 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. Itraconazole can be used for mild-to-moderate disease, and it is also used for treatment of blastomycosis.
Clinical Context: Decreases ATP production in worm, causing energy depletion, immobilization, and finally death. First-line agent for ascariasis, hookworm, strongyloidiasis, and C sinensis infection. Alternative agent for visceral larva migrans.
Efficacy in echinococcal disease not demonstrated but is used in conjunction with surgery.
Clinical Context: Causes worm death by selectively and irreversibly blocking uptake of glucose and other nutrients in susceptible adult intestine where helminths dwell. For treatment of ascariasis, hookworm infection, and toxocariasis. Alternative agent for visceral larva migrans and trichinosis.
Clinical Context: Inhibits helminth-specific mitochondrial fumarate reductase. Alleviates symptoms of trichinosis during invasive phase. Little value in disease that spreads beyond lumen of intestines because absorption from GI tract is poor. Alternative agent for treatment of strongyloidiasis, toxocariasis, and hookworm infection (eg, Necator species, Ancylostoma species).
Clinical Context: First-line therapy for strongyloidiasis and filariasis (W bancrofti or B malayi). Binds selectively with glutamate-gated chloride ion channels in invertebrate nerve and muscle cells, causing cell death.
Clinical Context: DOC in most infections and active against all schistosomal species. Increases cell membrane permeability in susceptible worms, resulting in loss of intracellular calcium, massive contractions, and paralysis of musculature. In addition, produces vacuolization and disintegration of schistosome tegument. This is followed by attachment of phagocytes to parasite and death.
Tabs should be swallowed completely with some liquid during meals. Keeping tabs in mouth may reveal bitter taste, which can produce nausea or vomiting.
Clinical Context: First-line therapy for visceral larval migrans. Alternative therapy for filariasis. Not generally available in United States but possible through Wyeth-Ayerst or Parasite Disease Service of CDC.
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.