Eosinophillic Pneumonia

Dr. Rikin Hasnani

• Introduction • Classification• Eosinophillic Pneumonia with Acute presentations• Tropical Pulmonary Eosinophillia• Chronic eosinophillic Pneumonia• Allergic Bronchopulmonary Aspergillosis• Churg Strauss Syndrome• Idiopathic Hypereosinophillic Syndrome

Introduction

• In 1932, Loeffler first identified the association between pulmonary infiltrates and eosinophilia.

• In 1969, Liebow and Carrington coined the term eosinophilic pneumonia it includes all disorders characterized by infiltration of the lungs with eosinophils, with or without eosinophillia in the peripheral blood.

Classification • Pulmonary Eosinophilic Syndromes of Known Cause• Parasitic-induced eosinophilic pneumonias (including Loeffler’s

syndrome)• Drug-or toxin-induced eosinophilic pneumonias• Tropical pulmonary eosinophilia• Allergic bronchopulmonary mycosis• Pulmonary Eosinophilic Syndromes of Unknown Cause• Idiopathic acute eosinophilic pneumonia• Chronic eosinophilic pneumonia• Churg-Strauss syndrome (allergic granulomatosis and• angiitis)• Idiopathic hypereosinophilic syndrome

Other Lung Diseases Variably Associated with Eosinophilia• Asthma• Bronchocentric granulomatosis• Bronchiolitis obliterans-organizing pneumonia• Infections• Fungal (esp. coccidioidomycosis, Aspergillus,)• Tuberculosis• Interstitial lung disease• Idiopathic pulmonary fibrosis• Collagen-vascular disease associated• Sarcoidosis• Eosinophilic granuloma (pulmonary histiocytosis X)• Malignancy• Non–small-cell cancer of lung• Non-Hodgkin’s lymphoma• Myeloblastic leukemia• Miscellaneous (e.g., lung transplantation, ulcerative colitis)

EOSINOPHILIC PNEUMONIAS WITHACUTE PRESENTATIONS

1.Loeffler’s Syndrome (Simple Pulmonary Eosinophilia)• In 1932, Loeffler first described a clinical syndrome

characterized by mild respiratory symptoms, peripheral blood eosinophilia, and transient, migratory pulmonary infiltrates.

• Immune hypersensitivity to Ascaris lumbricoides has been recognized as the likely cause of most of the earliest reported cases, although several other parasitic infections and exposures to numerous drugs and other agents have also been recognized to induce a Loeffler’s-like syndrome.

• Clinical features : It affects people of all ages. It is characterized clinically by the presence of low-grade fever, nonproductive cough, dyspnea (mild to severe), and occasionally hemoptysis.

• The respiratory manifestations of Loeffler’s syndrome are usually self-limited, typically resolving in 1 to 2 weeks.

• Laboratory investigation :• Eosinophilia is present, which may be at peak levels as

respiratory symptoms resolve. • Sputum, frequently contains eosinophils.• Chest X ray shows Transient, migratory, non segmental

interstitial and alveolar infiltrates (often peripheral or pleural based).

• Spirometry - a mild to moderate restrictive defect is present.• DLCO shows reduced diffusing capacity for carbon monoxide .• Ascaris larvae may be identified in sputum or gastric

aspirates.• HPE - Eosinophilic infiltration of interstitium and alveolar-

capillary units & Increased numbers of macrophages is seen. Tissue necrosis and vasculitis are not features of the disorder.

Life cycle of ascaris

• Since Loeffler’s syndrome may be induced by a variety of exposures, a search for an etiologic agent (e.g., parasitic infection or drug reaction) should be undertaken.

• Bronchodilators are used for alleviation of pulmonary symptoms.

• In cases due to Ascaris, treatment with oral mebendazole (100 mg twice a day for 3 days) should be given to prevent late GI manifestations of Ascaris infestation.

2. Parasitic infections

• The prevalence of infection with each of these organisms varies with geographical location, socioeconomic status, and host immunity.

• Strongyloides stercoralis (an intestinal nematode),

• Ancylostoma brasiliensis (cutaneous helminthiasis, “creeping eruption”), and

• Toxocara canis (dog roundworm, “visceral larva migrans”) are the parasitic agents most commonly associated with pulmonary eosinophilia.

Strongyloides• Strongyloides is widely distributed in the tropical and

subtropical regions.• Following initial transcutaneous infection, a Loeffler’s-

like syndrome may occur as larvae migrate through the lungs.

• Chronic strongyloidiasis occurs as a result of autoinfection.

• Chronic strongyloidiasis can be associated with recurrent asthma-like symptoms that may worsen with the administration of corticosteroids.

• The hyperinfection syndrome results from accelerated autoinfection seen usually in HIV pt.

Life cycle of strongyloides

• Clinical features include cough, dyspnea, chronic bronchitis, wheezing, hemoptysis, and pulmonary infiltrates, in association with blood eosinophilia.

• GI manifestations are abdominal pain, paralytic ileus, nausea and vomiting, bowel perforation, and secondary sepsis from gram-negative bacteria.

• Central nervous system (CNS) manifestations such as meningitis have also been noted.

• Strongyloides may be identified in BAL. • Treatment : Thiabendazole or ivermectin are

drug of choice. ivermectin is generally better tolerated in terms of side effects.

• Albendazole is an alternative agent.

Ancylostomiasis• The organism is present in soil contaminated by stool from

infected domestic animals.• It penetrates human skin most commonly through the feet.• This results in the development of the “creeping eruption”

lesion—a raised, erythematous, serpiginous, tunnel-like, and often itchy lesion on areas of exposed skin.

• A Loeffler’s-like syndrome occurs in up to 50 percent of cases of “creeping eruption.”

• Specific treatment for pulmonary involvement is typically not required as illness is usually self-limited.

Toxocara canis

• Infection with T. canis leads to the clinical syndrome of “visceral larva migrans.”

• This syndrome is characterized by hepatomegaly, leukocytosis, fever, hypergammaglobulinemia, and persistent blood eosinophilia.

• Respiratory symptoms, including cough and wheezing, may occur after ingestion of substantial numbers of larvae.

• Laboratory evaluation reveals peripheral blood and BAL eosinophilia, elevated serum IgE,

• Chest X ray shows poorly defined, diffuse nodular alveolar infiltrates.

• Although the disease may be self-limited, treatment with albendazole, mebendazole, or corticosteroids may hasten recovery in patients who are severely ill.

3.Drug and Toxin-Induced PulmonaryEosinophilic Syndromes

• A vast number of drugs and toxic exposures have been associated with the development of pulmonary infiltrates and blood or pulmonary eosinophilia.

• Drugs associated with pulmonary eosinophillia are Amiodarone, Ampicillin, Azathioprine, Bleomycin, Clarithromycin, Dapsone, Ethambutol, Isoniazid, PAS, Penicillin, Streptomycin, tetracyclin.

4. Idiopathic Acute Eosinophilic Pneumonia

• Idiopathic AEP presents as an acute illness with fever, myalgias, cough, dyspnea, pleuritic chest pain, and hypoxemia (arterial PO2 under 60 mmHg).

• Symptom duration is on average 3 days. • Patients often have diffuse crackles on chest auscultation and

develop overt respiratory failure requiring mechanical ventilation. • A moderate leukocytosis is typical, but in contrast to other forms of

AEP, blood eosinophilia is usually absent.• Serum IgE levels may be moderately elevated.• Eosinophil count of 25 to 50 percent is present in BAL fluid. • Pulmonary function tests reveal a restrictive ventilatory defect with a

reduced DlCO.

• HPE reveals prominent eosinophil infiltration in alveolar spaces, bronchial walls, and, to a lesser degree, the interstitium.

• The pathological pattern of diffuse alveolar damage with eosinophilic infiltrates should suggest the possibility of AEP.

• The pathogenesis of idiopathic AEP is poorly understood.• The occurrence of cases following unusual environmental

exposures (such as plant repotting, cave exploration, wood pile moving, smokehouse cleaning, gas tank cleaning, and indoor renovation work) and recent commencement of cigarette smoking suggests these exposures as possible disease-inciting events, as triggers for a hypersensitivity reaction to an unidentified antigen.

• Elevated levels of the fungal cell wall component β-d-glucan have been described in the BAL fluid of patients with AEP, suggesting a possible association between exposure to fungus and development of disease.

• X ray -Early in the course of illness, the chest radiograph reveals subtle, patchy infiltrates with Kerley B lines.

• Diffuse, symmetric alveolar and interstitial infiltrates resembling ARDS with a ground-glass or micronodular develop within 48 hours.

• Mild to moderate B/L Pleural Effusion is seen.• Fluid analysis typically reveals a high pH and

marked eosinophilia.

TROPICAL PULMONARY EOSINOPHILIA

• Tropical pulmonary eosinophilia (TPE) was first described in the early 1940s as a syndrome characterized by fevers, malaise, anorexia, weight loss, paroxysmal dry cough with dyspnea or wheezing, marked peripheral blood eosinophilia, and spontaneous resolution over several weeks’ time.

• In 1950s and 1960s, filarial infections were recognized as the cause of this disorder.

• TPE is most prominent in India, Africa, and Southeast Asia.• TPE occurs in less than 1 percent of patients infected with

lymphatic filariae and results from a hypersensitivity reaction to microfilariae from Wuchereria bancrofti and Brugia malayi.

Life cycle of Wucheraria

• Clinical manifestations. • More common in males, 25 to 30 years .• There is no known seasonal or genetic propensity to this

disease.• The most common symptom of TPE is cough that usually

occurs at night.• Other typical symptoms include lowgrade fevers, weight loss,

fatigue, and malaise. • Dyspnea and wheezing, which can be severe, are common,

and the clinical presentation may resemble status asthmaticus.

• Investigations. • AEC is usually more than 3,000/cumm, with >90%

Eosinophils.• Total serum IgE is raised and is usually more than

1000IU/ml.• Microfilariae are not found in blood or sputum, and

examination of stool or urine for ova and parasites is negative.

• PFT – Obstructive pattern is seen in acute disease and restrictive or mixed pattern is seen in chronic disease.

• Chest X Ray - Ill-defined, diffuse reticulonodular infiltrates with a mottled appearance are characteristic radiographic findings in TPE.

• The mid- to lower lung fields are most commonly affected, but disease may appear anywhere in the lung.

• Treatment : Diethylcarbamazine (DEC) is given in a dose of 2mg/kg for 14 to 21 days.

CHRONIC EOSINOPHILIC PNEUMONIA

• It is more common in females, 30 – 40 years of age.• History if allergic rhinitis or polyp is present in 1/3rd cases.

It is associated with adult onset asthma in upto 50% cases.• Clinical features include low-grade fevers, drenching night

sweats, and moderate weight loss. • Cough, often dry initially and later productive of small

amounts of mucoid sputum, is a virtually universal finding. • Patients ultimately develop progressive dyspnea, which

may be associated with wheezing in those with adult-onset asthma.

• Lab Investigations. • Moderate leukocytosis with or without

eosinophillia.• Anemia, Thrombocytosis with raised ESR is

seen.• BAL Eosinophil count is usually more than 40%

• X ray Chest : 3 characteristic features of CEP are• (1) peripherally based, progressive dense infiltrates;• (2) rapid resolution of infiltrates following corticosteroid

treatment, with recurrences in identical locations; and • (3) the appearance of infiltrates as the “photographic negative

of pulmonary edema.”• In contrast to Loeffler’s syndrome, the pulmonary infiltrates

associated with CEP are typically nonmigratory and affect the outer two-thirds of the lung fields

• Infiltrates are most commonly bilateral, are located in the mid- to upper lung zones

• Treatment : Corticosteroids are the mainstay of therapy for CEP.

• Dramatic clinical, radiographic, and physiological improvements have been documented following steroid treatment. Even patients presenting with severe respiratory failure may respond well to steroid treatment.

• In most cases, treatment with steroids leads to defervescence within 6 hours,

• reduced dyspnea, cough, and blood eosinophilia within 24 to 48 hours,

• resolution of hypoxia in 2 to 3 days,• radiographic improvement within 1 to 2weeks,

• complete resolution of symptoms within 2 to 3 weeks, and

• normalization of the chest radiograph within 2 months.

• Prednisone (40 to 60 mg a day) continued until 2 weeks after resolution of symptoms and radiographic abnormalities.

• The dose of prednisone can then be tapered slowly. Treatment is usually maintained for at least 3 months and optimally for 6 to 9 months.

ALLERGIC BRONCHOPULMONARYASPERGILLOSIS (MYCOSIS)

• Allergic bronchopulmonary aspergillosis is a disorder caused by a complex hypersensitivity response to inhaled fungal antigens.

• ABPA complicates approximately 7 to 14 percent of cases of chronic steroid-dependent asthma and occurs in up to 15 percent of patients with cystic fibrosis.

Criteria in cystic fibrosis

• Typical radiographic manifestations of ABPA include transient, irregular pulmonary infiltrates with a predilection for the upper lobes. Other common radiographic features include “finger-in-glove opacities,” “tramline shadows,” “toothpaste shadows,” “ring shadows,” and lobar consolidation.

• These findings result from bronchial and bronchiolar wall inflammation, edema, and remodeling, and from mucoid impaction of the bronchi with or without parenchymal involvement.

• Histopathological findings of ABPA include intense bronchocentric inflammation with eosinophils, lymphocytes, plasma cells, and monocytes, as well as mucoid impaction of bronchi.

• The features of ABPA are believed to result from a complex immunologic reaction to chronic airway colonization by Aspergillus (or other relevant fungal species) that includes features of type I, type III, and type IV immune responses.

• Stage I: Acute• Acute asthma symptoms• Elevated serum IgE (typically > 1000 ng/ml)• Infiltrate on chest radiograph• Peripheral blood eosinophilia• Positive precipitating antibodies to Aspergillus fumigatus• Stage II: Remission• Resolution of symptoms• Radiographic clearing• Reduction or stabilization of IgE levels

Clinical Stages of AllergicBronchopulmonary Aspergillosis

• Stage III: Exacerbation• Recurrence of elevated IgE levels• Development of a new pulmonary infiltrate on chest• radiograph• +/− Escalation of asthma symptoms• Stage IV: Steroid-dependent Asthma• Difficult to control, steroid-dependent asthma• Persistently elevated total IgE, Aspergillus precipitins and• Aspergillus-specific IgE and IgG despite corticosteroid• therapy• Stage V: Fibrotic lung disease• Persistent steroid-dependent asthma• Fibrotic lung disease with gas exchange disturbances• Chronic sputum production and frequent infections• common

• Treatment :Goals of treatment are to control symptoms, prevent exacerbations and preserve normal lung function.

• Systemic corticosteroids, with careful patient monitoring of clinical symptoms, IgE levels, and chest radiograph, are the mainstay of therapy.

• Treatment with the antifungal agent itraconazole can also help control the symptoms and immunologic features of the disease.

• Bronchodilators and antibiotics help control bronchospasm and secondary respiratory infections.

CHURG-STRAUSS SYNDROME (ALLERGICGRANULOMATOSIS AND ANGIITIS)

• It is characterised by necrotizing vasculitis in several organs, associated with eosinophilic tissue inflammation and extravascular granulomas, occurring in asthmatics, with associated fever and peripheral hypereosinophilia.

• The mean annual incidence has been estimated at 1 to 2.4 per million population across various countries.

• Approximately 10 percent of all patients with vasculitis prove ultimately to have CSS.

• Clinical features : • Equal in males and females, more common in 38 to 50 years

age.• Three distinct clinical phases of the disease have been

recognized: the prodromal phase, the eosinophilic phase, and the vasculitic phase.

• The prodromal phase is characterized by “late-onset” (in the second or third decade) allergic rhinitis and atopy in persons often lacking a family history of atopy.

• Severe allergic rhinitis, sinusitis, drug sensitivity, and asthma are usually present for 8 to 10 years, and up to 30 years before CSS disease recognition.

• The eosinophilic phase is typified by the development of marked peripheral blood eosinophilia and eosinophilic tissue infiltration, most commonly of the lung, GI tract, and skin.

• The vasculitic phase is characterized by vasculitis of the small and medium vessels with vascular and extravascular granulomas.

• At the onset of the vasculitic phase there is often development of constitutional symptoms, including fever, malaise, weight loss, and increased allergic or asthmatic symptoms.

• Most of the respiratory manifestations of CSS occur in the prodromal and eosinophilic phases of the disease.

• A Loeffler’s-like syndrome with eosinophilic infiltration of the lung parenchyma is seen in 38 to 40 percent of patients.

• These patients may develop dyspnea, cough, and wheezing.

• Their chest radiographs have transient, migratory nonlobar, nonsegmental, often peripheral pulmonary infiltrates, with no regional predilection.

• Nodular lesions, interstitial lung disease, and hilar adenopathy are less common findings.

• High-resolution CT scanning shows patchy peribronchial thickening, pulmonary artery enlargement (in comparison to the corresponding bronchi), irregular stellate configuration of some vessels, areas of septal thickening, and scattered patchy parenchymal opacities with ground-glass or consolidated appearance.

• Spirometry shows obstructive pattern.

• Cardiac manifestations – CHF is seen in 40% of patient and is the most common cause of death in CSS.

• Neurological manifestations- Include mono or poly neuropathy. CNS manifestations occur in approximately two-thirds of patients and include cranial nerve impairment (especially optic neuritis), seizure, subarachnoid hemorrhage, and cerebral infarction.

• Skin manifestations- are nonthrombocytopenic purpura, tender cutaneous or subcutaneous nodules (which may ulcerate), urticaria, a maculopapular rash, petechiae, ecchymoses, or livedo reticularis

• Investigation • Fluctuating peripheral eosinophillia, anemia, raised ESR

is seen.• IgE is raised.• 70 – 75% are p- ANCA positive.• Low rhematoid factor with hypergammaglobunemia.• Pleural fluid analysis reveals low pH, high eosinophil

count, high protiens and low sugar.• The histopathological hallmarks of CSS include tissue

infiltration by eosinophils; necrotizing vasculitis of small arteries, arterioles, and, to a lesser extent, small veins, venules, and capillaries and extravascular and interstitial eosinophilic granulomas.

• Treatment : Prednisone, 0.5 to 1.5 mg/kg/day (or 60 mg/day in adults) is given for 6 to 12 weeks, aiming to eliminate constitutional symptoms and cardiac, renal, neurological, or other vasculitic manifestations.

• Once the vasculitic phase is controlled, steroids may be tapered, with doses titrated to maintain disease control.

• Treatment with cytotoxic immunosuppressive agents such as azathioprine, cyclophosphamide, high-dose methylprednisolone, or chlorambucil may prove effective and should be considered in patients with steroid resistance.

• Cyclophosphamide (2 mg/kg/day orally or 0.6 g/m2 intravenously per month)may be given concurrently with corticosteroids.

• Intravenous immunoglobulin may be beneficial in patient with severe organ involvement.

IDIOPATHIC HYPEREOSINOPHILICSYNDROME

• It is characterized by a persistently elevated eosinophil count (≥ 1500 eosinophils/mm³) in the blood for at least six months without any recognizable cause, with involvement of either the heart, nervous system, or bone marrow.

• It is a diagnosis of exclusion, after clonal eosinophilia (such as leukemia) and reactive eosinophilia (in response to infection, autoimmune disease, atopy, hypoadrenalism, tropical eosinophilia, or cancer) have been ruled out.

• The respiratory system is affected in an estimated 40 percent of patients with IHS.

• A majority of patients develop a predominantly nocturnal cough, which is either nonproductive or productive of small quantities of nonpurulent sputum.

• Pulmonary hypertension, ARDS, and pleural effusions may be present.

• Cardiac involvement cause eosinophilic myocarditis and endocarditis, intracardiac thrombi, and endocardial fibrosis.

• hematological manifestations are venous and arterial thromboembolism, anemia, thrombocytopenia, elevated vitamin B12 levels, hepatosplenomegaly, and lymphadenopathy.

• Laboratory investigations shows an elevated total serum IgE (25 to 38 percent), hypergammaglobulinemia, circulating immune complexes (32 to 50 percent), and an ESR above 15 mm/h (68 percent). Elevated serum B12 and leukocyte alkaline phosphatase levels are also noted.

• A variety of chromosomal abnormalities (including the Philadelphia chromosome) and immunologic abnormalities have been described in patients with IHS.

• (1) patients with clonal abnormalities in eosinophils; • (2) patients with features of myeloproliferative

disorder and chromosomal aberrations leading to abnormal constitutive production of tyrosine kinases; and

• (3) patients with dysregulation of T lymphocytes with overproduction of IL-5, a cytokine important for eosinophil growth

• Treatment : • Corticosteroid is mainstay of treatment.• Hydroxyurea (0.5 to 1.5 g per day) may be

added to the regimen if there is evidence of further disease progression.

• Vincristine, Etoposide and chlorambucil can also be used in patients with high WBC count.

• Imitanib is used in myeloproliferative variant of disease.

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