eosinophilic lung diseases

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Eosinophilic Lung Diseases:

Eosinophilic Lung Diseases

“To enjoy a red sunrise”:

“To enjoy a red sunrise” Eosinophil Granules of eosinophils stain red Greek: eos means “dawn” Histologist Named after the staining appearance “seeing red skies”

Eosinophil – our friend and foe:

Eosinophil – our friend and foe Two-lobed, polymorphonuclear leukocyte 12 to 15 um diameter Created by IL-3, Il-5 and GM-CSF Three granule types, largest made up of MBP (major basic protein), kills Parasites, tumor cells, respiratory epithelium Hypodense and normodense varieties

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human blood eosinophil Ultra structure The bilobed nucleus specific granules primary granules lipid bodies

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human blood eosinophil Activated in vitro with eotaxin Specific granules undergoing piecemeal degranulation Granules with residual cores Reduced internal electron density membrane empty chambers

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Circulates <18 hours Chemotaxis complement, histamine, ECF-A, PAF, leukotrienes, lymphokines, tumor factos, IL-5 100-400x more in tissues than in blood

Eosinophil – competing theories:

Eosinophil – competing theories Host defense Modulator of inflammation Tissue destroyer

Eosinophils: What’s Normal:

Eosinophils: What’s Normal Blood EOS (#) = 50-250 per microliter Bronchoscopy (BAL) EOS Percentage (%) rather than absolute number Normal volunteers = < 1% ARDS usually none Increased (= >5%) five percent of the time Mostly PCP, drug-related, idiopathic

Classification:

Classification In 1932, Loeffler : -Association between pulmonary infiltrates and eosinophilia Reeder and Goodrich, 1952 Pulmonary Infiltrates & Eosinophilia (coined ‘PIE syndrome’)

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Croften et al, 1952 (clinical criteria) * Simple pulmonary eosinophilia (Loffler’s) Prolonged pulmonary eosinophilia Tropical eosinophilia Pulmonary eosinophilia with asthma Polyarteritis nodosa (PAN) *Crofton JW, Livingstone JL, Oswald NC, et al: Pulmonary eosinophilia.  Thorax  1952; 7:1-35 .

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characterized by the presence and presumed pathogenetic role of eosinophils in the lesional processes They are mainly represented by the eosinophilic pneumonias, which are defined by a prominent infiltration of the lung parenchyma by eosinophils. The other eosinophilic lung diseases mainly concern the airways, as in the allergic bronchopulmonary mycoses

Diseases Associated with Pulmonary Infiltrates and Eosinophilia:

Diseases Associated with Pulmonary Infiltrates and Eosinophilia

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Pulmonary Eosinophilic Syndromes of Known Cause Pulmonary Eosinophilic Syndromes of Unknown Cause Other Lung Diseases Variably Associated with Eosinophilia

Pulmonary Eosinophilic Syndromes of Known Cause:

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:

Pulmonary Eosinophilic Syndromes of Unknown Cause Idiopathic acute eosinophilic pneumonia Chronic eosinophilic pneumonia Churg-Strauss syndrome (allergic granulomatosis and angiitis) Idiopathic hypereosinophilic syndrome

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Other Lung Diseases Variably Associated with Eosinophilia Asthma/allergy Bronchocentric granulomatosis Bronchiolitis obliterans-organizing pneumonia Infections - Fungal(esp.Coccidioidomycosis, Aspergillus,Pneumocystis jirovecii) -Tuberculosis

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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 WITH ACUTE PRESENTATIONS:

EOSINOPHILIC PNEUMONIAS WITH ACUTE PRESENTATIONS

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Loeffler’s Syndrome (Simple Pulmonary Eosinophilia) Parasitic Infections Drug and Toxin-Induced Pulmonary Eosinophilic Syndromes Idiopathic Acute Eosinophilic Pneumonia

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Loeffler’s Syndrome (Simple Pulmonary Eosinophilia)

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In 1932, Loeffler first described a clinical syndrome characterized by: -mild respiratory symptoms -peripheral blood -eosinophilia and -transient, migratory pulmonary infiltrates. Affects all ages Immune hypersensitivity to Ascaris lumbricoides - likely cause.

CLINICAL FEATURES:

CLINICAL FEATURES Low-grade fever Nonproductive cough Dyspnea (mild to severe) and Hemoptysis(occ.) Respiratory manifestations- self-limited Typically resolving in 1 to 2 weeks.

Investigations:

Investigations Peripheral blood - moderate to extreme eosinophilia Sputum - contains eosinophils. C X ray-Transient, migratory, nonsegmental interstitial and alveolar infiltrates (often peripheral or pleural based). PFT: typically Reveals mild to moderate restrictive ventilatory defect with a reduced diffusing capacity for carbon monoxide (D L CO )

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Drug and Toxin-Induced Pulmonary Eosinophilic Syndromes

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Onset :Acute or subacute. Respiratory symptoms: vary widely in severity -from a mild Loeffler’s-like illness with dyspnea, cough, and fever to severe fulminant respiratory failure. PFT:obstructive physiology is not common.

Radiographic findings:

Radiographic findings Not specific Interstitial or alveolar infiltrates are typical. 23-year-old woman with acute sulfasalazine-induced eosinophilic pneumonia. Bilateral interstitial and alveolar infiltrates are present

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(CT) findings: Bilateral consolidation and ground-glass opacities, both of which are frequently peripherally located. A concomitant skin rash and pleural effusion can support the diagnosis of drug-induced eosinophilic pneumonia.

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Prognosis is favorable in most cases. Elimination of exposure to the drug or other toxin usually leads to resolution of : -symptoms -eosinophilia -pulmonary infiltrates, and -normalization of lung function within a month. Supplemental therapy with corticosteroids is not universally required, but it may hasten recovery in ill patients.

Idiopathic Acute Eosinophilic Pneumonia:

Idiopathic Acute Eosinophilic Pneumonia

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More common in younger men, with a mean age of approximately 30 years Occurs commonly in previously healthy persons.

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** Diagnostic Criteria for Idiopathic Acute Eosinophilic Pneumonia 1. Acute onset of febrile respiratory manifestations (≤1 month duration before consultation) 2. Bilateral diffuse infiltrates on chest radiography 3. Hypoxemia, with Pa o 2 on room air < 60 mm Hg, and/or Pa o 2 /F io 2 <= 300 mm Hg, and/or oxygen saturation on room air < 90% 4. Lung eosinophilia , with > 25% eosinophils in BAL(or eosinophilic pneumonia at lung biopsy) 5. Absence of infection, or of other known causes of eosinophilic lung disease (especially exposure to drug known to induce pulmonary eosinophilia ) * * Tazelaar HD, Linz LJ, Colby TV, et al: Acute eosinophilic pneumonia: Histopathologic findings in nine patients.  Am J Respir Crit Care Med  1997; 155:296-302. Pope-Harman AL, Davis WB, Allen ED, et al: Acute eosinophilic pneumonia: A summary of 15 cases and a review of the literature.  Medicine (Baltimore)  1996; 75:334-342Philit F, Etienne- Mastroianni B, Parrot A, et al: Idiopathic acute eosinophilic pneumonia: A study of 22 patients.  Am J Respir Crit Care Med  2002; 166:1235-1239

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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, although longer courses of up to 30 days have been described. Patients often have diffuse crackles on chest auscultation and develop overt respiratory failure requiring mechanical ventilation.

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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. Striking eosinophilia (25 to 50 percent) is present in BAL fluid. Pulmonary function tests reveal a restrictive ventilatory defect with a reduced DlCO

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bilateral infiltrates is a defining feature of the disease. Small to moderate bilateral pleural effusions is common. Fluid analysis typically reveals a high pH and marked eosinophilia.

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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 appearance develop within 48 hours. Diffuse bilateral alveolar and interstitial infiltrates apparent on chest radiograph

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CT scanning confirms the presence of: -diffuse parenchymal ground-glass attenuation and consolidation. -prominence along bronchovascular bundles and septae. -pleural effusion.

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Light microscopic examination of lung tissue 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.

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Eosinophils infiltrate the arteriolar wall (non-necrotizing vasculitis ) and are present within the alveolar lumen (B) . (Courtesy of Françoise Thivolet-Béjui , MD, Department of Pathology, Louis- Pradel Hospital and Claude Bernard University, Lyon.)

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The occurrence of cases following unusual environmental exposures(such as plant repotting, cave explorationwood pile moving, smokehouse cleaning, gas tank cleaning,and indoor renovation work) recent commencement of cigarette smoking- triggers hypersensitivity reaction to an unidentified antigen.

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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. Idiopathic AEP is a diagnosis of exclusion and should be considered in a patient who presents with apparent acute lung injury (ALI) or ARDS without a typical antecedent illness.

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Idiopathic AEP carries an excellent prognosis. rapid dramatic responses to corticosteroid therapy,with abatement of fever and respiratory symptoms within hours and complete resolution of infiltrates usually within 1 month.

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initial doses of methylprednisolone typically used range from 60 to 125 mg administeredevery 6 hours.After resolution of respiratory failure, oral prednisone (in doses of 40 to 60 mg per day) may be continued for 2 to 4weekswith a subsequent slowtaper over the next several weeks

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absence of clinical relapse is characteristic. Follow-up pulmonary function testing is generally normal, although a small number of patients may demonstrate mild reductions in DlCO or lung volumes.

TROPICAL PULMONARY EOSINOPHILIA:

TROPICAL PULMONARY EOSINOPHILIA

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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

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Globally… >120 million people are infected with filaria Only <0.5% of people developed TPE 90% W. bancrofti Endemic in tropical/subtropical areas Eg. Asia, Africa, Oceania, South America Transmitted by mosquitos 4 genera Anopheles Culex Aedes Mansonia

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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. 4 times more common in men. Most manifest the disease between the age of 25 and 40. most prominent in India,Africa, and Southeast Asia, but it may be seen worldwide in filarial endemic regions.

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cough that usually occurs at night. lowgrade fevers, weight loss, fatigue, and malaise. Dyspnea and wheezing, which can be severe, are common. Clinical presentation may resemble status asthmaticus. Chest pain,muscle tenderness, and cardiac, pericardial, and CNS involvement have also been reported. Rarely, patients remain asymptomatic

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Clinical Syndrome Peripheral blood eosinophilia Pulmonary infiltrates Paroxysmal non-productive cough Wheezing Occasional weight loss Lymphadenopathy Low grade fevers

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Physical examination:coarse rales or rhonchi and wheezing, although no abnormalities are found Generalized lymphadenopathy and hepato splenomegalymay be present.

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Laboratory findings : Extreme peripheral blood eosinophilia (usually > 3000 eosinophils/cm3 and up to 90 percent of the leukocyte differential) that persists for several weeks. Total serum IgE is usually elevated (more than 1000 U/ml), and high titers of filarial-specific IgE and IgG

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(ESR) may be moderately elevated, and patients may also have an abnormal (ECG). Eosinophils may be identified in the sputum, and, in those with active disease, BAL may reveal intense eosinophilic alveolitis. Microfilariae are not found in blood or sputum, and examination of stool or urine for ova and parasites is negative (although patients from endemic countries may be simultaneously infected with other parasites). In contrast, microfilariae have been identified in lung and lymph node tissue, especially when lymphadenopathy is present.

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Pulmonary function tests reveal an obstructive ventilatory defect in up to 30 percent of patients, particularly when symptoms have been present less than 1 month. A restrictive ventilatory defect and reduced D LCO , with or without a concomitant obstructive defect, are typical of long-standing

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Ill-defined, diffuse reticulonodular infiltrates with a mottled appearance are characteristic radiographic findings. The mid- to lower lung fields are most commonly affected. disease may appear anywhere in the lung. Bronchovascular markings may be prominent and hilar adenopathy and pleural effusions have occasionally been reported. The chest radiograph may be normal at presentation in 20 percent of patients

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It represents a distinct immunological reaction to human lymphatic filarial parasites -Wuchereria bancrofti-Brugia malayi W. bancrofti B. malayi

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Pathogenesis of TPE Prominent immunological response against blood microfilariae Which become opsonised and trapped Within lung and reticuloendothelial organs Histology Early: histiocytic infiltration >1month: eosinophils, interstitial infiltrates Late: pulmonary fibrosis, microfilaria fragments can be seen on biopsy

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The histopathology of tropical pulmonary eosinophilia. A section from a lung biopsy showing a pulmonary granuloma. Microfilariae are notidentified, but there is an intense eosinophilic inflammatory reaction.

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Clinical Manifestations TPE Clinical onset is usually gradual Symptoms include Dry non-productive cough often becomes paroxysmal and nocturnal Breathlessness Wheezing Dyspnoea on exertion (less common) Systemic manifestations •Weight loss •Fatigue

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Examination findings Minimal or absent in most patients Wheezing, rhonchi and crepitations 15% lymphadenopathy, hepatomegaly or splenomegaly

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Diagnostic Criteria Based on the clinical and laboratory findings. 1. Clinical history supportive of exposure to lymphatic filariasis 2. Peripheral eosinophilia count (>3 x 109eosinophils/L) 3. Elevated serum IgE levels (> 1000 IU/ml) 4. Increased titres of anti-filarial antibodies 5. Peripheral blood negative for microfilariae 6.Rapid response to DEC-confirmatory evidence

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The release of antigens from degenerating microfilariae leads to an intense local and systemic inflammatory response. A striking antibody and eosinophilic response,similar to that seen in peripheral blood, is present within the lung. Increased numbers of total cells and eosinophils (up to 50 percent of differential), elevated levels of total IgE, and filarial-specific IgG, IgM, and IgE are present in fluid obtained by BAL.

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Respiratory function tests Predominantly restrictive together with mild-mod obstructive picture Airway obstruction is reversible with bronchodilators

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CXR Findings Increased bronchovesicular markings Diffuse interstitial lesions 1.3mm diameter Mottled opacities Fine miliary lesions may be overlooked Normal in 20-30% cases Pleural effusions and mediastinal lymphadenopathy do not occurMandell: CXR reticulonodular opacities throughout both lung fields

TREATMENT:

TREATMENT Diethylcarbamazine, a piperazine derivative-DOC for TPE Dose : 2 mg/kg three times daily for 14 to 21 days. A marked clinical improvement and decrease in eosinophil count usually occurs in the first 7 to 10 days of therapy. Radiographic clearing generally occur within 1 to 3 weeks of treatment.

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course and prognosis of the acute disease in patients treated with diethylcarbamazine are generally benign, and 3weeks of diethylcarbamazine therapy is curative in most patients. Acute relapses do occur in up to 20 percent of patients. acute relapses often respond to additional treatment with DEC at higher doses of 2 to 4 mg/kg three times a day for 21 to 30 days.

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inmild, chronic inflammation may persist, causing chronic interstitial lung disease, with persistent respiratory symptoms, radiographic findings, and hematological and serologic abnormalities in up to 13 percent of patients with TPE treated with a standard course of therapy. BAL in these patients reveals a mild,persistent eosinophilia

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Alternative antifilarial drugs (e.g., ivermectin) or a trial of corticosteroids may be useful therapies for the chronic variant of the disease. Untreated disease usually persists for weeks to months. Untreated TPE may remit spontaneously, but it commonly recurs within months to years. Untreated TPE often leads to the development of chronic interstitial lung disease.

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d/d: Loeffler’s syndrome, chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, drug reactions, other parasitic infections, hypereosinophilic syndrome, and Lymphangitic spread of carcinoma. In nonendemic areas,it may also masquerade as: asthma, atypical pneumonia, Sarcoidosis, Churg-Strauss syndrome, Wegener’s granulomatosis (WG),or tuberculosis (TB).

CHRONIC EOSINOPHILIC PNEUMONIA:

CHRONIC EOSINOPHILIC PNEUMONIA

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first described as a clinical entity by Carrington and coworkers in 1969. Peak incidence :-30 to 40 years of age. F:m::2:1, during pregnancy. Most cases occur in Caucasians 1/3 to ½ h/o: atopy, allergic rhinitis, or nasal polyps. 2/3 rd adult-onset asthma: preceding or concurrent with the occurrence of CEP

Clinical features:

Clinical features typically subacute presentation. symptoms present for several months before diagnosis. Common presenting complaints include: low-grade fevers, drenching night sweats moderate (10-to 50-pound) weight loss. Cough

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Patients ultimately develop progressive dyspnea, which may be associated with wheezing in those with adult-onset asthma no major extrapulmonary manifestations

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Moderate leukocytosis. The majority (66 to 95 percent) have peripheral blood eosinophilia(> 6≈90%) moderate normochromic,normocytic anemia and thrombocytosis may be present. The ESR is typically elevated (>20mm). IgE levels are elevated in up to 50% of cases. BAL : increased eosinophils, typically accounting for 40 percent or more of the WBC’S. Blood and sputum cultures routinely fail to identify an infectious etiology in these patients.

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Bronchoalveolar lavage

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PFT: Depends on the stage and severity of the disease. In the initial stage prior to treatment with corticosteroids, testing may reveal: -restrictive, -obstructive, or -normal physiology. Obstructive ventilatory defects, common in patients with a history of asthma. Restrictive physiology may result from changes in lung compliance due to acute eosinophilic infiltration of lung parenchyma.

radiographic features:

radiographic features 1)Peripherally based, progressive dense infiltrates; 2)Rapid resolution of infiltrates following corticosteroid treatment, with recurrences in identical locations; 3) the appearance of infiltrates as the “photographic negative of pulmonary edema.” pulmonary infiltrates associated with CEP are typically nonmigratory and affect the outer two-thirds of the lung fields.

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Diffuse, peripherally-based infiltrates (outer 2/3rds of lung) “photographic negative of pulmonary edema”

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Diffuse, peripherally-based infiltrates (outer 2/3rds of lung) “photographic negative of pulmonary edema”

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Diffuse, peripherally-based infiltrates (outer 2/3rds of lung) “photographic negative of pulmonary edema”

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Infiltrates are most commonly bilateral, are located in the mid- to upper lung zones, and may mimic loculated pleural fluid. The areas of consolidation are patchy and dense and can have ill-defined margins. They are frequently nonsegmental, subsegmental, or lobar in distribution and apposed to the pleura. The characteristic “photographic negative of pulmonary edema” appearance (which occurs in less than 50 percent of cases) results if extensive infiltrates surround major portions of or the entire lung.

CT scan findings:

CT scan findings ground-glass opacities without clear consolidation. Mediastinal adenopathy, Peripheral upper-lobe predominant infiltrates may have a ground-glass appearance

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Typical areas of dense, peripherally located airspace consolidation are found in most cases within the first severalweeks of disease onset. Streaky bandlike opacities may appear when symptoms have been present for more than 2 months. The pulmonary may appear as regions of dense consolidation or nodular opacity ( B).

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bilateral symmetrical peripheral alveolar opacities.

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The diagnosis of CEP is based on clinical, radiographic, and BAL findings, and on the inability to document pulmonary or systemic infection. The clinical signs and symptomsofCEPare nonspecific, however, and blood eosinophilia and typical radiographic featuresmay be absent insomecases. In most reported series, open lung biopsy has been required only rarely to establish the diagnosis. Transbronchial biopsy, usually performed to rule out other diagnostic entities, may reveal eosinophil and mononuclear cell infiltrates. Because of the rapid and dramatic responsiveness of CEP to steroid treatment, a therapeutic trial of steroids is often useful in establishing the diagnosi

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The differential diagnosis of CEP includes infection (especially TB and fungal diseases like cryptococcosis), sarcoidosis, Loeffler’s syndrome, desquamative interstitial pneumonitis, bronchiolitis obliterans-organizing pneumonia, chronic hypersensitivity pneumonitis, and eosinophilic granuloma.

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Corticosteroids are the mainstay of therapy for CEP. Dramatic clinical, radiographic, and physiological improvements have been documented following steroid treatment in all series Reported 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 improvementwithin 1 to 2weeks, complete resolution of symptoms within 2 to 3 weeks, and Normalization of the chest radiograph within 2 months.

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recommended regimen is 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

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Patientsmay require 1 to 3 years of initial steroid treatment to control the disease, and up to 25 percent may require long-term maintenance treatment (2.5 to 10 mg prednisone a day) to remain disease-free. Some patients may respond to inhaled corticosteroids allowing discontinuation of oral steroids. Clinical, hematological, or radiographic evidence of relapse occurs in approximately one-third to one-half of patients when steroids are tapered or discontinued . No obvious factors exist to identify personswhoare likely torelapse or require long-termsteroids, although relapses are more common in persons treated initially with a short course (less than 6 months) of steroids

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (MYCOSIS):

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (MYCOSIS)

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disorder caused by a complex hypersensitivity response to inhaled fungal antigens (type I,III,IV ) 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. The diagnosis of ABPA is based on appropriate clinical features in combination with supporting serologic and radiologic findings.

Diagnostic Criteria:

Diagnostic Criteria MAJOR 1)Asthma * 2)Positive immediate hypersensitivity skin-prick test to Aspergillus * 3)Precipitating antibodies against Aspergillus * 4)Elevated total IgE(>1000 ng/ml) * 5)Elevated serum Aspergillus–specific IgE, IgG * 6)History of pulmonary infiltrates 7)Peripheral blood eosinophilia(10,000 cells/ml) 8)+ /− Proximal bronchiectasis MINOR 1)Mucous plugs containing Aspergillus 2)Dual cutaneous (immediate & delayed)reaction to Aspergillus *Greenberger and Patterson have proposed five minimal essential criteria

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Diagnostic Criteria for Allergic Bronchopulmonary Aspergillosis Minimal Criteria Asthma Immunologic hypersensitivity to A. fumigatus : Immediate reaction to prick test Elevated specific immunoglobulin E Elevated serum immunoglobulin E (usually >400 kU/L) Central bronchiectasis * Adapted from Greenberger PA: Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 110:685–692, 2002; and Greenberger PA: Allergic bronchopulmonary aspergillosis, allergic fungal sinusitis, and hypersensitivity pneumonitis. Clin Allergy Immunol 16:449–468, 2002. * When absent, ABPA is called ABPA-seropositive.

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Other Criteria Pulmonary infiltrates on chest radiograph Serum precipitating antibodies to A. fumigatus Peripheral blood eosinophils >1 × 10 9 /L Other Common Findings Expectoration of mucous plugs Presence of Aspergillus in sputum Late skin reactivity to Aspergillus antigen Adapted from Greenberger PA: Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 110:685–692, 2002; and Greenberger PA: Allergic bronchopulmonary aspergillosis, allergic fungal sinusitis, and hypersensitivity pneumonitis. Clin Allergy Immunol 16:449–468, 2002. * When absent, ABPA is called ABPA-seropo sitive.

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Five clinical stages of ABPA have been recognized: acute illness (stage 1); remission (stage II); exacerbation(stage III); steroid-dependent asthma (stage IV); and Fibrotic lung disease (stage V)

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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

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S tage II: Remission Resolution of symptoms Radiographic clearing Reduction or stabilization of IgE levels Stage III: Exacerbation Recurrence of elevated IgE levels Development of a new pulmonary infiltrate on chest radiograph + /− Escalation of asthma symptoms tion of IgE levels

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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

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Stage V: Fibrotic lung disease Persistent steroid-dependent asthma Fibrotic lung disease with gas exchange disturbances Chronic sputum production and frequent infections common.

radiographic manifestations of ABPA:

radiographic manifestations of ABPA Typical manifestations 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

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These findings result from bronchial and bronchiolar wall inflammation, edema, and remodeling, and frommucoid impaction of the bronchi with or without parenchymal involvement. Central (proximal) bronchiectasis, characteristic radiographic manifestation of ABPA. .

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Extensive infiltrates with tubular configuration and ‘‘gloved finger” appearance are present, in this case predominantly in the lower lobes The bronchogram

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reveal extensive proximal bronchiectasis. Extensive mucoid impaction of the bronchi is evident on CT scan Central bronchiectasis and tram-track shadows in a patient with ABPA may also be present without mucoid impaction (D)

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The diagnosis of ABPA should be entertained in any patient with : -difficult to control asthma and/or -the combination of asthma and eosinophilia, - patients with cystic fibrosis with progressive worsening of symptoms. ABPA may also be challenging to recognize due to overlap of clinical features with allergic, mold-sensitive asthma as well as other pulmonary eosinophilic disorders such as Churg-Strauss syndrome .

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Goals of treatment control symptoms, Prevent exacerbations and preserve normal lung function Corticosteroid doses that reduce IgE levels by at least half of acute stage levels and induce clearing of radiographic infiltrates must be used to control the disease; such doses are typically higher than those needed to control symptoms alone. 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 (ALLERGIC GRANULOMATOSIS AND ANGIITIS):

CHURG-STRAUSS SYNDROME (ALLERGIC GRANULOMATOSIS AND ANGIITIS)

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In 1939, Rackemann and Greene reported a subgroup of patients with polyarteritis nodosa and concomitant allergic disease. Churg and Strauss ,in 1951 first described The histopathology and clinical features. They Reported a form of necrotizing vasculitis in several organs, associated with eosinophilic tissue inflammation and extravascular granulomas, occurring in asthmatics, with associated fever and peripheral hypereosinophilia. This disease entity, now recognized as Churg-Strauss syndrome (CSS), is an uncommon systemic disease Typically affects multiple-organ systems.

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10 percent of all patients with vasculitis prove ultimately to have CSS. Increased incidence is seen in asthmatics. occur in patients of any age most commonly between 38 to 50yrs. no clear gender predominance. disease onset has been reported during pregnancy.

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subacute course (with symptoms ranging over months to years) Three distinct clinical phases of the disease have been recognized: 1) the prodromal phase, 2)the eosinophilic phase, and the 3)vasculitic phase .

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The prodromal phase : 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.

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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

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The vasculitic phase: characterized by vasculitis of the small and medium vessels with vascular and extravascular granulomas. The onset of the vasculitic phase is often heralded by development of constitutional symptoms, including fever, malaise,weight loss, and increased allergic or asthmatic symptoms . Granulomatous foci around medium-sized arteries

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vasculitis tends too ccur several years after the onset of allergic manifestations Insome cases it develops within months of, or concomitant with, the onset of asthma. Typically affects multiple-organ systems. Manifestations in the lungs, heart, skin, and nervous system are most common

respiratory manifestations::

respiratory manifestations: Occur in the prodromal and eosinophilic phases of the disease. Nearly all patients have asthma at some point in the illness. Upperairway allergic disease, sinusitis, rhinitis, and polyposis, is seen in 75 to 85 percent of patients. The asthma and upper-airway disease usually are long-standing and often require steroid therapy (systemic or inhaled) to maintain control of symptoms . PFT:obstructive ventilatory defect

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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.

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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. The chest radiograph may occasionally be normal.

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HRCT has demonstrate: 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.

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bilateral central and peripheral opacities with varying density ground-glass opacity of the right upper lobe right upper lobe opacity .

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Cardiac manifestations: NOT present on initial presentation occur during the vasculitic phase major source of morbidity(in up to 50 percent of cases). Progressive CHF occurs in 47 percent of cases because of myocardial infiltration by eosinophils or ischemic cardiomyopathy resulting from necrotizing vasculitis of the coronary arteries. Acute pericarditis. cardiac tamponade Constrictive pericarditis may develop over time cardiac>CNS> renal impairment>GI

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neurological manifestations Mono- or polyneuropathy (most notably mononeuritis multiplex) is present in 69 to 75 percent of cases. CNS manifestations occur in approximately two-thirds of patients and include : -cranial nerve impairment (especially optic neuritis), - seizure, - subarachnoid hemorrhage, and -cerebral infarction. Cerebral hemorrhage and infarction are common causes of patient death.

Dermatological manifestations:

Dermatological manifestations Dermatological manifestations: Seen in 2/3 rd cases They can manifest as: nonthrombocytopenic purpura, Tender cutaneous or subcutaneous nodules (which may ulcerate), urticaria, a maculopapular rash, petechiae, ecchymoses, or livedo reticularis

GI manifestations:

GI manifestations present 60 percent of cases. They include : eosinophilic gastroenteritis vasculitis that can lead to diarrhea, abdominal pain, intestinal obstruction, cholecystitis, pancreatitis, bleeding, liver function test abnormalities, and bowel perforation. GI disease is the fourth leading cause of death in patients with CSS

RENAL MANIEFESTATIONS:

RENAL MANIEFESTATIONS Renal insufficiency occurs in up to 50 percent of patients with CSS. Interstitial nephritis, focal segmental glomerulonephritis (oftenwith necrotizing features), hematuria, and albuminuria are common. Severe, difficult-to-control hypertension is also a major sequela of CSS (in 25 to 75 percent of cases) and may be due to recurrent renal infarction. In contrast to WG,overt renal failure is not commonly seen in CSS.

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Mild lymphadenopathy(in 30 to 40 percent), rheumatological manifestations (migratory polyarthralgias, myalgias, temporal arteritis), urological disease (ureteral, urethral, prostatic), and ocular manifestations have also been described OTHERS

INVESTIGATIONS:

INVESTIGATIONS Fluctuating degree of peripheral blood eosinophilia (20 to 90 percent of the WBC differential) Serum total IgE levels are typically elevated (range, 500 to 1000 U/ml) and may parallel disease activity. normochromic, normocytic anemia. moderate elevation of their ESR. 70 to 75 percent of patients have positive antinuclear cytoplasmic antibody with a perinuclear staining pattern (pANCA). pleural fluid, if present, reveals an acidotic eosinophilic exudate with low glucose levels. Pleural biopsy shows chronic pleuritis with eosinophilic infiltration. BAL reveals an increased percentage of eosinophil

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18FDG/13Nammonia positron emission tomography (PET) imaging may be useful to identify cardiac involvement . The histopathological hallmarks depends on stage of illness: --Early lesions demonstrate eosinophilic infiltration of the vessels and perivascular region. --Later lesions are characterized by necrotizing arteritis or vessel obliteration and scarring . Open lung biopsy is the gold-standard site for tissue biopsy. Transbronchial biopsy may reveal the diagnosis if there is alveolar involvement, but is often non diagnostic.

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Pathological appearance of small arteriole in Churg-Strauss vasculitis. Intense perivascular inflammation with eosinophilia is present(early) Lung Parenchyma infiltrated richly with eosinophils

differential diagnosis:

differential diagnosis Polyarteritis nodosa, microscopic angiitis, WG, CEP, ABPA idiopathic hypereosinophilic syndrome, Loeffler’s syndrome Asthma fungal or parasitic infection, drug-induced vasculitis, Sarcoidosis and Hodgkin’s lymphoma .

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WG significant necrotizing upper-airway lesions and cavitation of lung nodules CSS nasal polyps and allergic rhinitis Panca less likely to develop renal failure, and vasculitic neuropathy and asthma/eosinophilia are not typical features of WG.

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Patients in whom CSS goes untreated have a poor prognosis; up to 50 percent die within 3 months after the onset of vasculitis. early recognition and treatment are important. corticosteroid treatment generally leads to dramatic clinical improvement, with disease stabilization or cure.

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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. Once the vasculitic phase is controlled, steroids may be tapered with doses titrated to maintain disease control. Low-dose prednisone is often given every day or every other day for up to 1 year.

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Treatment with cytotoxic immunosuppressive agents should be considered in patients : whose condition fails to improve with steroid treatment or poor prognostic features, including cardiac or GI involvement, renal insufficiency or proteinuria greater than 1 g/day such as : azathioprine, cyclophosphamide, high-dose methylprednisolone, or chlorambucil .

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Cyclophosphamide (2 mg/kg/day orally or 0.6 g/m2 intravenously per month)may be given concurrently with corticosteroids.(look for- hemorrhagic cystitis, renal insufficiency, bone marrow suppression, bladder fibrosis, and urological malignancies) interferon- α (IFN-α) has led to improved pulmonary function tests, Plasma exchange may also be a successful adjunct treatment Beta blockers should be avoided in the management of CSSrelated hypertension, owing to the risk of bronchospasm and congestive heart failure (CHF)

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Cyclophosphamide (2 mg/kg/day orally or 0.6 g/m2 intravenously per month)may be given concurrently with corticosteroids.(look for- hemorrhagic cystitis, renal insufficiency, bone marrow suppression, bladder fibrosis, and urological malignancies) interferon- α (IFN-α) has led to improved pulmonary function tests, Plasma exchange may also be a successful adjunct treatment Beta blockers should be avoided in the management of CSSrelated hypertension, owing to the risk of bronchospasm and congestive heart failure (CHF)

IDIOPATHIC HYPEREOSINOPHILIC SYNDROME:

IDIOPATHIC HYPEREOSINOPHILIC SYNDROME

PowerPoint Presentation:

Several names—including eosinophilic leukemia, Loeffler’s fibroplastic endocarditis, and disseminated eosinophilic cardiovascular disease. In 1975, Chusid and colleagues revised the definition of IHS to include only cases in which no other underlying cause of hypereosinophilia could be found. clinically heterogeneous syndrome with a wide range of disease severity.

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IHS predominantly affects males. Most common between 20 and 50 years of age. Presenting complaints are often nonspecific and include: weakness, fatigue, low-grade fevers, myalgias, cough, angioedema, rash, retinal lesions, and dyspnea. Involvement of virtually every organ system has been described

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The three principal clinical features defining IHS are: (1) persistent blood eosinophilia greater than 1500/μl for more than 6 months; (2) symptoms and signs of end-organ dysfunction; and (3) no other identifiable underlying cause of eosinophilia.

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Predominantly nocturnal cough, which is either nonproductive or productive of small quantities of nonpurulent sputum. Wheezing and dyspnea are also common, without evidence of airflow obstruction on spirometric examination. Pulmonary hypertension, ARDS, and pleural effusions (which may be due to CHF) have been reported. C x ray reveal: transient focal or diffuse pulmonary infiltrates (with no predilection for any particular distribution )

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Cardiac disease, which occurs in most patients with IHS, is the major cause of morbidity and mortality. Progressive CHF due to eosinophilic myocarditis and endocarditis, intracardiac thrombi, and endocardial fibrosis. Involvement of the central or peripheral nervous system, which occurs in up to 60 percent of patients, is also a major cause of morbidity

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Neurological manifestations of IHS include encephalopathy with neuropsychiatric dysfunction,memory loss, gait disturbances with or without signs of upper motor neuron injury, visual changes, and sequelae of thromboembolic events, including hemiparesis. Peripheral neuropathy with sensory and/or motor axonal loss (no vasculitic or eosinophilic infiltration) is extremely common in IHS.

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The bone marrow is universally affected with a striking eosinophilia (up to 25 to 75 percent of the differential). Other hematological manifestations are venous and arterial thromboembolism, anemia, thrombocytopenia, elevated vitamin B12 levels, hepatosplenomegaly, and lymphadenopathy (in 12 to 20 percent

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Laboratory findings associated with IHS include 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. Fungal and parasitic serologies, as well as aspirates of body fluids for ova and parasites, are negative. Of interest is that whereas blood and BAL eosinophilia are both prominent in persons with pulmonary involvement, blood eosinophilia is present and BAL eosinophilia is absent in persons lacking pulmonary manifestations of the disease. This finding has raised the question whether BAL eosinophilia may serve as a marker for the development of pulmonary disease associated with IHS

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The organ damage in IHS is believed to be due both to eosinophilic infiltration of tissues and to tissue injury caused by thromboembolic events. chromosomal abnormalities (including the Philadelphia chromosome) and immunologic abnormalities have been described in patients with IHS.

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Three major pathogenetic and clinical variants ofIHShave been reported: (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, differentiation, and chemotaxis.

diagnosis:

diagnosis The diagnosis of IHS is established by demonstrating multi-organ dysfunction, severe peripheral blood eosinophilia (greater than 1500/ μL) for at least 6months (or with death before then), and an absence of any other known causes of peripheral blood eosinophili. peripheral leukocyte count is typically elevated to above 10,000 (typical range, 10,000 to 30,000), with a preponderance of eosinophils (up to 70 percent).

differential diagnosis:

differential diagnosis parasitic infection, acute eosinophilic leukemia, CSS, episodic angioedema with eosinophilia, tuberculous or fungal infection, allergic or autoimmune disease, other acute or CEPs, TPE, and other lymphoproliferative disorders.

PowerPoint Presentation:

Patients with eosinophilic leukemia have immature eosinophils or blasts in the bone marrow and/or blood, whereas patients with IHS typically do not. Patients with IHS do not have asthma or vasculitis characteristically associated with CSS, and patients with episodic angioedema typically lack the multi-organ involvement associated with IHS.

PowerPoint Presentation:

Patients with the incidental finding of peripheral eosinophilia but without evidence of end-organ dysfunction can be followed closely at 3- to 6-month intervalswithout specific treatment, as they tend to follow a benign course. The mainstay of therapy for IHS with organ involvement includes corticosteroids such as prednisone at 1 mg/kg/day for several weeks, with taper of dose attempted to an every-other-day regimen once eosinophil levels are reduced.

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If the disease stabilizes or resolves, alternate-day corticosteroids should be continued for approximately 1 year at the minimal dose that effectively controls disease activity. Hydroxyurea (0.5 to 1.5 g per day) may be added to the regimen if there is evidence of further disease progression, with the aim of reducing the peripheral leukocyte count to the range of 5000 to 10,000. Vincristine may be used as a chemotherapeutic inducing agent in patients with extremely high peripheral WBC counts. Etoposide and chlorambucil are effective alternative agents for cases that prove refractory to standard treatmentwith corticosteroids.

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Cyclosporine may also be of benefit in controlling the disease, especially when used in combination with corticosteroids. IFN- α, amediator that suppresses eosinophil function in vitro, has been beneficial in management of IHS, perhaps by inhibiting eosinophil proliferation and differentiation. IFN- α should be tried as a second-line agent among patients with IHS who fail to respond to corticosteroid treatment. Existing data suggest that another anti-eosinophil strategy, the anti–IL-5 antibody, may reduce symptomsand eosinophilic organ involvement associatedwith IHS, andmay be particularly helpful in pati

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