23 y.o. white female with asthma Admitted to JHBMC for chest and abdominal pain Allergy and Clinical Immunology consult

1. Grand Rounds Case 23 y.o. white female with asthma Admitted to JHBMC for chest and abdominal pain Allergy and Clinical Immunology consulted for eosinophilia

2. History of Present Illness 6 wks PTA - dyspnea, fever, cough with yellow phlegm - CXR in ED: left LL infiltrate - treated with azithromycin

3. History of Present Illness 5 wks PTA - symptoms persisted - CXR: bilateral LL infiltrates with effusion - treated by PCP with amox/clavulanate with clarithromycin x 1 week

4. History of Present Illness 4 wks PTA - symptoms persisted, admitted to hospital - CXR: multilobar infiltrates

5. History of Present Illness 4 wks PTA - WBC: 27.6 k/µL (58% eos, 25% neu, 11% lym) (Cont’d) - PE: diffuse wheezing and rhonchi - Dx: atypical pneumonia & asthma exacerbation - Tx: cefuroxime, clarithromycin, methylprednisolone 125 mg x 1 then prednisone 40 mg/day - symptoms and CXR promptly improved

6. History of Present Illness Day 0 Day 3

7. History of Present Illness 4 wks PTA - eosinophil count: 16k to 0 /µL within 2 days (Cont’d) - sputum cultures: neg - discharged on cefuroxime, clarithromycin, and prednisone 20 mg/day tapered over 8 days - felt well for 2 weeks

8. History of Present Illness 12 days PTA - syncope, assessed to be vasovagal - Holter monitor: sinus tach, rare ventricular ectopy 10 days PTA - nonradiating chest pain w/o respiratory symptom - PE: tachycardia - hospitalized overnight - WBC: 8.7 k/µL (11% eos)

9. History of Present Illness 10 days PTA - serial cardiac enzymes: neg (Cont’d) - EKG: nonspecific changes, low QRS voltage

10. History of Present Illness 1 wk PTA - felt unimproved, developed abdominal pain, anorexia, nausea and vomiting prompting current admission to JHBMC

11. History of Present Illness Current admission - PE: tachycardia, abdominal tenderness - WBC: 14.6 k/µL (28% eos) - serum total IgE: 6,552 ng/mL - ANA, RF, ANCA, HIV: neg - Allergy and Clinical Immunology consulted

12. Past Medical History Asthma - diagnosed 2 yrs PTA - cough, dyspnea, chest tightness, wheezing - ED visits for asthma exacerbations 4x in 18 mos latest 3 mos PTA, treated with oral steroids tapered over 1-2 wk - triamcinolone MDI 600 µg/day started 11 mo PTA switched to fluticasone MDI 440µg/day 2 mos PTA - zafirlukast 20 mg BID started 4 mos PTA discontinued 1 week PTA Sinusitis - maxillary pain, purulent discharge treated with antibiotics 9 mos PTA

13. Past Medical History CBC - Normal during pregnancy 15 mos PTA CXR - Normal during past 3 ED visits latest at 3 mos PTA

14. Family History Father - rhinitis Environmental History Born and raised in Baltimore Pet bird in basement for the past 4 yrs

15. Differential Diagnoses?

16. Clinical Presentation Summary • Asthma • Eosinophilia • Elevated total IgE • Multi-organ involvement • - pulmonary infiltrates • - EKG low QRS voltage: pericardial effusion, • diffuse myocardial injury, and/ or myocardial infiltration • - abdominal pain?

17. Differential Diagnoses? In alphabetical order: Allergic bronchopulmonary aspergillosis (ABPA) Churg-Strauss syndrome Drug hypersensitivity reaction Hypereosinophilic syndrome (HES) Malignancy Parasitic disease

18. ABPA? Asthma √ CXR infiltrate √ Peripheral blood eosinophilia √ Elevated serum total IgE (>1000 ng/ml) √ Positive skin test to A. fumigatus Precipitating Abs to A. fumigatus Central bronchiectasis (No cardiac or GI involvement)

19. Churg-Strauss Syndrome * Need 4 out of 6 criteria: Asthma √ >10% blood eosinophilia √ Nonfixed pulmonary infiltrates on CXR √ Paranasal sinus abnormalities √ Extravascular eosinophils √ Mononeuropathy or polyneuropathy * American College of Rheumatology 1990

20. Hypereosinophilic Syndrome *3 Defining Features: Eosinophilia >1500 /µL for >6 mos ? No identifiable cause (parasitic or allergic ds) ? Signs and symptoms of organ involvement √ * Chusid et al, Medicine 1975

21. Hypereosinophilic Syndrome Organ Involvement: Pulmonary 14% - 28% Cardiovascular 54% - 95% Gastrointestinal 14% - 53% Chusid et al, Medicine 1975 Fauci et al, Ann Intern Med 1982 Weller et al, Blood 1994

22. Hospital Course Abdominal CT: neg Chest CT: pericardial effusion

23. Hospital Course Pericardiocentesis - 390 ml serous fluid removed - WBC: 2.8 k/µL (60% eos, 20% mesothelial cells, 15% lymphocytes, 5% monocytes)

24. Hospital Course Creatine phosphokinase (CPK) - 889 IU/L (Nl: 0 - 150) CK-MB fraction - 177 ng/mL (Nl: 0 - 5) Echocardiography - EF 45% - 50%, apical and inferior akinesis and diffuse hypokinesis, myocardial speckling, bilateral ventricular thickening EKG - diffuse low QRS voltage

25. Hospital Course Transvenous myocardial biopsy of right ventricular septum - myocarditis with intense inflammatory infiltrates, primarily eosinophils, and myocyte necrosis

26. Hospital Course Transvenous myocardial biopsy of right ventricular septum - immunofluorescence staining showing intracellular and extracellular Major Basic Protein (MBP)

27. Hospital Course Eosinophilic myocarditis - rare but serious condition - past reported cases were established post-mortem with myocyte necrosis and eosinophils on autopsy, death due to cardiac decompensation or arrhythmia - 5/34 died within 8 weeks, 22/34 died within 23 mos Mullick et al, JAMA 1977 Fenoglio et al, Hum Pathol 1981 Herzog et al, Br Heart J 1984 Taliercio et al, Mayo Clin Proc 1985

28. Hospital Course Treatment - Methylprednisolone 1 g/day x 3 days then Prednisone 80 mg/day After 8 days, patient was discharged asymptomatic on prednisone 80 mg/day and enalapril 10 mg/day

29. Short Term Follow-up Course 2 mos later - Repeat myocardial biopsy showed multiple foci of replacement fibrosis and mild hypertrophic changes, no infiltrates Original biopsy Biopsy 2 mos later

30. Short Term Follow-up Course 2 mos later - immunofluorescence staining of biopsy showed few intact eosinophils, but no extracellular MBP Original biopsy Biopsy 2 mos later

31. Long Term Follow-up Course 7 years later - Latest echocardiogram: LV dysfunction with EF 25% - 30% - Latest eosinophil count: 300 /µL - course characterized by occasional episodes of respiratory distress due to asthma and/or CHF - Present Tx includes: prednisone 10 mg/day, budesonide, salmeterol, losartan, spironolactone

32. Acknowledgements Romi Saini Hirohito Kita Kristen Leiferman

33. Post Script The NHLBI, NIAID, NIH, US FDA jointly sponsored a workshop to consider interrelationships among Churg-Strauss Syndrome (CSS), asthma, and asthma therapeutics. From published reports and reports to the US FDA, treatment of patients with asthma with any of 3 cysteinyl leukotriene receptor antagonists, a 5-lipoxygenase inhibitor, and inhaled corticosteroids has been associated with CSS development. Weller et al, NIH Workshop Summary Report JAMA 2001

34. Post Script It is unknown whether these agents were eliciting CSS. Because many asthma patients receiving these therapies were able to diminish their systemic corticosteroid therapy, it is possible that incipient CSS was unmasked by lessened steroid use. The underlying pathophysiologic mechanisms of CSS, however, are unknown, and there is no means of identifying which patients with asthma might be at risk for CSS. Weller et al, NIH Workshop Summary Report JAMA 2001