23 y.o. white female with asthma 23 y.o. white female with asthma

Admitted to JHBMC for chest and abdominal painAdmitted to JHBMC for chest and abdominal pain

Allergy and Clinical Immunology consulted for eosinophiliaAllergy and Clinical Immunology consulted for eosinophilia

Grand Rounds CaseGrand Rounds Case

6 wks PTA6 wks PTA - dyspnea, fever, cough with yellow phlegm- dyspnea, fever, cough with yellow phlegm - CXR in ED: left LL infiltrate- CXR in ED: left LL infiltrate

- treated with azithromycin- treated with azithromycin

History of Present IllnessHistory of Present Illness

5 wks PTA5 wks PTA - symptoms persisted- symptoms persisted- CXR: bilateral LL infiltrates with effusion- CXR: bilateral LL infiltrates with effusion- treated by PCP with amox/clavulanate - treated by PCP with amox/clavulanate with clarithromycin x 1 weekwith clarithromycin x 1 week

History of Present IllnessHistory of Present Illness

4 wks PTA4 wks PTA - symptoms persisted, admitted to hospital- symptoms persisted, admitted to hospital- CXR: multilobar infiltrates- CXR: multilobar infiltrates

History of Present IllnessHistory of Present Illness

4 wks PTA4 wks PTA - WBC: 27.6 k/µL (58% eos, 25% neu, 11% lym) - WBC: 27.6 k/µL (58% eos, 25% neu, 11% lym) (Cont’d)(Cont’d) - PE: diffuse wheezing and rhonchi- PE: diffuse wheezing and rhonchi

- Dx: atypical pneumonia & asthma exacerbation - Dx: atypical pneumonia & asthma exacerbation - Tx: - Tx: cefuroxime, clarithromycin, cefuroxime, clarithromycin,

methylprednisolone 125 mg x 1 then methylprednisolone 125 mg x 1 then prednisone 40 mg/dayprednisone 40 mg/day

- symptoms and CXR promptly improved- symptoms and CXR promptly improved

History of Present IllnessHistory of Present Illness

History of Present IllnessHistory of Present Illness

Day 0Day 0 Day 3Day 3

4 wks PTA4 wks PTA - eosinophil count: 16k to 0 /µL within 2 days- eosinophil count: 16k to 0 /µL within 2 days(Cont’d)(Cont’d) - sputum cultures: neg- sputum cultures: neg

- discharged on cefuroxime, clarithromycin, and- discharged on cefuroxime, clarithromycin, andprednisone 20 mg/day tapered over 8 daysprednisone 20 mg/day tapered over 8 days

- felt well for 2 weeks- felt well for 2 weeks

History of Present IllnessHistory of Present Illness

12 days PTA12 days PTA - syncope, assessed to be vasovagal- syncope, assessed to be vasovagal- Holter monitor: sinus tach, rare ventricular ectopy- Holter monitor: sinus tach, rare ventricular ectopy

10 days PTA10 days PTA - nonradiating chest pain w/o respiratory symptom- nonradiating chest pain w/o respiratory symptom- PE: tachycardia- PE: tachycardia- hospitalized overnight - hospitalized overnight - WBC: 8.7 k/µL (11% eos)- WBC: 8.7 k/µL (11% eos)

History of Present IllnessHistory of Present Illness

History of Present IllnessHistory of Present Illness

10 days PTA10 days PTA - serial cardiac enzymes: neg- serial cardiac enzymes: neg(Cont’d)(Cont’d) - EKG: nonspecific changes, low QRS voltage- EKG: nonspecific changes, low QRS voltage

History of Present IllnessHistory of Present Illness

1 wk PTA1 wk PTA - felt unimproved, developed abdominal pain,- felt unimproved, developed abdominal pain, anorexia, nausea and vomiting promptinganorexia, nausea and vomiting prompting current admission to JHBMCcurrent admission to JHBMC

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

History of Present IllnessHistory of Present Illness

AsthmaAsthma - diagnosed 2 yrs PTA- diagnosed 2 yrs PTA- cough, dyspnea, chest tightness, wheezing- cough, dyspnea, chest tightness, wheezing- ED visits for asthma exacerbations 4x in 18 mos- ED visits for asthma exacerbations 4x in 18 mos latest 3 mos PTA, latest 3 mos PTA, treated with oral steroids tapered over 1-2 wktreated with oral steroids tapered over 1-2 wk

- triamcinolone MDI 600 µg/day started 11 mo PTA- triamcinolone MDI 600 µg/day started 11 mo PTA switched to fluticasone MDI 440µg/day 2 mos PTAswitched to fluticasone MDI 440µg/day 2 mos PTA- zafirlukast 20 mg BID started 4 mos PTA- zafirlukast 20 mg BID started 4 mos PTA discontinued 1 week PTAdiscontinued 1 week PTA

SinusitisSinusitis - maxillary pain, purulent discharge - maxillary pain, purulent discharge treated with antibiotics 9 mos PTAtreated with antibiotics 9 mos PTA

Past Medical HistoryPast Medical History

CBC CBC - Normal during pregnancy 15 mos PTA- Normal during pregnancy 15 mos PTA

CXRCXR - Normal during past 3 ED visits- Normal during past 3 ED visits latest at 3 mos PTAlatest at 3 mos PTA

Past Medical HistoryPast Medical History

Family HistoryFamily History

FatherFather - rhinitis- rhinitis

Environmental HistoryEnvironmental History

Born and raised in BaltimoreBorn and raised in BaltimorePet bird in basement for the past 4 yrsPet bird in basement for the past 4 yrs

Differential Diagnoses?Differential Diagnoses?

AsthmaAsthma

EosinophiliaEosinophilia

Elevated total IgEElevated total IgE

Multi-organ involvementMulti-organ involvement- pulmonary infiltrates- pulmonary infiltrates- EKG low QRS voltage: pericardial effusion, - EKG low QRS voltage: pericardial effusion, diffuse myocardial injury, and/ or myocardial infiltrationdiffuse myocardial injury, and/ or myocardial infiltration- abdominal pain?- abdominal pain?

Clinical Presentation SummaryClinical Presentation Summary

In alphabetical order:In alphabetical order:

Allergic bronchopulmonary aspergillosis (ABPA)Allergic bronchopulmonary aspergillosis (ABPA)

Churg-Strauss syndromeChurg-Strauss syndrome

Drug hypersensitivity reactionDrug hypersensitivity reaction

Hypereosinophilic syndrome (HES)Hypereosinophilic syndrome (HES)

MalignancyMalignancy

Parasitic disease Parasitic disease

Differential Diagnoses?Differential Diagnoses?

ABPA?ABPA?

AsthmaAsthma √√

CXR infiltrateCXR infiltrate √√

Peripheral blood eosinophiliaPeripheral blood eosinophilia √√

Elevated serum total IgE (>1000 ng/ml)Elevated serum total IgE (>1000 ng/ml) √√

Positive skin test to Positive skin test to A. fumigatusA. fumigatus

Precipitating Abs to Precipitating Abs to A. fumigatusA. fumigatus

Central bronchiectasisCentral bronchiectasis

(No cardiac or GI involvement)(No cardiac or GI involvement)

Churg-Strauss SyndromeChurg-Strauss Syndrome

** Need 4 out of 6 criteria: Need 4 out of 6 criteria:

AsthmaAsthma √√

>10% blood eosinophilia>10% blood eosinophilia √√

Nonfixed pulmonary infiltrates on CXRNonfixed pulmonary infiltrates on CXR √√

Paranasal sinus abnormalitiesParanasal sinus abnormalities √√

Extravascular eosinophilsExtravascular eosinophils √√

Mononeuropathy or polyneuropathyMononeuropathy or polyneuropathy

** American College of Rheumatology 1990 American College of Rheumatology 1990

Hypereosinophilic SyndromeHypereosinophilic Syndrome

** 3 Defining Features:3 Defining Features:

Eosinophilia >1500 /µL for >6 mosEosinophilia >1500 /µL for >6 mos ??

No identifiable cause (parasitic or allergic ds)No identifiable cause (parasitic or allergic ds) ??

Signs and symptoms of organ involvementSigns and symptoms of organ involvement √√

** Chusid et al, Chusid et al, Medicine Medicine 19751975

Organ Involvement:Organ Involvement:

PulmonaryPulmonary 14% - 28%14% - 28%

CardiovascularCardiovascular 54% - 95%54% - 95%

GastrointestinalGastrointestinal 14% - 53%14% - 53%

Hypereosinophilic SyndromeHypereosinophilic Syndrome

Chusid et al, Chusid et al, Medicine Medicine 1975 1975 Fauci et al, Fauci et al, Ann Intern MedAnn Intern Med 1982 1982Weller et al, Weller et al, BloodBlood 1994 1994

Abdominal CT: negAbdominal CT: neg

Chest CT: pericardial effusionChest CT: pericardial effusion

Hospital CourseHospital Course

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

Hospital CourseHospital Course

Hospital CourseHospital Course

Creatine phosphokinase (CPK)Creatine phosphokinase (CPK) - 889 IU/L (Nl: 0 - 150)- 889 IU/L (Nl: 0 - 150)CK-MB fractionCK-MB fraction - 177 ng/mL (Nl: 0 - 5)- 177 ng/mL (Nl: 0 - 5)EchocardiographyEchocardiography - EF 45% - 50%, - EF 45% - 50%,

apical and inferior akinesisapical and inferior akinesis and diffuse hypokinesis,and diffuse hypokinesis, myocardial speckling,myocardial speckling, bilateral ventricular thickeningbilateral ventricular thickening

EKGEKG - diffuse low QRS voltage- diffuse low QRS voltage

Hospital CourseHospital Course

Transvenous myocardial biopsy of right ventricular septumTransvenous myocardial biopsy of right ventricular septum- myocarditis with intense inflammatory infiltrates,- myocarditis with intense inflammatory infiltrates, primarily eosinophils, and myocyte necrosisprimarily eosinophils, and myocyte necrosis

Hospital CourseHospital Course

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

Hospital CourseHospital Course

Eosinophilic myocarditisEosinophilic myocarditis

- - rare but serious conditionrare but serious condition- past reported cases were established post-mortem- past reported cases were established post-mortem with myocyte necrosis and eosinophils on autopsy,with myocyte necrosis and eosinophils on autopsy, death due to cardiac decompensation or arrhythmiadeath due to cardiac decompensation or arrhythmia- 5/34 died within 8 weeks, 22/34 died within 23 mos- 5/34 died within 8 weeks, 22/34 died within 23 mos

Mullick et al, Mullick et al, JAMAJAMA 1977 1977 Fenoglio et al, Fenoglio et al, Hum Pathol Hum Pathol 19811981Herzog et al, Herzog et al, Br Heart JBr Heart J 1984 1984 Taliercio et al, Taliercio et al, Mayo Clin ProcMayo Clin Proc 1985 1985

Hospital CourseHospital Course

TreatmentTreatment - Methylprednisolone 1 g/day x 3 days then- Methylprednisolone 1 g/day x 3 days then Prednisone 80 mg/day Prednisone 80 mg/day

After 8 days, patient was discharged asymptomaticAfter 8 days, patient was discharged asymptomaticon prednisone 80 mg/day and enalapril 10 mg/dayon prednisone 80 mg/day and enalapril 10 mg/day

Short Term Follow-up CourseShort Term Follow-up Course

2 mos later2 mos later - Repeat myocardial biopsy showed- Repeat myocardial biopsy showed multiple foci of replacement fibrosis and multiple foci of replacement fibrosis and mild hypertrophic changes, no infiltratesmild hypertrophic changes, no infiltrates

Original biopsyOriginal biopsy Biopsy 2 mos laterBiopsy 2 mos later

Short Term Follow-up CourseShort Term Follow-up Course

2 mos later2 mos later - immunofluorescence staining of biopsy- immunofluorescence staining of biopsy showed few intact eosinophils, showed few intact eosinophils, but no extracellular MBPbut no extracellular MBP

Original biopsyOriginal biopsy Biopsy 2 mos laterBiopsy 2 mos later

Long Term Follow-up CourseLong Term Follow-up Course

7 years later7 years later - Latest echocardiogram: LV dysfunction with- Latest echocardiogram: LV dysfunction with EF 25% - 30%EF 25% - 30%- Latest eosinophil count: 300 /µL- Latest eosinophil count: 300 /µL- course characterized by occasional episodes- course characterized by occasional episodes of respiratory distress due to asthma and/or CHFof respiratory distress due to asthma and/or CHF- Present Tx includes: prednisone 10 mg/day,- Present Tx includes: prednisone 10 mg/day, budesonide, salmeterol, losartan, spironolactonebudesonide, salmeterol, losartan, spironolactone

AcknowledgementsAcknowledgements

Romi SainiRomi Saini

Hirohito KitaHirohito Kita

Kristen LeifermanKristen Leiferman

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The NHLBI, NIAID, NIH, US FDA jointly sponsored a The NHLBI, NIAID, NIH, US FDA jointly sponsored a workshop to consider interrelationships among workshop to consider interrelationships among Churg-Strauss Syndrome (CSS), asthma, and asthma Churg-Strauss Syndrome (CSS), asthma, and asthma therapeutics. therapeutics.

From published reports and reports to the US FDA, From published reports and reports to the US FDA, treatment of patients with asthma with any of 3 treatment of patients with asthma with any of 3 cysteinyl leukotriene receptor antagonists, a 5-cysteinyl leukotriene receptor antagonists, a 5-lipoxygenase inhibitor, and inhaled corticosteroids lipoxygenase inhibitor, and inhaled corticosteroids has been associated with CSS development.has been associated with CSS development.

Weller et al, NIH Workshop Summary Report Weller et al, NIH Workshop Summary Report JAMAJAMA 2001 2001

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It is unknown whether these agents were eliciting It is unknown whether these agents were eliciting CSS. CSS.

Because many asthma patients receiving these Because many asthma patients receiving these therapies were able to diminish their systemic therapies were able to diminish their systemic corticosteroid therapy, it is possible that incipient corticosteroid therapy, it is possible that incipient CSS was unmasked by lessened steroid use. CSS was unmasked by lessened steroid use.

The underlying pathophysiologic mechanisms of The underlying pathophysiologic mechanisms of CSS, however, are unknown, and there is no means CSS, however, are unknown, and there is no means of identifying which patients with asthma might be of identifying which patients with asthma might be at risk for CSS. at risk for CSS.

Weller et al, NIH Workshop Summary Report Weller et al, NIH Workshop Summary Report JAMAJAMA 2001 2001