SACGR June 15, 2005 Ann Chen

History of Present Illness 31 yo male, residing at West Seattle Psychiatric Hospital, brought to HMC for fevers, chills, and dyspnea. 31 yo male, residing at West Seattle Psychiatric Hospital, brought to HMC for fevers, chills, and dyspnea. Father notes that he seems to be more agitated then at baseline. Father notes that he seems to be more agitated then at baseline. Poor historian. SOB for 1-4 days. Associated with chest pain. Does not appear to have cough or sputum production. Poor historian. SOB for 1-4 days. Associated with chest pain. Does not appear to have cough or sputum production. ROS positive for HA, whole-body myalgia, and diarrhea. Denies any weight loss, nightsweats. ROS positive for HA, whole-body myalgia, and diarrhea. Denies any weight loss, nightsweats.

Past Medical History PMH: PMH: Schizophrenia Schizophrenia SHx: SHx: + tobacco, 2-3ppd since 18yrs old + tobacco, 2-3ppd since 18yrs old Past EtOH Past EtOH Denies IVDU Denies IVDU Meds: Meds: Metoprolol (recently added) Metoprolol (recently added) Risperidone Risperidone Clozaril (dose increased recently) Clozaril (dose increased recently) Cogentin Cogentin Depakote Depakote Ranitidine Ranitidine

More History No travels in past 10 years No travels in past 10 years Has one dog at home, no birds Has one dog at home, no birds Had negative PPD when he started residing at the psych facility Had negative PPD when he started residing at the psych facility Family history with “some kind of cancer”, otherwise non-contributory Family history with “some kind of cancer”, otherwise non-contributory

Physical Exam T=40.6, BP=125/67, HR=130s, RR=40s to 50s, O2 sat=99% on 100NRB T=40.6, BP=125/67, HR=130s, RR=40s to 50s, O2 sat=99% on 100NRB AAOx3, mildly diaphoretic AAOx3, mildly diaphoretic HEENT: PERRL, EOMI, no JVD, oral mucosa without lesions, no cervical LAN HEENT: PERRL, EOMI, no JVD, oral mucosa without lesions, no cervical LAN Lungs: using accessory muscles, decreased breath sounds at bases, no crackles or wheezes Lungs: using accessory muscles, decreased breath sounds at bases, no crackles or wheezes CV: tachycardic, regular, good peripheral pulses CV: tachycardic, regular, good peripheral pulses Abd: obese, nontender, no rebound Abd: obese, nontender, no rebound LE: trace edema LE: trace edema Skin: no rash Skin: no rash Neuro: CN intact, nonfocal Neuro: CN intact, nonfocal

Labs WBC=11.8, Hct=38, Plt=165 WBC=11.8, Hct=38, Plt=165 Diff: neutrophils 70%, eosinophils 10% Diff: neutrophils 70%, eosinophils 10% Chem 7 normal Chem 7 normal LFTs normal, amylase and lipase normal LFTs normal, amylase and lipase normal ABG: 7.47/31/108 on 6L O2 via NC ABG: 7.47/31/108 on 6L O2 via NC Troponin=0.52, CK=316 Troponin=0.52, CK=316 BNP = 1337 BNP = 1337 EKG: sinus tach, otherwise normal EKG: sinus tach, otherwise normal

Pleural Effusion Pleural effusion: eosinophilic Pleural effusion: eosinophilic Gram stain and bacterial cultures negative Gram stain and bacterial cultures negative AFB negative AFB negative Fungal, viral negative Fungal, viral negative

ECHO EF of 40% EF of 40% LV with normal wall thickness and size but with mild global hypokinesis LV with normal wall thickness and size but with mild global hypokinesis RV normal size and function RV normal size and function Mild MR, otherwise no valvular abnormalities Mild MR, otherwise no valvular abnormalities Small pericardial effusion Small pericardial effusion

More Labs PCR for enteroviruses and adenovirus negative PCR for enteroviruses and adenovirus negative Resp FA: negative for influenza A & B, parainfluenza, RSV, adenovirus Resp FA: negative for influenza A & B, parainfluenza, RSV, adenovirus HIV negative HIV negative CMV IgG positive, CMV antigenemia negative CMV IgG positive, CMV antigenemia negative ESR=50, CRP=306 ESR=50, CRP=306 ANA, ds-DNA, ANCA negative ANA, ds-DNA, ANCA negative

Stool Studies Strongyloides antibody negative Strongyloides antibody negative Stool cultures negative for O&P Stool cultures negative for O&P C.diff toxin A & B negative C.diff toxin A & B negative

Clozapine Hypersensitivity Reported cases of clozapine causing: Reported cases of clozapine causing: Pleural effusion Pleural effusion Pericarditis Pericarditis Pericardial effusion, tamponade Pericardial effusion, tamponade Myocarditis Myocarditis Cardiomyopathy Cardiomyopathy Arrhythmias Arrhythmias Sudden cardiac death Sudden cardiac death Other side effects: Other side effects: Agranulocytosis Agranulocytosis Seizures Tachycardia Seizures Tachycardia Sedation Sedation Weight gain Weight gain Hypersalivation Hypersalivation

Clozapine-Induced Polyserositis & Myocarditis Onset of symptoms described as early as 1 week to as late as 7 years after starting clozapine Onset of symptoms described as early as 1 week to as late as 7 years after starting clozapine Patient age ranged from 25 to 66 years old Patient age ranged from 25 to 66 years old Dose ranged from 100mg to 750mg daily Dose ranged from 100mg to 750mg daily Patients presents with the usual clinical signs and symptoms of pleural effusions, pericarditis, and myocarditis Patients presents with the usual clinical signs and symptoms of pleural effusions, pericarditis, and myocarditis Peripheral eosinophilia Peripheral eosinophilia Pathology clozapine-induced myocarditis showed eosinophilic infiltration of myocardium Pathology clozapine-induced myocarditis showed eosinophilic infiltration of myocardium

Treatment Resolution of symptoms with stopping clozapine Resolution of symptoms with stopping clozapine Steroids??? Steroids??? Proposed mechanism: Clozapine stimulates release of TNF and other cytokines Proposed mechanism: Clozapine stimulates release of TNF and other cytokines Thus, steroids have been tried Thus, steroids have been tried One case of biopsy-proven myocarditis that improved with 8-day course of “low-dose corticosteroids” One case of biopsy-proven myocarditis that improved with 8-day course of “low-dose corticosteroids” Jury is still out… Jury is still out…

References Pieroni M, Cavallaro R, Chimenti C, Smeraldi E, Frustaci A. Clozapine-induced hypersensitivity myocarditis. Chest 2004;126: Pieroni M, Cavallaro R, Chimenti C, Smeraldi E, Frustaci A. Clozapine-induced hypersensitivity myocarditis. Chest 2004;126: Wehmeier PM, Heiser P, Remschmidt H. Myocarditis, pericarditis and cardiomyopathy in patients treated with clozapine. Journal of Clinical Pharmacy and Therapeutics 2005;30: Wehmeier PM, Heiser P, Remschmidt H. Myocarditis, pericarditis and cardiomyopathy in patients treated with clozapine. Journal of Clinical Pharmacy and Therapeutics 2005;30: Murko A, Clarke S, Black DW. Clozapine and pericarditis with pericardial effusion. Am J of Psychiatry 2002;159:494. Murko A, Clarke S, Black DW. Clozapine and pericarditis with pericardial effusion. Am J of Psychiatry 2002;159:494. Fineschi V, Neri M, Riezzo I, Turillazzi E. Sudden cardiac death due to hypersensitivity myocarditis during clozapine treatment. Int J Legal Med 2004;118: Fineschi V, Neri M, Riezzo I, Turillazzi E. Sudden cardiac death due to hypersensitivity myocarditis during clozapine treatment. Int J Legal Med 2004;118: