1. CASE PRESENTATION Patricia Baile – PL1 December 16, 2009

2. 16 year old male presents to the ER with chest pain

3. HPI Chest pain x 6 days ▫Sharp, stabbing sensation on left side of chest ▫Constant ▫PS 7/10 ▫Worse when lying on left side and on inspiration ▫Radiating to back ▫Mild improvement with aspirin and acetaminophen

4. HPI Chest pain ▫Associated with nausea, dizziness and blurring of vision 2 days prior ▫No diaphoresis On day of admission, chest pain persistent, no improvement with acetaminophen hence BIB EMS to ER

5. ROS Denies recent strenuous physical activity No fever No URI symptoms No sick contacts No joint pains No dyspnea

6. Past Medical History Asthma ▫9 previous hospitalizations, last 1 year prior ▫No ICU, no intubation ▫Advair BID ▫Singulair 10 mg PO QD ▫Albuterol PRN

7. Family History + Asthma + DM + Hypertension + CAD No sudden death No CVA No connective tissue disorders

8. Birth History ▫FT, NSVD, no complication Immunization History ▫Up to date

9. Adolescent History ▫Currently in 9 th grade (behind 2 years) ▫Lives with mother, stepfather and older brother ▫No sport or after-school activity ▫Denies drugs, alcohol, tobacco ▫Sexually active, has had 8 partners, uses condoms, no STD history (never tested)

10. Physical Examination BP 102/58 HR 72 RR 18 O2 100%RA T 98.3 Pain score: 6-7/10 Wt: 76.9 kg (90%) Ht: 185 cm (90%) GS: non-toxic appearing HEENT: NCAT, congested turbinates, TMI, mild erythema OP, no CLAD C/L: SCE, good air entry b/l, CTAB, no crackles, no rales, no tenderness on palpation of chest CV: RRR, no m/r/g Abdomen: soft, ND, NT, no organomegaly Ext: well-perfused, good distal pulses

11. EKG

12. Labs CBC: 6.9 > 13.7/39.1< 251 N 68 L 20 BMP: 138/3.8/100/26/7/0.6/104/8.3 LFT: 3.9/6.9/25/109/0.7/74 Lipase: 12 CPK: 1751 CKMB: 168.8 Troponin T: 8.77

13. Labs Lipid profile ▫Cholesterol: 106 ▫TG: 49 ▫HDL: 31 ▫LDL: 65 CRP: 7.5 Urine Drug Screen: Negative

14. Labs RSV/Flu: Negative Rapid strep test: negative Throat culture ASO: 165 Streptozyme: Positive Respiratory viral panel: Negative

15. Ancillary Tests Chest Radiograph ▫Normal chest

16. Ancillary Tests Initial Echo ▫Normal LV ejection fraction ▫Normal RV function ▫Mild inferolateral akinesis ▫Inferior wall akinesis ▫Small pericardial effusion

17. Initial Impression 16 year old male with Juvenile pattern pericarditis; Asthma exacerbation

18. Hospital Course Admitted to PICU Cardiac enymes gradually decreased Repeat Echo done Cardiac catheterization done

19. Ancillary Tests Repeat Echo ▫Myocarditis with LV inferior/posterior wall motion abnormality: persistent abnormal LV wall motion ▫Suboptimal LV shortening fraction ▫Normal diastolic LV function ▫Trace inferior and posterior pericardial effusion

20. Ancillary Tests Cardiac catheterization ▫Clear vessels ▫Decreased ejection fraction ▫Decreased motion of LV

21. FINAL DIAGNOSIS 16 year old male with chest pain secondary to Myocarditis; Asthma exacerbation

22. MYOCARDITIS

23. Introduction Clinical syndrome characterized by inflammation of myocytes resulting from infectious, toxic, and autoimmune etiologies. Ongoing viral infection, myocardial destruction, and adverse remodeling can lead to persistent ventricular dysfunction and dilated cardiomyopathy.

24. Introduction Infectious etiologies, particularly viral, are most common in children. The most common causes of viral myocarditis are enterovirus (coxsackie group B) and adenovirus

25. Incidence Incidence of myocarditis in children is unknown ▫Inflammatory infiltrates and myocardial cell damage were found at autopsy in 3 to 40% of infants and children who died suddenly unrelated to trauma ▫17 percent of infants who died of SIDS had histopathologic evidence of myocarditis

26. Incidence In one retrospective study from a single tertiary Canadian center, the estimated prevalence of myocarditis presenting to their emergency department was 0.5 cases per 10,000 visits A review of all the autopsies performed at a single English pediatric tertiary center over a ten-year period (1996 to 2005) identified 28 of 1516 cases with myocarditis (1.8 percent)

27. Pathophysiology In susceptible patients: ▫Viral RNA uptake  cytotoxic necrosis  rapid cell death More common presentation ▫4-14 days post-infection  immune response (macrophage activation and cytokine expression)  natural killer cells target myocardium expressing the viral RNA and continue myocyte necrosis

28. Pathophysiology ▫TNF is involved in rapidly clearing virus and signals additional proinflammatory cells, activates endothelial cells, and has direct negative inotropic effects ▫Cytotoxic T lymphocytes infiltrate myocytes and trigger lysis of these cells

29. Pathophysiology In the chronic phases, the effects of either inadequate or inappropriately abundant immune response can lead to the long-term sequelae of dilated cardiomyopathy and heart failure

30. Pathophysiology Ongoing study has demonstrated the presence of antimyosin autoantibodies and other immunomodulators long after initial viral infection

31. Clinical Manifestation Nonspecific illness ▫Fatigue ▫Mild dyspnea ▫Myalgias ▫Fever (20%) Chest pain (35%) ▫most commonly described as a pleuritic, sharp, stabbing precordial pain ▫may be substernal and squeezing

32. Clinical Manifestation In a 6-year study of pediatric ED patients, the most common presenting symptom was dyspnea and more than half of patients were initially diagnosed with asthma or pneumonia. May be asymptomatic

33. Clinical manifestation Symptoms of heart failure Dyspnea on exertion Orthopnea Shortness of breath Palpitation

34. Physical Findings Tachypnea and retractions S3 and occasionally S4 gallops may be present and are important signs of impaired ventricular function If the right or left ventricular dilation is severe, auscultation may reveal murmurs of functional mitral or tricuspid insufficiency

35. Physical Findings Signs of low cardiac output Pericardial friction rub and effusion may become evident in some patients with myopericarditis A widely inflamed heart shows the classic signs of ventricular dysfunction including the following: ▫Jugular venous distention ▫Bibasilar crackles ▫Ascites ▫Peripheral edema

36. Causes Infectious Toxic Immunologic

37. Infectious Causes Viral myocarditis is the most common ▫Parvovirus B19, 36.6% ▫Enterovirus, 32.6% ▫Human herpesvirus 6 (HHV-6), 10.5% ▫Adenovirus, 8.1% ▫Co-infection with HHV-6 and parvovirus B19, 12.6% HIV

38. Infectious Causes Bacterial causes ▫Most common worldwide is Diphtheria ▫Streptococcal and staphylococcal species and Bartonella, Brucella, Leptospira, and Salmonella species can spread to the myocardium as a consequence of severe cases of endocarditis Chagas disease Parasitic myocarditis from trypanosomiasis

39. Toxic Causes Numerous medications (eg, lithium, doxorubicin, cocaine, numerous catecholamines, acetaminophen) may exert a direct cytotoxic effect on the heart Zidovudine (AZT) has been associated with myocarditis

40. Toxic causes Environmental toxins include lead, arsenic, and carbon monoxide Wasp and scorpion stings and spider bites, specifically black widows, may cause myocarditis Radiation therapy

41. Immunologic Etiology Connective tissue disorders ▫Systemic lupus erythematosus (SLE) ▫Rheumatoid arthritis ▫Scleroderma ▫Dermatomyositis Idiopathic inflammatory and infiltrative disorders such as Kawasaki disease, sarcoidosis, and giant cell arteritis may be a cause

42. Differential Diagnoses Acute Coronary Syndrome Pneumonia Congestive Heart Failure Aortic Dissection Pulmonary Embolism Esophageal Perforation, Rupture and Tears Viral syndrome

43. Diagnostic Studies EKG CXR Cardiac enzymes Echo MRI with contrast Cardiac catheterization Other tests

44. EKG Classical triad ▫Sinus tachycardia (>100 in a child; >120 in an infant; >150 in a neonate) ▫Low voltage complexes ▫ST segment and T wave changes Other abnormalities like, varying AV blocks, bundle branch blocks, both supraventricular and ventricular arrhythmias and an even an anterior wall myocardial infarction pattern

46. Chest Radiograph Typically include cardiomegaly, although heart size may be normal Pulmonary vascular congestion is often present

47. Cardiac Enzymes Elevation reflects myocardial necrosis Seen in some patients with myocarditis Experimental and clinical findings in adults suggest that elevations of cardiac troponin I or T (cTnI or cTnT) levels may be more common than CK-MB elevations in patients with biopsy- proven myocarditis

48. Echocardiography Enlarged Left Ventricular (LV) dimensions, left atrial enlargement and impaired ejection fraction (EF) and shortening fraction Normal EF in children is 64+4% 2D echo reveals a large, hypo contractile LV which is globular, with thin walls, mild pericardial effusion and occasional regional wall motion abnormalities

49. MRI Said to pick up earliest abnormality in Myocarditis Document the location and extent of inflammation Gadolinium enhancement was greater in patients with myocarditis than in normal controls

50. Cardiac Catheterization Reveals depressed cardiac index, elevated left ventricular end diastolic pressure, and elevated mean atrial pressure Angiography shows decreased left ventricular function with or without mitral regurgitation Main purpose is to obtain samples by endomyocardial biopsy (EMB) for pathologic and microbiologic analysis

51. Endomyocardial Biopsy (EMB) Gold standard for the diagnosis of myocarditis Dallas criteria ▫Active myocarditis is defined as "an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of the ischemic damage associated with coronary heart disease"

52. EMB Dallas criteria ▫Borderline myocarditis is the term used if lymphocytic infiltration is present without myocyte destruction ▫Ongoing Myocarditis – both inflammation and necrosis present. ▫Resolving Myocarditis – inflammation may be present; cell necrosis not ▫Resolved Myocarditis – No inflammation / cell necrosis.

53. EMB The American Heart Association, the American College of Cardiology, and the European Society of Cardiology released a scientific statement on the role of EMB ▫Limited data are available on EMB in children ▫EMB is reasonable in the setting of unexplained cardiomyopathy in children. ▫Indications include fulminant or acute unexplained heart failure, cardiac transplant rejection monitoring, certain unexplained arrhythmias, and idiopathic dilated cardiomyopathy

54. Treatment Mainstays of therapy for acute or fulminant myocarditis are monitoring, supportive care, and standard regimens for heart failure Patients should be monitored in a pediatric intensive care unit

55. Treatment of Heart Failure In the acute phase, diuretics, afterload reducing agents, and inotropic drugs are used to treat heart failure Dopamine, dobutamine, and milrinone are used to prevent circulatory collapse in the case of acute fulminant myocarditis

56. Treatment of Heart Failure Mechanical ventilation ECMO Ventricular Assist Device For patients who progress from acute myocarditis to chronic heart failure, diuretics, angiotensin inhibitors, digoxin, and aldosterone inhibitors (ie, spironolactone) are well-accepted therapies

57. Anti-arrhythmic Drugs Most antiarrhythmic drugs have negative inotropic activity and may therefore worsen cardiac function and lead to acute hemodynamic instability Should be used only when the expected benefit exceeds the risk, and only in consultation with a pediatric cardiologist

58. Immunosuppressive Therapy Myocardial damage in infectious myocarditis is thought to be due to both direct viral damage and the immune response to infection. ▫Myocarditis Treatment Trial:  111 patients with a histopathologic diagnosis of myocarditis and a left ventricular ejection fraction (LVEF) of less than 45 percent were randomly assigned to receive conventional therapy alone or immunosuppression with either cyclosporine or azathioprine for 28 weeks [7]. There was no difference in outcome in the two treatment groups.

59. Immunosuppressive Therapy Corticosteroids ▫ Case series and a small trial are inconclusive with respect to the beneficial effects of prednisone and/or other immunosuppressive agents (azathioprine, cyclosporine) on left ventricular function and ventricular arrhythmias in children with myocarditis, but definitive data are lacking

60. Immunosuppressive Therapy IVIG ▫use is supported by experimental data in which polyclonal immunoglobulin protects against myocardial or arterial damage in mouse models of viral and autoimmune myocarditis ▫no randomized controlled trials of IVIG for the treatment of myocarditis in children have been reported, some clinical evidence suggests it may be beneficial

61. Pain control Narcotic analgesic Avoid NSAIDs which are relatively contraindicated in this condition

62. PROGNOSIS Most cases are believed to be clinically silent and resolve spontaneously without sequelae Patients who present with CHF experience morbidity and mortality based on the degree of left ventricular dysfunction. Patients who do not fully recover cardiac function may develop dilated cardiomyopathy.

63. OUTPATIENT FOLLOW UP Recovered patients should have restricted activity for 6 months because rapid return to activity has provoked recurrent inflammation in animal models Follow-up visits with a cardiologist