Myocarditis in children

MYOCARDITIS IN CHILDRENDr. Pradeep Singh

TO BE COVER…..• DEFINITION• EPIDEMIOLOGY AND ETIOLOGY• PATHOPHYSIOLOGY• CLINICAL PRESENTATION• DIFFERENTIAL DIAGNOSIS• DIAGNOSIS• TREATMENT• PROGNOSIS

definition• Acute myocarditis -inflammation, necrosis, or

myocytolysis and caused by many infectious, conn. tissue, granulomatous, toxic, or idiopathic processes affecting the myocardium with or without associated systemic manifest of the disease process or involvement of the endocardium or pericardium

Nelson Textbook of Pediatrics, 18th ed.• Acute fulm myocarditis - myocellular necrosis,

lead to sudden onset of heart failure, arrhythmia and sudden death

•True incidence is difficult to determine

•Incidence of biopsy documented myocarditis in patients with unexplained heart failure is 9.6%. Progress in Cardiovascular Diseases 52 (2010) 274–288• 29 children with DCM -38% have histopatho evidence of ‘definite’ or

-borderline’ myocarditis accord to the Dallas criteria.

Cardiac symposium on Viral myocarditis in childhood:Juan Pablo Kaski , Michael Burch

Epidemiology

ETIOLOGY

• 624 patients with -biopsy-proven myocarditis (66%)

-borderline myocarditis (34%). - viral genome of adenovirus-enterovirus-cmv in dec freq

• detected in 239 (38%)

Bowles NE, et al Detection of viruses in myocardial tissues by PCR: J Am Coll Cardiol. 2003;42:466–472.

Adenovirus - common cause of myocarditis

DENGUE VIRUS – CAUSE OF MYOCARDITIS

• DHF/DSS- poor LVEF • Worsened by the hypotension and shock

• Sinus node dysfunction reported

Wali JP, Biswas A, Chandra S, Malhotra A, Aggarwal P, Handa R, et al. Cardiac involvement in dengue haemorrhagic fever. Int J Cardiol 1998;64:31-

RISK FACTORS• Increased risk of virus-induced myocarditis• The course is hyperacute

– Young males – pregnant women– children ( neonates) – immunocompromised patients – selenium deficiency

-vitamin E deficiency Beck MA, Levander OA, Handy J: Selenium deficiency and viralinfection. J Nutr 2003;133(5 Suppl 1):1463-1467

PATHOPHYSIOLOGY

Toxins & hypersensitivity reactions

• Direct toxic effect on the heart or by hypersensitivity reactions •Hypersensitivity reactions – eosinophilic myocarditis

•Responds to withdrawal of the offending medication

myocardial injury

cardiac enlargement and an inc. in the vent end-diastolic volu.

myocardium is unable to respond to these stimuli reduced cardiac outputMoss and Adams' Heart Disease in Infants, Children, and Adolescents: Including the Fetus and Young Adults, 7th Edition

Preserve systemic blood flow via vasoconstriction & elevated afterload. intact sympathetic nervous system input

tachycardia and diaphoresis,CHF

prog ventricular end-diastolic volu

left atrial pres pulmonary edema.

Concomitantly

All cardiac chambers dilate(LV)

Dilation causes poor ventricular function

Worsening pulmonary edema & cardiac function.

Stretching of the mitral annulus & mitral regurg

Further increasing left atrial volume & pressure

Moss and Adams' Heart Disease in Infants, Children, and Adolescents: Including the Fetus and Young Adults, 7th Edition

Clinical features• Presentation in children varies according to

age.• Lesser the age ,poor prognosis• Newborns or infants- poor appetite, fever,

irritability or listlessness• Pallor and diaphoresis,Sudden death

• Mild cyanosis to sympts of CHF

Children and Adolescents

• Recent history of viral disease 10 to 14 days prior to presentation

•Lethargy, low-grade fever, pallor decreased appetite• Diaphoresis, palpitations, rashes, exercise intolerance

•Raised JVP,Rales,with resting techycardia

• Respiratory symptoms become predominant; syncope or sudden death Moss and Adams' Heart Disease in Infants, Children, and Adolescents: Including the Fetus and Young Adults, 7th Edition

• Presentation at the emerg. department -Respiratory distress (68%); -Tachycardia (58%) - Lethargy (39%) -Hepatomegaly (36%) -Abnormal heart sounds, murmur (32%); -Fever (30%)

Progress in Cardiovascular Diseases 52 (2010) 274–288 Lori A. Blauwet, Leslie T. Cooper†

Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN

DIFFERENTIAL DIAGNOSIS

Newborn and Infant Child

• Sepsis • Hypoxia • Hypoglycemia• Hypocalcemia• Idiopathic dialated

cardiomyopathy• Endocardial

fibroelastosis• Anomalous left coronary

artery from Pulm artery

• Idiopathic dilated cardiomyopathy

• X-linked dilated cardiomyopathy

• Autosomal dominant dilated cardiomyopathy

• Endocardial fibroelastosis • Chronic tachyarrhythmia

• Pericarditis• Cerebral arteriovenous

malformation

Laboratory• CBC, Blood c/s• E.S.R, C-reactive protein and leukocyte count

are elevated BUT nonspecific• (TnI) or troponin T (TnT) are more common

than inc.CPK-MB with acute myocarditis

• In children, TnT have a specificity of 83% and a sensitivity of 71%

• Higher levels of TnT poor prognostic marker• Viral serology n viral PCR MyocarditisLori A. Blauwet, Leslie T. Cooper† Division of

Cardiovascular Diseases, Mayo Clinic, Rochester, MN

DISEASE NO. OF SAMPLES

NO. OF POSITIVE PCR SAMPLES

NO. OF PCR AMPLIMERS

MYOCARDITIS 624 239(38%) Adenovirus 142 (23%)Enterovirus 85 (14%)CMV 18 (3%)Parvovirus 6 (<1%)Influenza A 5 (<1%)HSV 5 (<1%)EBV 3 (<1%)RSV 1 (<1%)

DCM 149 30(20%) Adenovirus 18 (12%)Enterovirus 12 (8%

CONTROLS 215 3(1.4%) Enterovirus 1 (<1%)CMV 2 (<1%)

VIRAL GENOMES IN TRACHEAL SECRETION


newer markers serum Fas and Fas ligand on initial presentation asso.with increased mortality

IL-10 has a poor prognosis in fulminant myocarditis

Progress in Cardiovascular Diseases 52 (2010) 274–288 .Myocarditis,Lori A. Blauwet, Leslie T. Cooper†Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN

Electrocardiogram• Sensitivity is only 47%• Findings are nonspecific - PR depression, -Pathologic Q waves. -ST-segment elevation/ depression -T-wave changes

• Low QRS voltages (< 5mm in any precordial lead)

• New-onset supraventricular or ventricular arrhythmias in up to 55%

Chest x-ray• Cardiomegaly due to chamber dilatation,

pericardial effusion or both.

• Pulmonary venous congestion, interstitial

infiltrates• Pleural effusions.

Echocardiography• Chamber size, wall thickness,systolic diastolic

functions & intracavitary thrombi

• Rule out other causes of heart failure• LV systolic dysfunction is common • Rt ventricular dysfunction is relatively

uncommon• Rt vent dysfunction most powerful predictor of

death or need for cardiac transplantation in a series of 23 patients with biopsy-confirmed myocarditis

Mendes LA, Dec GW, Picard MH, et al: Right ventricular dysfunction: an independent predictor of adverse outcome inpatients with myocarditis. Am Heart J 1994;128:301-307.

• Segmental or global wall motion abnormalities

• Diastolic filling patterns are abnormal


Cardiac MRI• Intracellular and interstitial edema,hyperemia

and capillary leakage,necrosis and fibrosis

• symptomatic patients with clinical suspicion of myocarditis

• Diagnostic accuracy of 78%

Proposed cardiac MRI diagnostic criteria for myocarditis(Lake Louise Criteria )A. In clinically suspected myocarditis-consistent with myocardial inflammation if at least 2 of the following criteria are present:1.Regional or global myocardial signal intensity increase in T2- weighted images2. Increased global myocardial early enhancement ratio between myocardium and skeletal muscle in gadolinium-enhanced T1-weighted images

3. There is at least 1 focal lesion with non ischemic regional distribution in inversion recovery-prepared gadolinium-enhanced T1-weighted images (delayed enhancement)

Progress in Cardiovascular Diseases 52 (2010) 274–288 .Myocarditis,Lori A. Blauwet, Leslie T. Cooper†

Lake Louise Criteria contd..• B. Cardiac MRI study is consistent with

myocyte injury and/or scar caused by myocardial inflammation if criterion 3 is present

• C. A repeat cardiac MRI study between 1 to 2 weeks after the initial,cardiac MRI study is recommended if

• None of the criteria are present, but onset of symptoms is very recent and there is strong clinical evidence for myocardial inflammation One of the criteria is present

• D. The presence of LV dysfunction or pericardial effusion provides additional supportive evidence for myocarditis

Endomyocardial biopsy• Recommended in---1.Fulminant myocarditis- unexplained new-onset

CHF symptoms < 2 weeks in duration a/w - normal sized or dilated left ventricle -hemodynamic compromise2.Unexplained new onset CHF symptoms 2 weeks

to 3 months in duration a/w with a -dilated left ventricle -new ventricular arrhythmias, -high-degree AV heart block, or -failure to respond to usual care within 1 to 2

weeks

The Dallas criteria(1986)- based on the presence of histological evidence Four types of myocarditis are recognised: Active myocarditis- the presence of both myocyte degeneration or necrosis and definite cellular infiltrate, withor without fibrosis;

Borderline myocarditis-when there is a definite cellular infiltrate but no evidence of myocyte injury;

Persistent myocarditis- continued active myocarditison repeat EMB;

Resolving/resolved myocarditis, determined by diminished orabsent infiltrate with evidence of connective tissue healing

LIMITATIONS OF DALLAS CRITERIA

• Lack of prognostic value• Discrepancy with other markers of

viral infection and immune activation in the myocardium,

• Low sensitivity that is at least partly due to sampling error

World Health Organization (Marburg)

Classification

Cooper LT Jr. Myocarditis. N Engl J Med. 2009 Apr 9;360(15):1526-38.

First biopsy:

•Acute (active) myocarditis: a clear-cut infiltrate (diffuse, focal or confluent) of >14 leukocytes/mm Infiltrate quantified by immunohistochemistry. Necrosis or degeneration is compulsory;• fibrosis- absent or present and should be graded.

•Chronic myocarditis: Infiltrate of >14 leukocytes/mm2 (diffuse, focal or confluent), Quantified by immunohistochemistry. Necrosis or degeneration not + usually.

•No myocarditis: No infiltrating cells or <14 leukocytes/mm2.

Subsequent biopsies:

•Ongoing (persistent) myocarditis. Criteria as in acute or chronic myocarditis

•Resolving (healing) myocarditis. Criteria as in acute or chronic myocarditis, but the immunologic process is sparser than in the first biopsy.

•Resolved (healed) myocarditis. Corresponds to the Dallas classification

Expanded criteria for diagnosis of myocarditis•Suspected= 2 positive categories•Compatible = 3 positive categories•High probability = all 4 categories positive.

NOTE: Any matching feature in category = positive for category

Category I: symptoms:•Clinical heart failure•Fever•Viral prodrome•Fatigue•Dyspnoea on exertion•Chest pain•Palpitations•Pre-syncope or syncope

Category II: evidence of cardiac structural/functional perturbation in the absence of regional coronary ischaemia•Echo evidence•Regional wall motion abnormalities•Cardiac dilation•Regional cardiac hypertrophy•Troponin release•Troponin result has high sensitivity (>0.1 nanogram/mL)•+ve indium-111 antimyosin scintigraphy and normal coronary angiography or

-sence of reversible ischaemia on perfusion scan

Category III: cardiac MRI•Increased myocardial T2 signal on inversion recovery sequence•Delayed contrast enhancement following gadolinium- DTPA infusion.

Category IV: myocardial biopsy, pathologic or molecular analysis•Pathology findings compatible with Dallas criteria•Presence of viral genome by PCR or in situ hybridisation.

Treatment

•Stabilze the patient- ABC

•Any previously well child with a viral prodrome and non-specific organ dysfunction• A/w dysrhythmias, shock or acute heart failure

•Even in the absence of cardiomegaly

Early mechanical support can be very favourable

•Delay in diagnosis may result in poor outcome.

The Challenges of Prompt Identification and Resuscitation in Children with Acute Fulminant Myocarditis: Geethanjali Ramachandra; Lynn Shields et al Journal of Paediatrics and Child Health Vol: 46, No: 10, October, 2010

Heart failure therapy• Ac. myocarditis - standard heart failure therapy - diuretics-furosemide -ACE Inhibitor -captopril (1 to 3 mg/kg/dX8hrly

) enalapril (0.2 mg/kg/d x 12h)• Introduction of β-blockers such as bisoprolol,

metoprolol or carvedilol in clinically stable• Digoxin should be used with caution and only in

low doses in patients with viral myocarditis

Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 8th ed.

Antiviral therapy

• Data in humanbeing not available

• In the single case series of antiviral therapy use in humans with fulminant myocarditis, ribavirin therapy did not prove effective

• T/t with interferon b resulted in the elimination of the viral genomes and improved LVEF is in trials

Kuhl U, Pauschinger M, Schwimmbeck PL, et al. Interferon- b treatment eliminates cardiotropic viruses and improves LVF in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 2003;107:2793

Immunosuppressive therapy• Prednisone (2 mg/kg daily, tapered to 0.3 mg/kg

daily over a period of 3 mo) • Reduce myocardial inflammation and

improvedcardiac function. • Relapse -in some patient on discontinuation

• Beneficial in treating patients with chronic DCM unresponsive to standard heart failure therapy.

Nelson Textbook of Pediatrics, 18th ed.

• Prednisolone given 3-month duration

•44 prednisolone group & control group of 24children.

•Prednisolone-treated group increased EF > 40%

• Prednisolone improved EF and cure in persistent LVF

Acute Viral Myocarditis: Role of Immunosuppression: A Prospective Randomised Study Kalim U. Aziz; Najma Patel; et al Cardiology in the Young Vol: 20, No: 5, October, 8 2010

•No randomized controlled trials in children

•Case series shown that use of high-dose IVIG improved recovery of left ventricular function and better survival.

• Routine use of IVIG is not recommended in adults

•Consider in acute myocarditis in children

Role of iv Ig

Intravenous Ig for Severe Acute Myocarditis in Children• high-dose (2g/kg) IVIG in 13 children •12 children treated with only conventional therapy.

•Both groups had poor LVEF on admission.

The mortality rate was 8% in the IVIG treated children as compared to 46% in controls. Anwarul Haque, Samreen Bhatti et al, Indian paediatrics,volume 46,september17, 2009

report two children with fulminant myocarditis successfully treated with a 10-h infusion of high-dose IVIG.

I.V Ig inT/t of Acute Myocarditis in the Pediatric Population•IVIG is a/w improved recovery of left vent.

function•Better survival during the first year

Nancy A. Drucker, MD; Steven D. Colan, MD;(Circulation. 1994;89:252-257.)

Nancy A. Drucker, MD; Steven D. Colan, MD; Alan B. Lewis, MD; Alexa S. Beiser, PhD;David L. Wessel, MD; Masato Takahashi, MD; Annette L. Baker, RN, MSN;Antonio R. Perez-Atayde, MD; Jane W. Newburger, MD, MPH

•Patients with recent-onset DCM IVIG does not augment the improvement in LVEF .

• LVEF improved significantly during follow-up.

Controlled Trial of Intravenous Immune Globulin in recent-Onset Dilated Cardiomyopathy. Dennis M. McNamara, MD; Richard Holubkov, PhD; Randall C. Starling, MD; G. William Dec, MD Circulation. 2001;103:2254-2259.)

•Lupus Myocarditis: Marked Improvement in Cardiac Function after IVIg Therapy

• 18-year-old man of active lupus with worse cardiac systolic function who did not respond to pulse methylprednisolone and cyclophosphamide,

•Improved cardiac function after IVIg

• IVIg -dermatomyositis/polymyositis, Kawasaki dis, and viral myocarditis

Vikas Suri; S.Verma; Sanjay Jain etal PGIMER chandigarh Rheumatology International Vol: 30, No:11, September, 2010

Ant arrhythmic treatment•AV block & tachyarrhythmias treated with approp. medications• Placement of a temporary or permanent pacemaker

•Arrhythmias resolve after several weeks.

• Symptomatic or sustained vent tachycardia require antiarrhythmic therapy or

• Implantable cardioverter-defibrillator or cardiac transplantation if arrhythmias persist after

the acute inflammatory phase.

Patient with myocarditis

Stablize with

diuretics/vasodilator

Inotrope/balloon pump/VAD

Remodelling therapy(ACE/ARB-,

BETA BLOCKER

Immune Rx, consider bx,

Steroids/azathiopri/IFs

F/U repeat echoIf LVEF <35%-

CONSIDER AICD

Cardiac transplantationMechanical assist

unstable

stable

stable

unstable

unstable

unstable

stable

FUTURE TRENDS

•Sophora flavescens (SF) - viral hepatitis, cancer, viral myocarditis, gastrointestinal hemorrhage, and skin disease•SF up-regulates CYP3A expression. • Cetirizine- beneficial in viral myocarditis by suppressing expression of pro-inflammatory cytokines

•Antiviral Effect of Bosentan and Valsartan during Coxsackievirus B3 Infection of Human Endothelial Cells •CAR-downregulation in human umbilical vein endothelial cells (HUVEC) & helpful in viral myocarditis

•Cinnamaldehyde has antiviral effects on VMC & directly reduces the inflammation by inhibiting

the TLR4

Physical activity• Withdraw from competitive sports &

vigorous exercise >6months or longer OR• Recovery of left ventricular function.


Prognosis• fulm myocarditis-excellent long-term prognosis

complete recovery of LVF than patients with acute myocardit- after acute phase over

• 70 children with acute myocarditis - 73%had histologic resolution of myocarditis at 6 month- 96% survived to 1 year


Outcome of acute fulminant myocarditis in children•Diagnostic criteria- +sence of severe and acute heart failure; -LV dysfunction on echo - recent history of viral illness -no history of cardiomyopathy. •Results: 11 pt from 1998 to 2003, median age 0 to 9 yr. •LVEF was 22 at presentation

• Inotropic support required in 9 pt & 8 ventilated.• All patients received corticosteroid, IVIg in seven. •5 pt had arrest & revived in four. •F/U of 58.7 (33.8–83.1) months• 10 survivors are asymptomatic with normal LVEF

Heart 2006;92:1269-1273

Prognosis…..With severe left ventricular dysfunction

-25% progress to transplantation-50% develop chronic DCM - 25% recover spontaneously

• 41 children with acute myocarditis treated with immunosuppressive Rx,

• At 5 years, 3/4 th patients had complete recovery• 1/4th died or required cardiac transplantation

Gagliardi MG, Bevilacqua M, Bassano C, et al: Long term followup of children with myocarditis treated by immunosuppression and of children with dilated cardiomyopathy. Heart (British CardiacSociety) 2004;90:1167-1171.

THANKS

Taylor and Jennifer J. Kimberly Haladyn, Alejandro Floh, Joel A. Kirsh, GlennPediatrics 2007;120;1278-1285,

MOST COMMON • Viral- Adenovirus 9% to 39% of cases. • Enterovirus 71 (coxsackie B) hepatitis C

virus,herpes viruses (HHV-6) HIV,Parvovirus B 19• BACTERIAL-Coryne. Diphtheriae, Mycobac.

tuberculosis Strept A,Strept. pneumoniae• Spirochetal: Borrelia burgdorferi

• Hypoxia, hypothermia in neonates


Progress in Cardiovascular Diseases 52 (2010) 274–288 .Myocarditis,Lori A. Blauwet, Leslie T. Cooper†Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN

Healthcare

Myocarditis in children