Cardiology Cardiology PresentationPresentation

Myocarditis - A Review Myocarditis - A Review of Management in of Management in

PaediatricsPaediatrics

Case 1Case 1 Three month old female, HIV IC2 but not Three month old female, HIV IC2 but not

yet on HAART, admitted on the 1/7/07 with yet on HAART, admitted on the 1/7/07 with a 4 day history of a 4 day history of

- cough- cough

- shortness of breath- shortness of breath

- diarrhoea- diarrhoea Birth history: Born at term at a clinic - Birth history: Born at term at a clinic -

3200g3200g Past medical history: previous cough Past medical history: previous cough

treated at a peripheral hospitaltreated at a peripheral hospital

On ExaminationOn Examination

Anthropometry: wt 4.9kg ( =10Anthropometry: wt 4.9kg ( =10thth););

Length 57cm ( =10Length 57cm ( =10thth)) Afebrile; RR 80/min; PR 140bpm; Afebrile; RR 80/min; PR 140bpm;

oxygen saturation 58% on nasal oxygen saturation 58% on nasal oxygenoxygen

Dusky in colour, 5% dehydration,Dusky in colour, 5% dehydration,

generalised significant generalised significant lymphadenopathylymphadenopathy

Examination continued:Examination continued: Chest: Severe distress with subcostal and Chest: Severe distress with subcostal and

intercostal recession; harsh breath sounds intercostal recession; harsh breath sounds bilaterally with soft crackles at bases; bilaterally with soft crackles at bases; bronchial breathing RUL, anteriorbronchial breathing RUL, anterior

CVS: All pulses palpable; Apex beat not CVS: All pulses palpable; Apex beat not displaced; Normal S1 and S2; no gallop butdisplaced; Normal S1 and S2; no gallop but

tachycardictachycardic Abdomen: Soft not distended; 2cm hepar Abdomen: Soft not distended; 2cm hepar

and and

tip of spleentip of spleen CNS: IrritableCNS: Irritable

CXR: enlarged CTR of 69%CXR: enlarged CTR of 69%

RUL and LUL consolidationRUL and LUL consolidation

“ “globular” heartglobular” heart Blood investigations:Blood investigations:

1.1. FBC 47.7/9.1/408FBC 47.7/9.1/408

2.2. CRP 4.3CRP 4.3

3.3. U+E 135/6.6/94/7/7.5/50U+E 135/6.6/94/7/7.5/50

4.4. CK 704CK 704

5.5. CKMB 16.9%CKMB 16.9%

6.6. Troponin T 0.05Troponin T 0.05

7.7. Blood culture grew Strep pneumoniaeBlood culture grew Strep pneumoniae

8.8. LP clearLP clear Patient commenced on ampicillin and Patient commenced on ampicillin and

gentamicin and PCP treatment (was later gentamicin and PCP treatment (was later changed to cefotaxime)changed to cefotaxime)

Serial cardiac enzymes done:Serial cardiac enzymes done:

2/7/2007: CK 606; CKMB 44%; Trop T <0.032/7/2007: CK 606; CKMB 44%; Trop T <0.03

3/7/2007: CK 514; CKMB 100%; Trop T 3/7/2007: CK 514; CKMB 100%; Trop T <0.03<0.03

5/7/2007: CK 680; CKMB 59%; Trop T <0.035/7/2007: CK 680; CKMB 59%; Trop T <0.03 Cardiologists consulted on 2/7/2007 and an Cardiologists consulted on 2/7/2007 and an

echo was done : LV function decreasedecho was done : LV function decreased

Normal coronariesNormal coronaries

Normal intracardiac anatomyNormal intracardiac anatomy Digoxin was addedDigoxin was added Patient demised on 6/7/07Patient demised on 6/7/07

Case 2Case 2 2 month old female, ex-prem at 32/40, 2 month old female, ex-prem at 32/40,

admitted to hospital on 2/7/07 with history admitted to hospital on 2/7/07 with history of:of:

- cough and blocked nose- cough and blocked nose - fever- fever - vomited once- vomited once Birth history: Born in hospital at 32/40Birth history: Born in hospital at 32/40 Birthweight of 2750gBirthweight of 2750g Normal deliveryNormal delivery Past medical history: Admitted to hospital Past medical history: Admitted to hospital

one week previously with bronchopneumoniaone week previously with bronchopneumonia

ExaminationExamination Anthropometry: wt 4.3kg; length 58 cm = 50Anthropometry: wt 4.3kg; length 58 cm = 50thth

Vital signs: Temp 38.5; PR 230bpm; RR Vital signs: Temp 38.5; PR 230bpm; RR 100/min100/min

General: No lymphadenopathy, 10% General: No lymphadenopathy, 10% dehydrated, pallordehydrated, pallor

CVS: TachycardicCVS: Tachycardic

Apex beat 4Apex beat 4thth interspace, mid-clavicular interspace, mid-clavicular line; normal heart sounds; no gallopline; normal heart sounds; no gallop

Chest: Acidotic breathing with harsh breath Chest: Acidotic breathing with harsh breath soundssounds

Abdomen: Soft; no organomegalyAbdomen: Soft; no organomegaly CNS: Increased tone globallyCNS: Increased tone globally

Initial Investigations:Initial Investigations:

FBC 17.7/10.1/429FBC 17.7/10.1/429

CRP 29.1CRP 29.1

U+E 151/5/109/11/10.9/94U+E 151/5/109/11/10.9/94

HIV negativeHIV negative

CK 352CK 352

CKMB 46.9%CKMB 46.9%

Trop T 0.21Trop T 0.21 Pt was commenced on Tazocin and Pt was commenced on Tazocin and

AmikacinAmikacin Slow rehydrationSlow rehydration

Cardiologists consulted on 2/7/07 and an Cardiologists consulted on 2/7/07 and an echo was done: echo was done:

- Poor LV function - Poor LV function - Normal intracardiac anatomy- Normal intracardiac anatomyAssessment of probable myocarditis was Assessment of probable myocarditis was

made on basis of poor LV function, and made on basis of poor LV function, and Polygam was ordered as well as digoxinPolygam was ordered as well as digoxin

Repeat echo done 3 days later showed Repeat echo done 3 days later showed significant improvement in LV functionsignificant improvement in LV function

Discharged home on 8/7/07 on digoxinDischarged home on 8/7/07 on digoxin

Trend of cardiac Trend of cardiac enzymesenzymes

2/72/7 3/73/7 5/75/7 6/76/7 7/77/7 9/79/7

CKCK 352352 32373237 13141314 380380 277277 9696

CKMCKMBB

46.946.9%%

6.5%6.5% 11%11% 7.6%7.6% 10.810.8%%

Trop Trop TT

0.210.21 0.270.27 <0.0<0.033

<0.0<0.033

<0.0<0.033

<0.0<0.033

MyocarditisMyocarditis

Despite three decades of study, the Despite three decades of study, the diagnosis and management remain diagnosis and management remain controversial.controversial.

The exact incidence and prevalence The exact incidence and prevalence remain unknown.remain unknown.

Clinical presentation variesClinical presentation varies Most patients are asymptomatic and Most patients are asymptomatic and

recover without treatmentrecover without treatment

So why then should So why then should physicians concern physicians concern themselves with a disease themselves with a disease that is clinically uncommon, that is clinically uncommon, diagnostically challenging diagnostically challenging and that has an excellent and that has an excellent recovery?!recovery?!

Myocarditis represents a clinically Myocarditis represents a clinically and pathogenetically highly variable and pathogenetically highly variable disease entity.disease entity.

Fulminant disease Fulminant disease acute heart acute heart failure and arrhythmiasfailure and arrhythmias

Some patients are asymptomaticSome patients are asymptomatic However, asymptomatic myocarditis However, asymptomatic myocarditis

may be a cause of unexplained may be a cause of unexplained deaths in 1% of casesdeaths in 1% of cases

Causes of myocarditisCauses of myocarditisVirusesViruses:: Enteroviruses Enteroviruses Influenza A and BInfluenza A and B AdenovirusAdenovirus Herpes Herpes HIVHIVBacteria:Bacteria: Beta-hemolytic Streptococcus Beta-hemolytic Streptococcus Corynebacterium diphtheriaCorynebacterium diphtheria Borrelia burgdorferiBorrelia burgdorferi Enterococcus sppEnterococcus spp Chlamydia psittaciChlamydia psittaci Neisseria meningitidisNeisseria meningitidis Mycoplasma pneumoniaMycoplasma pneumonia Staphylococcus aureusStaphylococcus aureus

ProtozoaProtozoa: Trypanosoma cruzii: Trypanosoma cruzii Toxoplasma gondiToxoplasma gondiHelminthsHelminths: Trichinella spiralis: Trichinella spiralis EchinococcusEchinococcusAutoimmunityAutoimmunity: Infection associated: Infection associated Auto-immune disease associatedAuto-immune disease associated Primary autoimmunityPrimary autoimmunityHypersensitivityHypersensitivity: Penicillins: Penicillins MethyldopaMethyldopa SulfamethoxazoleSulfamethoxazoleToxicity:Toxicity: Catecholamines Catecholamines CocaineCocaine Ethanol Ethanol

PathogenesisPathogenesis

Three phases:Three phases:

Viral ReplicationViral Replication

Autoimmune injuryAutoimmune injury

Dilated cardiomyopathy Dilated cardiomyopathy

Phase 1Phase 1

Viral replicationViral replication Cardiotropic RNA viruses are taken into Cardiotropic RNA viruses are taken into

myocytes by receptor-mediated myocytes by receptor-mediated endocytosis.endocytosis.

Directly translated intracellularly to produce Directly translated intracellularly to produce viral protein.viral protein.

Virus infection directly contributes to Virus infection directly contributes to cardiac tissue destruction by cleaving the cardiac tissue destruction by cleaving the cytoskeleton protein dystrophin, leading to cytoskeleton protein dystrophin, leading to a disruption of the dystrophin-glycoprotein a disruption of the dystrophin-glycoprotein complex.complex.

Phase 2Phase 2

AutoimmunityAutoimmunity Phase 1 concludes with activation of the Phase 1 concludes with activation of the

host system.host system. Ideally, the immune system should down-Ideally, the immune system should down-

regulate to a resting state once viral regulate to a resting state once viral proliferation is controlled.proliferation is controlled.

If host immune activation continues If host immune activation continues unabated unabated autoimmune disease. autoimmune disease.

T cells target the host’s own tissue through T cells target the host’s own tissue through molecular mimicry.molecular mimicry.

Phase 3Phase 3

Dilated CardiomyopathyDilated Cardiomyopathy Re-modelling mechanisms lead to dilated Re-modelling mechanisms lead to dilated

cardiomyopathy (DCM)cardiomyopathy (DCM).. The persistent myocyte viral gene The persistent myocyte viral gene

expression expression progressive DCM. progressive DCM. Cytokines: activate matrix Cytokines: activate matrix

metalloproteinases (gelatinase, collagenase, metalloproteinases (gelatinase, collagenase, elastases).elastases).

Clinical PresentationClinical Presentation

Asymptomatic to cardiogenic shock.Asymptomatic to cardiogenic shock. May include a viral prodrome of fevers, May include a viral prodrome of fevers,

myalgias, respiratory symptoms or myalgias, respiratory symptoms or gastroenteritis.gastroenteritis.

May present with rapidly deteriorating LV May present with rapidly deteriorating LV function or arrhythmias and heart block.function or arrhythmias and heart block.

DiagnosisDiagnosis

Acute myocarditis is defined histologically as Acute myocarditis is defined histologically as inflammation of the myocardium with associated inflammation of the myocardium with associated myocellular necrosis.myocellular necrosis.

Gold Standard is endomyocardial biopsy.Gold Standard is endomyocardial biopsy. Previously Dallas criteria were used, now WHO/ Previously Dallas criteria were used, now WHO/

International Society and Federation of Cardiology International Society and Federation of Cardiology Task Force define: Task Force define:

- Active myocarditis: > 14 leucocytes/mm with - Active myocarditis: > 14 leucocytes/mm with necrosis and degenerationnecrosis and degeneration

- Chronic myocarditis >14 leucocytes/mm but no - Chronic myocarditis >14 leucocytes/mm but no necrosis or degenerationnecrosis or degeneration

Further classified according to inflammatory Further classified according to inflammatory infiltrate i.e. neutrophils, monocytes and infiltrate i.e. neutrophils, monocytes and macrophages in the acute stage, with lymphocytes macrophages in the acute stage, with lymphocytes and fibroblasts in the later stages.and fibroblasts in the later stages.

Diagnosis continued:Diagnosis continued: Cardiac biomarkers i.e. creatine kinase and Cardiac biomarkers i.e. creatine kinase and

troponin T and I are routinely measuredtroponin T and I are routinely measured CKMB is not useful due to low predictive CKMB is not useful due to low predictive

value.value. Lauer et al reported 28 of 80 patients (35%) Lauer et al reported 28 of 80 patients (35%)

with suspected myocarditis had elevated with suspected myocarditis had elevated troponin levels.troponin levels.

Trop T > 0.1ng/mL had a sensitivity of 53% Trop T > 0.1ng/mL had a sensitivity of 53% and a specificity of 94%and a specificity of 94%

ESR found to have low sensitivity and ESR found to have low sensitivity and specificity.specificity.

Echo changes i.e. LV dysfunction (in 69%), Echo changes i.e. LV dysfunction (in 69%), and segmental wall motion abnormalities and segmental wall motion abnormalities (64%), do not differentiate myocarditis from (64%), do not differentiate myocarditis from other cardiomyopathies.other cardiomyopathies.

Management of myocarditis

Management is dictated by clinical signs Management is dictated by clinical signs and symptoms.and symptoms.

MANY proposed therapies, most have only MANY proposed therapies, most have only a theoretical basis. Some have been a theoretical basis. Some have been tested in animal modelstested in animal models

Conventional heart failure therapy is Conventional heart failure therapy is currently the only accepted therapy for currently the only accepted therapy for myocarditis including ACE inhibitors, myocarditis including ACE inhibitors, angiotensin receptor blocking agents, angiotensin receptor blocking agents, diuretics, diuretics, ββ-blockers or amiodarone. -blockers or amiodarone.

Diet and LifestyleDiet and Lifestyle

Restrict salt intake to 2-3g of sodium per Restrict salt intake to 2-3g of sodium per dayday

Exercise especially during the acute phase Exercise especially during the acute phase of Coxsackie virus B3 murine myocarditis of Coxsackie virus B3 murine myocarditis enhances viral replication rate, enhances enhances viral replication rate, enhances immune mechanisms and increases immune mechanisms and increases inflammatory lesions and necrosis.inflammatory lesions and necrosis.Resumption of physical activity can take Resumption of physical activity can take place within 2 months of the acute place within 2 months of the acute disease.disease.

Controversial Therapy:Controversial Therapy: Immunosuppresive (IS) Therapy Immunosuppresive (IS) Therapy

The idea that autoimmune mechanisms play an The idea that autoimmune mechanisms play an important role in the pathogenesis of myocarditis important role in the pathogenesis of myocarditis and post-viral cardiomyopathy suggests the and post-viral cardiomyopathy suggests the potential benefits of immunosuppressives.potential benefits of immunosuppressives.

The Myocarditis Treatment Trial studied the effect The Myocarditis Treatment Trial studied the effect of IS on ventricular function in 111 pts with of IS on ventricular function in 111 pts with myocarditis (Dallas criteria) and LVEF <45%myocarditis (Dallas criteria) and LVEF <45%

Patients were randomised with some on Patients were randomised with some on prednisone and cyclosporine, or prednisone and prednisone and cyclosporine, or prednisone and azathioprine , or to conventional therapy for 6 azathioprine , or to conventional therapy for 6 months.months.

Both IS and control groups showed an increase in Both IS and control groups showed an increase in LVEF from 25% to 34% at 28 weeksLVEF from 25% to 34% at 28 weeks

No survival differenceNo survival difference Conclusion: selected pts might benefit from Conclusion: selected pts might benefit from

appropriately timed ISappropriately timed IS

However the study included patients with However the study included patients with symptom duration as long as 2 years! Can symptom duration as long as 2 years! Can they extrapolate the results for a paediatric they extrapolate the results for a paediatric population with a much shorter symptom population with a much shorter symptom duration?duration?

Latham et al studied the effect of prednisone Latham et al studied the effect of prednisone on survival in 52 pts with new onset DCM. on survival in 52 pts with new onset DCM.

Patients were randomised to prednisone or no Patients were randomised to prednisone or no prednisone for 3 months.prednisone for 3 months.

Myocardial inflammation resolved in all Myocardial inflammation resolved in all patients and there was no survival difference patients and there was no survival difference at 2 years.at 2 years.

One matched-cohort trial showed a benefit of One matched-cohort trial showed a benefit of prednisone with azathioprine or cyclosporine prednisone with azathioprine or cyclosporine in childrenin children

The role of immunosuppressive therapy in The role of immunosuppressive therapy in lymphocytic myocarditis remains controversial lymphocytic myocarditis remains controversial due to limitations in research field:due to limitations in research field:

1.1. Low incidence of symptomatic myocarditisLow incidence of symptomatic myocarditis

2.2. Myocarditis varies in presentation – wide Myocarditis varies in presentation – wide spectrum of diseasespectrum of disease

3.3. Immunosuppressive agents influence Immunosuppressive agents influence inflammatory mediators differently i.e. effect inflammatory mediators differently i.e. effect of prednisone vs intravenous immune globulinof prednisone vs intravenous immune globulin

4.4. Numerous viruses implicated with different Numerous viruses implicated with different treatment response i.e. adenovirus-positive treatment response i.e. adenovirus-positive myocarditis may benefit from Ig treatment.myocarditis may benefit from Ig treatment.

5. Myocarditis affects persons of all ages, 5. Myocarditis affects persons of all ages, and disease and treatment response vary and disease and treatment response vary between children and adults.between children and adults.

6. Previous trials show an improvement in 6. Previous trials show an improvement in myocarditis with conservative treatment. myocarditis with conservative treatment. Therefore difficult to interpret the Therefore difficult to interpret the effectiveness of IS in studies without a effectiveness of IS in studies without a control group.control group.

7. The validity of the historical gold standard 7. The validity of the historical gold standard of endomyocardial biopsy as the basis of of endomyocardial biopsy as the basis of diagnosis if conservative therapies are the diagnosis if conservative therapies are the standard treatment?standard treatment?

Randomised Treatment Trial on Randomised Treatment Trial on Myocarditis (ESETCID)Myocarditis (ESETCID)

The ESETCID is the 1The ESETCID is the 1stst trial of immune therapy for trial of immune therapy for myocarditis that uses different treatment regimens myocarditis that uses different treatment regimens based on the causes of myocardial inflammation based on the causes of myocardial inflammation

The ESETCID is an ongoing prospective, The ESETCID is an ongoing prospective, randomised, placebo-controlled trial studying the randomised, placebo-controlled trial studying the effects of immune therapy on ventricular function effects of immune therapy on ventricular function and exercise capacity in pts with biopsy-proven and exercise capacity in pts with biopsy-proven myocarditis and LVEF <45%myocarditis and LVEF <45%

Three treatment arms:Three treatment arms:

- acute viral infection - acute viral infection no IS is given no IS is given

Enterovirus-positive patients treated Enterovirus-positive patients treated with interferon-alphawith interferon-alpha

CMV and adenovirus+ patients are CMV and adenovirus+ patients are treated with immunoglobulinstreated with immunoglobulins

Autoreactive myocarditis is treated Autoreactive myocarditis is treated with azathioprine and prednisone for with azathioprine and prednisone for 6 months6 months

Human immunoglobulin for Human immunoglobulin for IV use (IGIV)IV use (IGIV)

Appropriate use can be life-savingAppropriate use can be life-saving IGIV is produced from human plasma using IGIV is produced from human plasma using

a number of preparatory steps a number of preparatory steps supply is supply is finitefinite

Can lead to numerous side effects and Can lead to numerous side effects and potential adverse consequencespotential adverse consequences

Currently Currently only 6only 6 clinical indications for clinical indications for which IGIV has been licensed by the United which IGIV has been licensed by the United States Food and Drug Administration (FDA):States Food and Drug Administration (FDA):

1)1) Primary immunodeficiency or primary humoral Primary immunodeficiency or primary humoral immunodeficiencyimmunodeficiency

2)2) Idiopathic thrombocytopenic purpura Idiopathic thrombocytopenic purpura when a when a rapid increase in platelet count is neededrapid increase in platelet count is needed

3)3) Kawasaki disease Kawasaki disease prevention of coronary prevention of coronary artery aneurysmsartery aneurysms

4)4) B-cell chronic lymphocytic leukemia B-cell chronic lymphocytic leukemia prevention of bacterial infections in patients prevention of bacterial infections in patients with hypogammaglobulinemia or recurrent with hypogammaglobulinemia or recurrent bacterial infectionsbacterial infections

5)5) HIV infection - indicated for HIV positive HIV infection - indicated for HIV positive paediatric patients to decrease the frequency of paediatric patients to decrease the frequency of serious and minor bacterial infectionsserious and minor bacterial infections

6)6) Bone marrow transplantation Bone marrow transplantation patients older patients older than 20 years of age to decrease septicemia and than 20 years of age to decrease septicemia and acute GVHD in the 1acute GVHD in the 1stst 100 days post transplant. 100 days post transplant.

ProductsProducts Products are produced from plasma from Products are produced from plasma from

whole blood donations or from a pool of whole blood donations or from a pool of plasmapheresis donors.plasmapheresis donors.

Tests for Hep B s-Ag, HIV p24 antigen and Tests for Hep B s-Ag, HIV p24 antigen and antibodies to HIV, Hep C and syphilis are antibodies to HIV, Hep C and syphilis are done.done.

IGIV is supplied in lyophilized powder or as a IGIV is supplied in lyophilized powder or as a premixed solution with final concentration of premixed solution with final concentration of IgG of 3%, 5%, 6%, 10% or 12%IgG of 3%, 5%, 6%, 10% or 12%

The IgA content varies from <0.4ug/mL to The IgA content varies from <0.4ug/mL to 720ug/mL720ug/mL

DoseDose

Dose for antibody replacement is 0.3 Dose for antibody replacement is 0.3 – 0.6g/kg per month given every 2 – – 0.6g/kg per month given every 2 – 4 weeks IVI.4 weeks IVI.

For other uses a dose of 0.4g/kg per For other uses a dose of 0.4g/kg per day for 5 daysday for 5 days

For a rapid course For a rapid course 1 to 2 g/kg over 1 to 2 g/kg over 1 or 2 days1 or 2 days

Adverse ReactionsAdverse Reactions Most are mild i.e. back or abdominal pain, Most are mild i.e. back or abdominal pain,

nausea, rhinitis, asthma, chills, low grade nausea, rhinitis, asthma, chills, low grade fever, myalgias or headache.fever, myalgias or headache.

Slowing or stopping the infusion for several Slowing or stopping the infusion for several minutes will reverse the symptoms.minutes will reverse the symptoms.

Adverse reactions are more likely in 1Adverse reactions are more likely in 1stst infusion of IGIV or if there has been a recent infusion of IGIV or if there has been a recent bacterial infectionbacterial infection

More serious reactions include anaphylaxis, More serious reactions include anaphylaxis, Stevens-Johnson syndrome, hypotension, MI, Stevens-Johnson syndrome, hypotension, MI, thrombosis, hemolysis, stroke, ARDS, thrombosis, hemolysis, stroke, ARDS, seizures, pulmonary oedema and acute seizures, pulmonary oedema and acute bronchospasm.bronchospasm.