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Cardiology Presentation Myocarditis - A Review of Management in Paediatrics.

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1 Cardiology Presentation Myocarditis - A Review of Management in Paediatrics

2 Case 1 Three month old female, HIV IC2 but not yet on HAART, admitted on the 1/7/07 with a 4 day history of Three month old female, HIV IC2 but not yet on HAART, admitted on the 1/7/07 with a 4 day history of - cough - cough - shortness of breath - shortness of breath - diarrhoea - diarrhoea Birth history: Born at term at a clinic - 3200g Birth history: Born at term at a clinic - 3200g Past medical history: previous cough treated at a peripheral hospital Past medical history: previous cough treated at a peripheral hospital

3 On Examination Anthropometry: wt 4.9kg ( =10 th ); Anthropometry: wt 4.9kg ( =10 th ); Length 57cm ( =10 th ) Length 57cm ( =10 th ) Afebrile; RR 80/min; PR 140bpm; oxygen saturation 58% on nasal oxygen Afebrile; RR 80/min; PR 140bpm; oxygen saturation 58% on nasal oxygen Dusky in colour, 5% dehydration, Dusky in colour, 5% dehydration, generalised significant lymphadenopathy generalised significant lymphadenopathy

4 Examination continued: Chest: Severe distress with subcostal and intercostal recession; harsh breath sounds bilaterally with soft crackles at bases; bronchial breathing RUL, anterior Chest: Severe distress with subcostal and intercostal recession; harsh breath sounds bilaterally with soft crackles at bases; bronchial breathing RUL, anterior CVS: All pulses palpable; Apex beat not displaced; Normal S1 and S2; no gallop but CVS: All pulses palpable; Apex beat not displaced; Normal S1 and S2; no gallop but tachycardic tachycardic Abdomen: Soft not distended; 2cm hepar and Abdomen: Soft not distended; 2cm hepar and tip of spleen tip of spleen CNS: Irritable CNS: Irritable

5 CXR: enlarged CTR of 69% CXR: enlarged CTR of 69% RUL and LUL consolidation RUL and LUL consolidation “globular” heart “globular” heart Blood investigations: Blood investigations: 1. FBC 47.7/9.1/408 2. CRP 4.3 3. U+E 135/6.6/94/7/7.5/50 4. CK 704 5. CKMB 16.9% 6. Troponin T 0.05 7. Blood culture grew Strep pneumoniae 8. LP clear Patient commenced on ampicillin and gentamicin and PCP treatment (was later changed to cefotaxime) Patient commenced on ampicillin and gentamicin and PCP treatment (was later changed to cefotaxime)

6 Serial cardiac enzymes done: Serial cardiac enzymes done: 2/7/2007: CK 606; CKMB 44%; Trop T <0.03 2/7/2007: CK 606; CKMB 44%; Trop T <0.03 3/7/2007: CK 514; CKMB 100%; Trop T <0.03 3/7/2007: CK 514; CKMB 100%; Trop T <0.03 5/7/2007: CK 680; CKMB 59%; Trop T <0.03 5/7/2007: CK 680; CKMB 59%; Trop T <0.03 Cardiologists consulted on 2/7/2007 and an echo was done : LV function decreased Cardiologists consulted on 2/7/2007 and an echo was done : LV function decreased Normal coronaries Normal coronaries Normal intracardiac anatomy Normal intracardiac anatomy Digoxin was added Digoxin was added Patient demised on 6/7/07 Patient demised on 6/7/07

7 Case 2 2 month old female, ex-prem at 32/40, admitted to hospital on 2/7/07 with history of: 2 month old female, ex-prem at 32/40, admitted to hospital on 2/7/07 with history of: - cough and blocked nose - cough and blocked nose - fever - fever - vomited once - vomited once Birth history: Born in hospital at 32/40 Birth history: Born in hospital at 32/40 Birthweight of 2750g Birthweight of 2750g Normal delivery Normal delivery Past medical history: Admitted to hospital one week previously with bronchopneumonia Past medical history: Admitted to hospital one week previously with bronchopneumonia

8 Examination Anthropometry: wt 4.3kg; length 58 cm = 50 th Anthropometry: wt 4.3kg; length 58 cm = 50 th Vital signs: Temp 38.5; PR 230bpm; RR 100/min Vital signs: Temp 38.5; PR 230bpm; RR 100/min General: No lymphadenopathy, 10% dehydrated, pallor General: No lymphadenopathy, 10% dehydrated, pallor CVS: Tachycardic CVS: Tachycardic Apex beat 4 th interspace, mid-clavicular line; normal heart sounds; no gallop Apex beat 4 th interspace, mid-clavicular line; normal heart sounds; no gallop Chest: Acidotic breathing with harsh breath sounds Chest: Acidotic breathing with harsh breath sounds Abdomen: Soft; no organomegaly Abdomen: Soft; no organomegaly CNS: Increased tone globally CNS: Increased tone globally

9 Initial Investigations: Initial Investigations: FBC 17.7/10.1/429 CRP 29.1 U+E 151/5/109/11/10.9/94 HIV negative CK 352 CKMB 46.9% Trop T 0.21 Pt was commenced on Tazocin and Amikacin Pt was commenced on Tazocin and Amikacin Slow rehydration Slow rehydration

10 Cardiologists consulted on 2/7/07 and an echo was done: Cardiologists consulted on 2/7/07 and an echo was done: - Poor LV function - Poor LV function - Normal intracardiac anatomy - Normal intracardiac anatomy Assessment of probable myocarditis was made on basis of poor LV function, and Polygam was ordered as well as digoxin Repeat echo done 3 days later showed significant improvement in LV function Repeat echo done 3 days later showed significant improvement in LV function Discharged home on 8/7/07 on digoxin Discharged home on 8/7/07 on digoxin

11 Trend of cardiac enzymes 2/73/75/76/77/79/7 CK3523237131438027796 CKMB 46.9 % 6.5%11%7.6% 10.8 % Trop T 0.210.27<0.03<0.03<0.03<0.03

12 Myocarditis Despite three decades of study, the diagnosis and management remain controversial. Despite three decades of study, the diagnosis and management remain controversial. The exact incidence and prevalence remain unknown. The exact incidence and prevalence remain unknown. Clinical presentation varies Clinical presentation varies Most patients are asymptomatic and recover without treatment Most patients are asymptomatic and recover without treatment

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

14 Myocarditis represents a clinically and pathogenetically highly variable disease entity. Myocarditis represents a clinically and pathogenetically highly variable disease entity. Fulminant disease  acute heart failure and arrhythmias Fulminant disease  acute heart failure and arrhythmias Some patients are asymptomatic Some patients are asymptomatic However, asymptomatic myocarditis may be a cause of unexplained deaths in 1% of cases However, asymptomatic myocarditis may be a cause of unexplained deaths in 1% of cases

15 Causes of myocarditis Viruses: Enteroviruses Influenza A and B Influenza A and B Adenovirus Adenovirus Herpes Herpes HIV HIV Bacteria: Beta-hemolytic Streptococcus Corynebacterium diphtheria Corynebacterium diphtheria Borrelia burgdorferi Borrelia burgdorferi Enterococcus spp Enterococcus spp Chlamydia psittaci Chlamydia psittaci Neisseria meningitidis Neisseria meningitidis Mycoplasma pneumonia Mycoplasma pneumonia Staphylococcus aureus Staphylococcus aureus

16 Protozoa: Trypanosoma cruzii Toxoplasma gondi Toxoplasma gondi Helminths: Trichinella spiralis Echinococcus Echinococcus Autoimmunity: Infection associated Auto-immune disease associated Auto-immune disease associated Primary autoimmunity Primary autoimmunity Hypersensitivity: Penicillins Methyldopa Methyldopa Sulfamethoxazole Sulfamethoxazole Toxicity: Catecholamines Cocaine Cocaine Ethanol Ethanol

17 Pathogenesis Three phases: Three phases: Viral Replication Viral Replication Autoimmune injury Autoimmune injury Dilated cardiomyopathy Dilated cardiomyopathy

18 Phase 1 Viral replication Cardiotropic RNA viruses are taken into myocytes by receptor-mediated endocytosis. Cardiotropic RNA viruses are taken into myocytes by receptor-mediated endocytosis. Directly translated intracellularly to produce viral protein. Directly translated intracellularly to produce viral protein. Virus infection directly contributes to cardiac tissue destruction by cleaving the cytoskeleton protein dystrophin, leading to a disruption of the dystrophin-glycoprotein complex. Virus infection directly contributes to cardiac tissue destruction by cleaving the cytoskeleton protein dystrophin, leading to a disruption of the dystrophin-glycoprotein complex.

19 Phase 2 Autoimmunity Phase 1 concludes with activation of the host system. Phase 1 concludes with activation of the host system. Ideally, the immune system should down- regulate to a resting state once viral proliferation is controlled. Ideally, the immune system should down- regulate to a resting state once viral proliferation is controlled. If host immune activation continues unabated  autoimmune disease. If host immune activation continues unabated  autoimmune disease. T cells target the host’s own tissue through molecular mimicry. T cells target the host’s own tissue through molecular mimicry.

20 Phase 3 Dilated Cardiomyopathy Re-modelling mechanisms lead to dilated cardiomyopathy (DCM). Re-modelling mechanisms lead to dilated cardiomyopathy (DCM). The persistent myocyte viral gene expression  progressive DCM. The persistent myocyte viral gene expression  progressive DCM. Cytokines: activate matrix metalloproteinases (gelatinase, collagenase, elastases). Cytokines: activate matrix metalloproteinases (gelatinase, collagenase, elastases).

21 Clinical Presentation Asymptomatic to cardiogenic shock. Asymptomatic to cardiogenic shock. May include a viral prodrome of fevers, myalgias, respiratory symptoms or gastroenteritis. May include a viral prodrome of fevers, myalgias, respiratory symptoms or gastroenteritis. May present with rapidly deteriorating LV function or arrhythmias and heart block. May present with rapidly deteriorating LV function or arrhythmias and heart block.

22 Diagnosis Acute myocarditis is defined histologically as inflammation of the myocardium with associated myocellular necrosis. Acute myocarditis is defined histologically as inflammation of the myocardium with associated myocellular necrosis. Gold Standard is endomyocardial biopsy. Gold Standard is endomyocardial biopsy. Previously Dallas criteria were used, now WHO/ International Society and Federation of Cardiology Task Force define: Previously Dallas criteria were used, now WHO/ International Society and Federation of Cardiology Task Force define: - Active myocarditis: > 14 leucocytes/mm with necrosis and degeneration - Active myocarditis: > 14 leucocytes/mm with necrosis and degeneration - Chronic myocarditis >14 leucocytes/mm but no necrosis or degeneration - Chronic myocarditis >14 leucocytes/mm but no necrosis or degeneration Further classified according to inflammatory infiltrate i.e. neutrophils, monocytes and macrophages in the acute stage, with lymphocytes and fibroblasts in the later stages. Further classified according to inflammatory infiltrate i.e. neutrophils, monocytes and macrophages in the acute stage, with lymphocytes and fibroblasts in the later stages.

23 Diagnosis continued: Cardiac biomarkers i.e. creatine kinase and troponin T and I are routinely measured Cardiac biomarkers i.e. creatine kinase and troponin T and I are routinely measured CKMB is not useful due to low predictive value. CKMB is not useful due to low predictive value. Lauer et al reported 28 of 80 patients (35%) with suspected myocarditis had elevated troponin levels. Lauer et al reported 28 of 80 patients (35%) with suspected myocarditis had elevated troponin levels. Trop T > 0.1ng/mL had a sensitivity of 53% and a specificity of 94% Trop T > 0.1ng/mL had a sensitivity of 53% and a specificity of 94% ESR found to have low sensitivity and specificity. ESR found to have low sensitivity and specificity. Echo changes i.e. LV dysfunction (in 69%), and segmental wall motion abnormalities (64%), do not differentiate myocarditis from other cardiomyopathies. Echo changes i.e. LV dysfunction (in 69%), and segmental wall motion abnormalities (64%), do not differentiate myocarditis from other cardiomyopathies.

24 Management of myocarditis Management is dictated by clinical signs and symptoms. Management is dictated by clinical signs and symptoms. MANY proposed therapies, most have only a theoretical basis. Some have been tested in animal models MANY proposed therapies, most have only a theoretical basis. Some have been tested in animal models Conventional heart failure therapy is currently the only accepted therapy for myocarditis including ACE inhibitors, angiotensin receptor blocking agents, diuretics, β-blockers or amiodarone. Conventional heart failure therapy is currently the only accepted therapy for myocarditis including ACE inhibitors, angiotensin receptor blocking agents, diuretics, β-blockers or amiodarone.

25 Diet and Lifestyle Restrict salt intake to 2-3g of sodium per day Restrict salt intake to 2-3g of sodium per day Exercise especially during the acute phase of Coxsackie virus B3 murine myocarditis enhances viral replication rate, enhances immune mechanisms and increases inflammatory lesions and necrosis. Resumption of physical activity can take place within 2 months of the acute disease. Exercise especially during the acute phase of Coxsackie virus B3 murine myocarditis enhances viral replication rate, enhances immune mechanisms and increases inflammatory lesions and necrosis. Resumption of physical activity can take place within 2 months of the acute disease.

26 Controversial Therapy: Immunosuppresive (IS) Therapy The idea that autoimmune mechanisms play an important role in the pathogenesis of myocarditis and post-viral cardiomyopathy suggests the potential benefits of immunosuppressives. The idea that autoimmune mechanisms play an important role in the pathogenesis of myocarditis and post-viral cardiomyopathy suggests the potential benefits of immunosuppressives. The Myocarditis Treatment Trial studied the effect of IS on ventricular function in 111 pts with myocarditis (Dallas criteria) and LVEF <45% The Myocarditis Treatment Trial studied the effect of IS on ventricular function in 111 pts with myocarditis (Dallas criteria) and LVEF <45% Patients were randomised with some on prednisone and cyclosporine, or prednisone and azathioprine, or to conventional therapy for 6 months. Patients were randomised with some on prednisone and cyclosporine, or prednisone and azathioprine, or to conventional therapy for 6 months. Both IS and control groups showed an increase in LVEF from 25% to 34% at 28 weeks Both IS and control groups showed an increase in LVEF from 25% to 34% at 28 weeks No survival difference No survival difference Conclusion: selected pts might benefit from appropriately timed IS Conclusion: selected pts might benefit from appropriately timed IS

27 However the study included patients with symptom duration as long as 2 years! Can they extrapolate the results for a paediatric population with a much shorter symptom duration? However the study included patients with symptom duration as long as 2 years! Can they extrapolate the results for a paediatric population with a much shorter symptom duration? Latham et al studied the effect of prednisone on survival in 52 pts with new onset DCM. Latham et al studied the effect of prednisone on survival in 52 pts with new onset DCM. Patients were randomised to prednisone or no prednisone for 3 months. Patients were randomised to prednisone or no prednisone for 3 months. Myocardial inflammation resolved in all patients and there was no survival difference at 2 years. Myocardial inflammation resolved in all patients and there was no survival difference at 2 years. One matched-cohort trial showed a benefit of prednisone with azathioprine or cyclosporine in children One matched-cohort trial showed a benefit of prednisone with azathioprine or cyclosporine in children

28 The role of immunosuppressive therapy in lymphocytic myocarditis remains controversial due to limitations in research field: The role of immunosuppressive therapy in lymphocytic myocarditis remains controversial due to limitations in research field: 1. Low incidence of symptomatic myocarditis 2. Myocarditis varies in presentation – wide spectrum of disease 3. Immunosuppressive agents influence inflammatory mediators differently i.e. effect of prednisone vs intravenous immune globulin 4. Numerous viruses implicated with different treatment response i.e. adenovirus-positive myocarditis may benefit from Ig treatment.

29 5. Myocarditis affects persons of all ages, and disease and treatment response vary between children and adults. 6. Previous trials show an improvement in myocarditis with conservative treatment. Therefore difficult to interpret the effectiveness of IS in studies without a control group. 7. The validity of the historical gold standard of endomyocardial biopsy as the basis of diagnosis if conservative therapies are the standard treatment?

30 Randomised Treatment Trial on Myocarditis (ESETCID) The ESETCID is the 1 st trial of immune therapy for myocarditis that uses different treatment regimens based on the causes of myocardial inflammation The ESETCID is the 1 st trial of immune therapy for myocarditis that uses different treatment regimens based on the causes of myocardial inflammation The ESETCID is an ongoing prospective, randomised, placebo-controlled trial studying the effects of immune therapy on ventricular function and exercise capacity in pts with biopsy-proven myocarditis and LVEF <45% The ESETCID is an ongoing prospective, randomised, placebo-controlled trial studying the effects of immune therapy on ventricular function and exercise capacity in pts with biopsy-proven myocarditis and LVEF <45% Three treatment arms: Three treatment arms: - acute viral infection  no IS is given - acute viral infection  no IS is given

31 Enterovirus-positive patients treated with interferon-alpha Enterovirus-positive patients treated with interferon-alpha CMV and adenovirus+ patients are treated with immunoglobulins CMV and adenovirus+ patients are treated with immunoglobulins Autoreactive myocarditis is treated with azathioprine and prednisone for 6 months Autoreactive myocarditis is treated with azathioprine and prednisone for 6 months

32 Human immunoglobulin for IV use (IGIV) Appropriate use can be life-saving Appropriate use can be life-saving IGIV is produced from human plasma using a number of preparatory steps  supply is finite IGIV is produced from human plasma using a number of preparatory steps  supply is finite Can lead to numerous side effects and potential adverse consequences Can lead to numerous side effects and potential adverse consequences Currently only 6 clinical indications for which IGIV has been licensed by the United States Food and Drug Administration (FDA): Currently only 6 clinical indications for which IGIV has been licensed by the United States Food and Drug Administration (FDA):

33 1) Primary immunodeficiency or primary humoral immunodeficiency 2) Idiopathic thrombocytopenic purpura  when a rapid increase in platelet count is needed 3) Kawasaki disease  prevention of coronary artery aneurysms 4) B-cell chronic lymphocytic leukemia  prevention of bacterial infections in patients with hypogammaglobulinemia or recurrent bacterial infections 5) HIV infection - indicated for HIV positive paediatric patients to decrease the frequency of serious and minor bacterial infections 6) Bone marrow transplantation  patients older than 20 years of age to decrease septicemia and acute GVHD in the 1 st 100 days post transplant.

34 Products Products are produced from plasma from whole blood donations or from a pool of plasmapheresis donors. Products are produced from plasma from whole blood donations or from a pool of plasmapheresis donors. Tests for Hep B s-Ag, HIV p24 antigen and antibodies to HIV, Hep C and syphilis are done. Tests for Hep B s-Ag, HIV p24 antigen and antibodies to HIV, Hep C and syphilis are done. IGIV is supplied in lyophilized powder or as a premixed solution with final concentration of IgG of 3%, 5%, 6%, 10% or 12% IGIV is supplied in lyophilized powder or as a premixed solution with final concentration of IgG of 3%, 5%, 6%, 10% or 12% The IgA content varies from <0.4ug/mL to 720ug/mL The IgA content varies from <0.4ug/mL to 720ug/mL

35 Dose Dose for antibody replacement is 0.3 – 0.6g/kg per month given every 2 – 4 weeks IVI. Dose for antibody replacement is 0.3 – 0.6g/kg per month given every 2 – 4 weeks IVI. For other uses a dose of 0.4g/kg per day for 5 days For other uses a dose of 0.4g/kg per day for 5 days For a rapid course  1 to 2 g/kg over 1 or 2 days For a rapid course  1 to 2 g/kg over 1 or 2 days

36 Adverse Reactions Most are mild i.e. back or abdominal pain, nausea, rhinitis, asthma, chills, low grade fever, myalgias or headache. Most are mild i.e. back or abdominal pain, nausea, rhinitis, asthma, chills, low grade fever, myalgias or headache. Slowing or stopping the infusion for several minutes will reverse the symptoms. Slowing or stopping the infusion for several minutes will reverse the symptoms. Adverse reactions are more likely in 1 st infusion of IGIV or if there has been a recent bacterial infection Adverse reactions are more likely in 1 st infusion of IGIV or if there has been a recent bacterial infection More serious reactions include anaphylaxis, Stevens-Johnson syndrome, hypotension, MI, thrombosis, hemolysis, stroke, ARDS, seizures, pulmonary oedema and acute bronchospasm. More serious reactions include anaphylaxis, Stevens-Johnson syndrome, hypotension, MI, thrombosis, hemolysis, stroke, ARDS, seizures, pulmonary oedema and acute bronchospasm.


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