MYOCARDIAL DYSFUNCTION IN PATIENTS ADMITTED WITH DENGUE FEVER

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MYOCARDIAL DYSFUNCTION IN PATIENTS ADMITTED WITH DENGUE FEVER: REPORT FROM A TERTIARY CARE CENTER

MYOCARDIAL DYSFUNCTION IN PATIENTS ADMITTED WITH DENGUE FEVER: REPORT FROM A TERTIARY CARE CENTER IN NORTH INDIA Nampoothri Ram 1, Prasanth B 1, Arjun Lakshman 1, Ashish Bhalla 1, S C Varma 1 1. Department of Internal Medicine, PGIMER, Chandigarh (U. T. ), India

 Conflict of interest : None

Conflict of interest : None

INTRODUCTION • Dengue is a mosquito-borne febrile illness • Genus: Flavivirus • Serotypes 1,

INTRODUCTION • Dengue is a mosquito-borne febrile illness • Genus: Flavivirus • Serotypes 1, 2, 3 and 4 (DENV- 1 to 4) • Vector: Aedes aegypti

EPIDEMOLOGY • Endemic in more than 125 countries and affects up to 200 million

EPIDEMOLOGY • Endemic in more than 125 countries and affects up to 200 million people with about 5 lakh severe dengue cases and 20, 000 deaths per year Wilder-Smith A et al. Clin Epidemiol. 2013 Aug; 299 • India, belonging to the South East Asian region, is estimated to have the maximum dengue burden with about 33 million apparent cases and up to 100 million subclinical infections annually. Bhatt S Nature. 2013 Apr 7; 496(7446): 504– 7

DENGUE MAP http: //www. who. int/entity/denguecontrol/Aedes_aegypti. jpg

DENGUE MAP http: //www. who. int/entity/denguecontrol/Aedes_aegypti. jpg

COURSE OF ILLNESS

COURSE OF ILLNESS

CLINICAL FEATURES Ref: DENGUE GUIDELINES FOR DIAGNOSIS, TREATMENT, PREVENTION CONTROL, WHO 2009 (http: //apps.

CLINICAL FEATURES Ref: DENGUE GUIDELINES FOR DIAGNOSIS, TREATMENT, PREVENTION CONTROL, WHO 2009 (http: //apps. who. int/iris/bitstream/10665/44188/1/9789241547871_eng. pdf)

CARDIAC INVOLVEMENT IN DENGUE • Incidence - 1. 25% to 70%* in different studies

CARDIAC INVOLVEMENT IN DENGUE • Incidence - 1. 25% to 70%* in different studies Yadav Dk et al. Pediatr Cardiol. 2013 Aug; 34(6): 1307– 13 • Incidence in Indian studies is 9 -35% Gupta E. Infect Drug Resist. 2014 Dec; 337 *Depending on the diagnostic tests and criteria used

CARDIAC INVOLVEMENT IN DENGUE Rhythm abnormalities (30 -62%) Asymptomatic systolic and diastolic dysfunction with

CARDIAC INVOLVEMENT IN DENGUE Rhythm abnormalities (30 -62%) Asymptomatic systolic and diastolic dysfunction with biomarker elevation (15% - 30%) Myocardial depression with symptoms of heart failure and shock (4 -45%) Pericarditis* Ref: Yacoub S et al. Nat Rev Cardiol. 8; 11(6): 335– 45 * Only case reports available

CARDIAC INVOLVEMENT IN DENGUE • Outbreaks of dengue caused by serotypes DENV-1, DENV-2 and

CARDIAC INVOLVEMENT IN DENGUE • Outbreaks of dengue caused by serotypes DENV-1, DENV-2 and DENV-3 Wali et al. Int J Cardiol. 1998 Mar 13; 64(1): 31– 6 • Endocardial involvement is rare in dengue Wiwanitkit V. Int J Cardiol. 2006 Oct 10; 112(3): 386

CARDIAC INVOLVEMENT IN DENGUE Dire c inva t viral sion tigen n a l

CARDIAC INVOLVEMENT IN DENGUE Dire c inva t viral sion tigen n a l a r i V d mediate ical olog immun ry inju Cyto k respo ine nse- TNFα, IL and 1 6, 13 8 Miranda et al. Clin Infect Dis. 2013 Sep 15; 57(6): 812– 9 Hober et al. Am J Trop Med Hyg. 1993 Mar; 48(3): 324– 31

OBJECTIVE • Cardiac involvement in dengue fever is often under diagnosed due to 1.

OBJECTIVE • Cardiac involvement in dengue fever is often under diagnosed due to 1. Low index of clinical suspicion 2. Its overlapping clinical manifestations such as hypotension, tachycardia, pulmonary edema and capillary leak associated with dengue virus infection 3. Lack of routine screening of the patients for myocardial involvement using sensitive assays Yacoub S et al. Nat Rev Cardiol. 8; 11(6): 335– 45

AIM • To conduct a prevalence study of myocardial involvement in patients with dengue

AIM • To conduct a prevalence study of myocardial involvement in patients with dengue fever using 1. Cardiac biomarkers namely Cardiac Myoglobin (Mb), Creatinine-Kinase MB (CK-MB) and Cardiac Troponin-I (Trop-I) 2. 2 -dimensional echocardiography (2 D-echo) and 3. Electrocardiogram (ECG) • To evaluate for possible clinical predictors of myocardial involvement.

STUDY DESIGN • DESIGN OF STUDY: Institution - based prospective study • SETTING: Medical

STUDY DESIGN • DESIGN OF STUDY: Institution - based prospective study • SETTING: Medical Emergency, Department of Internal Medicine, PGIMER (Chandigarh), a tertiary care center in North India • TIME OF THE STUDY: September 2015 • NUMBER OF PATIENTS: 50

ELIGIBILITY CRITERIA Inclusion Criteria: • Acute febrile illness with suggestive symptoms and • Tested

ELIGIBILITY CRITERIA Inclusion Criteria: • Acute febrile illness with suggestive symptoms and • Tested positive for dengue infection by NS 1 antigen bedside rapid diagnostic kit and/or positive serology (Ig. M) by ELISA and • Platelet count less than 100 ✕ 103 Exclusion criteria: • Patient or attendant not willing to give consent • Acute febrile illness due to any etiology other than dengue

STUDY METHODOLOGY 50 patients meeting the inclusion criteria enrolled Detailed clinical history taken and

STUDY METHODOLOGY 50 patients meeting the inclusion criteria enrolled Detailed clinical history taken and examination done Laboratory Investigations Complete blood count Serum electrolytes Renal & liver function test Chest skiagram Classified into 1. Dengue without warning signs 2. Dengue with warning signs 3. Severe dengue

STUDY METHODOLOGY 1. 12 lead Electrocardiogram Sinus tachycardia QRS or QT prolongation T wave

STUDY METHODOLOGY 1. 12 lead Electrocardiogram Sinus tachycardia QRS or QT prolongation T wave inversion in at least 9 leads Arrythmias 2. Cardiac biomarkers (point-of-care testing)1 Cardiac myoglobin (Mb) Creatinine-kinase MB (CK-MB) Cardiac troponin-I (Trop-I) 3. 2 D Trans thoracic echocardiography 2 Left ventricle ejection fraction (LVEF) by Simpsons’ method Left ventricle systolic dysfunction when LVEF< 50% 1. Alere Triage® Cardiac Panel, Alere Inc. , MA, US 2. GE Vivid q cardiovascular ultrasound system, GE Healthcare, UK

STATISTICAL ANALYSIS • Quantitative variables were summarized as medians and categorical variables as frequencies.

STATISTICAL ANALYSIS • Quantitative variables were summarized as medians and categorical variables as frequencies. • Association between categorical variables were tested for statistical significance using Fisher’s exact test and continuous variables using Mann-Whitney U-test. • Variables with statistically significant association on univariate analysis were further tested for significance using logistic regression analysis. • A two sided p-value <0. 05 was considered significant. • Statistical analysis was done using SPSS 22. 0.

DEMOGRAPHY SEX AGE DISTRIBUTION Female 30% 16 Mean 38. 5 years Male 70% Range

DEMOGRAPHY SEX AGE DISTRIBUTION Female 30% 16 Mean 38. 5 years Male 70% Range 13 to 70 years 10 7 1 20 o t 3 7 30 2 o 1 t 3 40 o t 1 5 60 o t 1 70 o t 1 50 5 4 o 1 t 5 6

 B um ra gh e ed le 2% em or al H iv

B um ra gh e ed le 2% em or al H iv ct nj u G is 4% Su bc o ax ist ed le I b 12% Ep G g di n ee 12% Bl ng iti om 30% V ch e da ea H n er ai p in al bd om A Fe v SYMPTOMS 100% 24% 2% 2%

CARDIAC INVOLVEMENT IN THE STUDY GROUP 30% 26% 20% 16% 14% 16% 6% ac

CARDIAC INVOLVEMENT IN THE STUDY GROUP 30% 26% 20% 16% 14% 16% 6% ac rdi a C ft v Le m sy en ul tric ms pto h ar o yp a o esi kin ea Atl n e ark m io b c dia ar e c n st o -I ve ho -ec D 2 ti osi p r in on p o r T d ise a kin e atin Ra R r d c e s ai e M se- B i orm sof ges n a ch in d m ise a R y lob og G EC

ECG CHANGES 20% 10% 4% 4% 0% Sinus tachycardia QT prolongation Diffuse T-wave AV

ECG CHANGES 20% 10% 4% 4% 0% Sinus tachycardia QT prolongation Diffuse T-wave AV conduction inversion defects Ventricular arrhythmias

COMPARISON OF PREVALENCE OF BIOMARKER ELEVATION, LV HYPOKINESIA ON 2 D-ECHO AND ECG ABNORMALITIES

COMPARISON OF PREVALENCE OF BIOMARKER ELEVATION, LV HYPOKINESIA ON 2 D-ECHO AND ECG ABNORMALITIES IN DIFFERENT CATEGORIES OF SEVERITY OF DENGUE INFECTION Dengue without Dengue with warning signs (n=10) (n=33) Severe dengue p-value for (n=7) Fischers exact test Biomarker elevation 2 (20%) 7 (21. 2%) 4 (57. 1%) 0. 132 LV hypokinesia on 0 (0) 2 D echo 6 (18. 2%) 2 (28. 6%) 0. 206 ECG abnormality 9 (27. 3%) 2 (28. 6%) 0. 896 4 (40%)

CORRELATION BETWEEN CARDIAC DYSFUNCTION BY ECG, 2 D ECHO AND CARDIAC BIOMARKERS ECG Changes

CORRELATION BETWEEN CARDIAC DYSFUNCTION BY ECG, 2 D ECHO AND CARDIAC BIOMARKERS ECG Changes Echo Changes Spearmans’ rho Correlation ECG Changes Coefficient 1. 0 Sig. (2 -tailed) Spearmans’ rho Correlation Echo Changes Coefficient Cardiac Biomarker . 129 . 193 . 377 . 178 1. 0 . 175 Sig. (2 -tailed) . 377 . 229 Spearmans’ rho Correlation Coefficient . 193 . 175 Sig. (2 -tailed) . 178 . 229 1. 0

UNIVARIATE ANALYSIS FOR ASSOCIATION BETWEEN PROPOSED RISK FACTORS AND MYOCARDIAL INVOLVEMENT Presumed risk factor

UNIVARIATE ANALYSIS FOR ASSOCIATION BETWEEN PROPOSED RISK FACTORS AND MYOCARDIAL INVOLVEMENT Presumed risk factor Patients with biomarker elevation (n=13) Patients without biomarker elevation (n=37) p- value Patients with LV hypokinesia (n=8) Patients p-value Patients p- value without LV with ECG without ECG hypokinesia changes (n=42) (n=15) (n=35) Age* 40 (13 -70) 35 (14 -71) 0. 408 36. 5 (13 -65) 39. 5 (14 -71) 0. 746 35 (18 -71) 40 (13 -70) 0. 849 Age < 40 years** 9 (69. 2% 1. 000 5 (62. 5%) 28 (66. 7%) 1. 000 10 (66. 7%) 23 (65. 7%) 1. 000 Male gender** Duration of fever at admission* Fever ≥ 4 days at admission** Presence of any warning sign** 8 (61. 5%) 6/24 (64. 9%) 27 (73%) 0. 493 5 (62. 5%) 3 (71. 4%) 0. 683 9 (60%) 26 (74. 3%) 0. 502 5 (3 -7) 5 (1 -7) 0. 457 5. 5 (3 -7) 5 (1 -7) 0. 397 5 (1 -7) 0. 478 12 (92. 3%) 25 (67. 6%) 0. 141 7 (87. 5%) 30 (71. 4%) 0. 430 13 (86. 7%) 24 (68. 6%) 0. 294 4 (30. 8%) 9 (24. 3%) 1. 000 6 (75%) 31 (73. 8%) 1. 000 10 (66. 7%) 27 (77. 1%) 0. 493 *Mann Whitney U-test, **Fischers exact test

UNIVARIATE ANALYSIS FOR ASSOCIATION BETWEEN PROPOSED RISK FACTORS AND MYOCARDIAL INVOLVEMENT Presumed risk factor

UNIVARIATE ANALYSIS FOR ASSOCIATION BETWEEN PROPOSED RISK FACTORS AND MYOCARDIAL INVOLVEMENT Presumed risk factor Patients with biomark er elevation (n=13) 11 (84. 6%) Patients without p-value biomarker elevation (n=37) Patients with LV hypokinesia (n=8) Patients p-value without LV hypokinesia (n=42) Patients with ECG changes (n=15) 36 (97. 3%) 0. 162 8 (100%) 39 (92. 9%) 1. 000 14 (93. 3%) 33 (94. 3%) 1. 000 43 (16 -69) 37. 5 (19. 154) 43 (16 -69) 0. 130 38 (16 -51) 43 (19 -69) 0. 034 Hematocrit* 40 (3258) Raised hematocrit** 5 (38. 5%) 17 (45. 9%) 0. 751 2 (25%) 20 (47. 6%) 0. 278 5 (33. 3%) 17 (48. 6%) 0. 367 Presence of bleeding symptoms** 1 (7. 7%) 5 (13. 5%) 0. 676 2 (25%) 4 (9. 5%) 0. 242 2 (13. 3%) 4 (11. 4%) 1. 000 Severe dengue** 4 (31. 8%) 3 (8. 1%) 0. 065 2 (25%) 5 (11. 9%) 0. 580 2 (13. 3%) 5 (14. 3%) 1. 000 Presence of cardiac symptoms** 5 (38. 5%) 2 (5. 4%) 0. 009 1 (12. 5%) 6 (14. 3%) 1. 000 3 (20%) 4 (11. 4%) 0. 659 Presence of shock** 4 (30. 8%) 0 (0) 0. 003 1 (12. 5%) 3 (7. 1%) 1. 000 2 (13. 3%) 2 (5. 7%) 0. 574 Dengue confirmation by NS 1** 0. 731 Patients without ECG changes (n=35) p-value *Mann Whitney U-test, **Fischers exact test

DISCUSSION 1) CARDIAC BIOMARKERS 26% had elevation of at least one cardiac biomarkers in

DISCUSSION 1) CARDIAC BIOMARKERS 26% had elevation of at least one cardiac biomarkers in our study Miranda et al. Clin Infect Dis. 2013 Sep 15; 57(6): 812– 9 • 81 adult patients with dengue underwent testing for Trop-I and NT-pro-BNP • 15% (n=12) had elevation of at least one biomarker

DISCUSSION 1) CARDIAC BIOMARKERS (Contd) Miranda et al. Clin Infect Dis. 2013 Sep 15;

DISCUSSION 1) CARDIAC BIOMARKERS (Contd) Miranda et al. Clin Infect Dis. 2013 Sep 15; 57(6): 812– 9 • Biomarker elevation was associated with higher leukocyte count, higher platelet count, higher serum creatinine and C-reactive protein and lower viral load • Two patients died of refractory cardiogenic shock and postmortem examination showed positive immunohistochemical staining for dengue virus in cardiac tissue • Cardiac function was not assessed as part of this study

DISCUSSION 2) 2 D ECHOCARDIOGRAPHY 16% patients had myocardial dysfunction on 2 D-echo •

DISCUSSION 2) 2 D ECHOCARDIOGRAPHY 16% patients had myocardial dysfunction on 2 D-echo • 2 D echo is operator dependent and inter-observer variability is possible Satarasinghe et al. Br J Cardiol. 2007 Jun; 14(3): 171– 3 • 24% out of 217 patients had echocardiographic abnormalities of which 65% were in the 12– 30 years age group

DISCUSSION 2) 2 D ECHOCARDIOGRAPHY (Contd. ) Satarasinghe et al. Br J Cardiol. 2007

DISCUSSION 2) 2 D ECHOCARDIOGRAPHY (Contd. ) Satarasinghe et al. Br J Cardiol. 2007 Jun; 14(3): 171– 3 57% RV Dilatation 21% 16% LV dilatation Both chamber dilatation

DISCUSSION 2) 2 D ECHOCARDIOGRAPHY (Contd. ) Satarasinghe et al. Br J Cardiol. 2007

DISCUSSION 2) 2 D ECHOCARDIOGRAPHY (Contd. ) Satarasinghe et al. Br J Cardiol. 2007 Jun; 14(3): 171– 3 • None complained of any chest discomfort or dyspnea of any grade • None had clinical features of overt myocarditis such as significant sinus tachycardia, raised jugular venous pressure, triple rhythm, bilateral pulmonary crepitations and peripheral edema. • All patients showed improvement at three months

DISCUSSION 3) ELECTROCARDIOGRAM (ECG) ECG changes in 30% of our patients Kularatne et al.

DISCUSSION 3) ELECTROCARDIOGRAM (ECG) ECG changes in 30% of our patients Kularatne et al. Trans R Soc Trop Med Hyg. 2007 Aug; 101(8): 804– 8. • 62. 5% of 120 adult dengue patients had ECG changes. • Divided into “Cardiac group” or “Non-cardiac group” based on presence or absence of ECG changes • Higher incidence of tachycardia, bradycardia and hypotension in “Cardiac group” with statistical significance

DISCUSSION 3) ELECTROCARDIOGRAM (ECG)(Contd. ) Kularatne et al. Trans R Soc Trop Med Hyg.

DISCUSSION 3) ELECTROCARDIOGRAM (ECG)(Contd. ) Kularatne et al. Trans R Soc Trop Med Hyg. 2007 Aug; 101(8): 804– 8. • Widespread T inversion in the 12 lead ECG was the hallmark feature • ST depression, right bundle branch block and ST elevation in the inferior leads were the other findings observed • Autonomic dysfunction and metabolic disturbances are common in patients with severe dengue and may be responsible for many ECG changes seen in patients with dengue thus increasing its sensitivity

DISCUSSION • 16 -30% patients admitted at our center with dengue fever had features

DISCUSSION • 16 -30% patients admitted at our center with dengue fever had features to suggest myocardial involvement on testing with 2 D echocardiography, point of care testing for cardiac biomarkers and ECG • The three parameters show poor correlation with each other and there is no single parameter which is associated with clinical severity

DISCUSSION • No significant difference in the biomarker elevation, myocardial dysfunction or ECG abnormality

DISCUSSION • No significant difference in the biomarker elevation, myocardial dysfunction or ECG abnormality among groups of patients with different severity of dengue infection • No single parameter exists which can define or detect cardiac involvement in dengue

DISCUSSION • Only a proportion of patients with LV dysfunction had biomarker elevation (37%)

DISCUSSION • Only a proportion of patients with LV dysfunction had biomarker elevation (37%) • Not all cases of myocardial dysfunction are due to direct or indirect myocardial structural damage • Possible reasons Plasma leakage Cytokine response associated with the infection (TNF-α and IL -6, IL -13, IL -18) Hober et al. Am J Trop Med Hyg. 1993 Mar; 48(3): 324– 31

STUDY HIGHLIGHTS • A reasonable sample size • Simultaneous evaluation of all included patients

STUDY HIGHLIGHTS • A reasonable sample size • Simultaneous evaluation of all included patients with biomarkers, ECG and 2 D-echo • Simultaneous testing for three cardiac biomarkers i. e. Cardiac myoglobin (Mb), creatinine-kinase MB (CK-MB) and cardiac troponin-I (Trop-I)

LIMITATIONS • Lack of follow-up to check for resolution of cardiac dysfunction • Lack

LIMITATIONS • Lack of follow-up to check for resolution of cardiac dysfunction • Lack of endomyocardial biopsy • Data on the treatment received including intravenous fluids and vasopressors

Danke

Danke