Prevalence and Outcomes of Myocarditis in Dengue-Infected Patients Admitted at a Tertiary Care Hospital of Low-Middle Income Country

 Accepted on 27 May 2022            Submitted on 21 Jan 2022

Introduction

Viral illnesses are frequently complicated by cardiovascular manifestations such as arrhythmia, myocarditis, and myocardial injury. Dengue fever is known to be associated with myocarditis. The complex interplay of pro-inflammatory cytokines, T-cell activation, and release of vasoactive substances and vascular injury leads to increased vessel wall permeability and capillary leakage. Consequently, there is a reduction in effective preload and myocardial tissue edema. This leads to a variety of cardiac manifestations of dengue fever ranging from an asymptomatic elevation of cardiac enzymes to cardiogenic shock and, arrhythmias [1].

Cardiac manifestations of Dengue fever can present with a mildly raised cardiac enzyme to severe myocarditis leading to congestive heart failure, arrhythmias, cardiogenic shock, and death [2, 3]. Cardiac complications during the illness carry significance in predicting length of stay (LOS) and in-hospital mortality [4].

The definitive diagnosis of myocarditis depends on an endomyocardial biopsy. However, the clinically suspected diagnosis is based on history, clinical examination, and biochemical and radiological profile. The European Society of Cardiology (ESC) 2013 consensus statement suggested the presence of at least one clinical and one diagnostic criterion for the diagnosis of clinically suspected myocarditis. Clinical criteria include acute new-onset, or worsening dyspnea, palpitations, and/or unexplained shock. The diagnostic criteria include ECG or Holter changes, raised cardiac biomarkers, functional and structural abnormalities on cardiac imaging, and tissue characterization on cardiac magnetic resonance (CMR) imaging [5, 6].

The exact prevalence of dengue myocarditis is unknown. It is essential to recognize the burden of cardiac manifestations in dengue fever. There is a need for preparedness at the physician’s end for early recognition and prompt management for patients with dengue fever being complicated by cardiovascular manifestations. Additionally, determining prognostic factors is essential for the risk stratification of patients. With dengue fever continuing to be a major health care concern, more studies are needed to predict in-hospital outcomes and mortality. In this retrospective study, we looked at the prevalence and outcomes of myocarditis in hospitalized patients admitted with dengue fever.

Material and Methods

It was a retrospective observational study done at the Aga Khan University hospital which is a 700-bedded multidisciplinary tertiary care hospital, located in the largest city of Pakistan. All patients (age more than 18 years) admitted with a clinical diagnosis of dengue viral infection from November 2018 to November 2019, were enrolled in the study. Data was retrieved from the electronic medical record system of the hospital. A positive dengue antigen (nonstructural protein-1, NS-1) or anti-dengue immunoglobulin M (IgM) assay (antibody-capture enzyme-linked immunosorbent assay, PanBio, Brisbane, Australia) was used as the inclusion criteria [7]. The platelet count on admission was used.

For all the patients, demographic and clinical information was recorded by reviewing individual medical records. Any patient, who during the hospital course, manifested with chest pain, shortness of breath, hemodynamic or electrical instability, new-onset heart failure, or shock underwent an ECG, cTn-I levels, and an ECHO to rule in the possibility of myocarditis. Patients were labeled as having suspected myocarditis as per the ESC criteria which required the presence of≥ 1 clinical feature and ≥1 diagnostic criteria in absence of known coronary artery disease (CAD) and other cardiac or extra-cardiac causes for the symptoms [5].

The 12 lead ECG was looked for any evidence of tachy-or bradyarrhythmia such as sinus arrest, atrioventricular block (AVB), bundle branch block, intraventricular conduction delay, atrial fibrillation, supraventricular tachycardia, frequent premature beats ventricular tachycardia or fibrillation and asystole, ST/T wave, reduced R-wave height, abnormal Q waves, or low voltage amplitude. The 12-lead ECG was interpreted by the cardiologist. The cutoff for the abnormal cardiac enzyme was cTn-I of more than 0.04 ng/ml. The echocardiographic features were looked for any evidence of systolic or diastolic dysfunction, pericardial effusion, ventricular dilatation, valvular regurgitation, or intra-cardiac thrombus. The troponin-I, CBC, and renal profiles were conducted using Advia Centaur, Sysmex Xn1000, and Advia 1800, respectively.

Patients with a history of myocarditis, heart failure, coronary artery disease, rheumatic heart disease, valvular heart disease, and congenital heart disease were excluded. Patients with acute and chronic toxicity, autoimmune diseases, renal failure, and pregnant women were also excluded, as well as, patients with an established dual infection such as dengue with malaria or dengue with Salmonella typhi.

Statistical Analysis

All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) version 23 (IBM Corp., Armonk, NY). We reported frequencies and proportions for the categorical variables. The incidence of myocarditis was calculated using ESC 2013 diagnostic criteria for myocarditis [5]. We reported median and interquartile range (IQR) for the non-Gaussian distribution of the continuous variables. Pearson Chi-squared test or Fisher’s exact was used for assessing the frequency distribution and the relationship between co-variates and length of stay and mortality for categorical variables. We performed a univariate logistic regression analysis to determine the association between myocarditis and the independent effect of each significant predictor on length of stay and mortality. We considered a p-value of less than 0.05 for significant results. Finally, we conducted a multivariable logistic regression analysis to determine the association between myocarditis and LOS and in-hospital mortality while adjusting for all clinical characteristics. We presented the results of regression analysis by crude/unadjusted Odds ratio (OR) odds adjusted Odds ratio (aOR) with 95% Confidence Intervals (CIs).

Ethical Consideration

The study was reviewed and approved by the ethical review committee of the Aga Khan University Hospital, Karachi, and was exempted from written informed consent.

Results Clinical and biochemical characteristics of dengue-infected patients

Most patients were older than 35 years (55.4%) and males (68.4%). Hypertension was the most common co-morbidity (12.4%), followed by chronic kidney disease (12.2%), and diabetes mellitus (DM) (10.8%). Fifty-six point two percent of dengue-infected patients had platelets in between 40,000–150,000. Amongst 1008 patients enrolled, the overall prevalence of myocarditis in hospitalized dengue-infected patients was 4.16% (42 from 1008 patients). The overall mortality in dengue-infected patients was 1.6% (16 out of 1008 patients). Most of the patients (93%) were discharged home. The prevalence of cardiogenic shock was 9.5%. The in-hospital mortality of dengue myocarditis was 21.4%. The mean EF in dengue myocarditis patients was 50.8% (range from 15% to 55%) (Table 1). Diastolic dysfunction was present in 81.5% of patients. Right ventricle function was mildly reduced in 10% of dengue myocarditis patients, and 16% had pericardial effusion.

Table 1

Clinical and biochemical characteristics of dengue-infected patients (n = 1008). SCD = sudden cardiac death; PBNP = Pro brain natriuretic peptide; ECG = electrocardiography; ECHO = echocardiography; LAMA = left against medical advice; IQR = interquartile range.

CHARACTERISTICS OF DENGUE-INFECTED PATIENTS (N= 1008) N (%) Age (>35 years) 558 (55.4) Gender (Male) 689 (68.4) DM 109 (10.8) Hypertension 125 (12.4) Creatinine (>1.3 mg/dl) 114 (12.2) Platelets × 109/L     >150,000 151 (15)     40,000 to 150,000 566 (56.2)     <40,000 291 (28.9) Discharge mode     Discharge 937 (93)     LAMA 55 (5.5)     In-hospital mortality 16 (1.6) PROFILE OF DENGUE MYOCARDITIS PATIENTS (N= 42) N (%) Dyspnea 18 (42.9) Palpitations 4 (9.5) Shock (any) 12 (28.6) Cardiogenic shock 4 (9.5) Syncope 1 (2.4) Aborted SCD – Fatigue 33 (78.6) Fever 36 (85.7) Troponin levels (>0.04) 42 (4.16) PBNP pg/ml (Median IQR) 4609 (86–23300) ECG abnormalities (at least one) 25 (59.5) ECHO abnormalities (at least one) 10 (24) Characteristics of Dengue-infected patients stratified by in-hospital mortality

We found that dengue-infected patients with myocarditis were 6.07 (OR = 6.07; [95% CI: 1.75–21.05]) times more likely to die when compared with patients without myocarditis. Dengue infected patients who were diabetic were 6.78 times likely to die when compared to the non-diabetic patients (OR = 6.78; [95% CI: 2.47–18.61]). Similarly, hypertensive patients were 5.76 times likely to die when compared to non-hypertensive patients (OR = 5.76; [95% CI: 2.11–15.76]). Patients presenting with shock (OR = 4.43; 95% [CI 0.53 – 37]) and atrial fibrillation (OR = 4.05; [95% CI: 0.68 – 23.9s]) had higher odds of in-hospital mortality (Table 2).

Table 2

Socio-demographic and clinical characteristics of dengue patients by length of stay and in-hospital mortality. (n=1008). DM = diabetes mellitus; AVB = atrioventricular block; SCD = sudden cardiac death; ECG = electrocardiography; ECHO = echocardiography.

LENGTH OF STAY CRUDE MORTALITY CRUDE ≤3 DAYS >3 DAYS P-VALUE OR 95%CI YES NO P-VALUE OR 95%CI N % N % N % N % Age (Years) ≤35 359 45.6 91 41.2 0.24 1 6 37.5 444 44.8 0.56 1 >35 428 54.4 130 58.8 1.19 0.88 1.62 10 62.5 548 55.2 1.35 0.48 3.74 Gender Male 549 69.8 140 63.3 0.07 1 10 62.5 679 68.4 0.61 1 Female 238 30.2 81 36.7 1.34 0.97 1.83 6 37.5 313 31.6 1.3 0.45 3.61 DM No 710 90.2 189 85.5 0.04 1 9 56.3 890 89.7 <0.001 1 Yes 77 9.8 32 14.5 1.56 1.01 2.43 7 43.8 102 10.3 6.78 2.47 18.61 Hypertension No 716 91 167 75.6 <0.001 1 9 56.3 874 88.1 <0.001 1 Yes 71 9 54 24.4 3.26 2.2 4.83 7 43.8 118 11.9 5.76 2.11 15.76 Dyspnea No 6 50 18 60 0.55 1 2 22.2 22 66.7 0.02 1 Yes 6 50 12 40 0.66 0.17 2.56 7 77.8 11 33.3 7 1.24 39.49 Chest Pain No 12 100 29 96.7 1 NA 9 100 32 97 1 NA Yes 0 0 1 3.3 0 0 1 3 Palpitations No 9 75 29 96.7 0.06 1 7 77.8 31 93.9 0.2 1 Yes 3 25 1 3.3 0.1 0.01 1.12 2 22.2 2 6.1 4.43 0.53 37.06 Syncope No 12 100 29 96.7 1 NA 9 100 32 97 1 NA Yes 0 0 1 3.3 0 0 1 3 Shock No 9 75 29 96.7 0.06 1 7 77.8 31 93.9 0.2 1 Yes 3 25 1 3.3 0.1 0.01 1.12 2 22.2 2 6.1 4.43 0.53 37.07 Aborted SCD No 12 100 30 100 NA NA 9 100 33 100 NA NA Yes 0 0 0 0 0 0 0 0 Platelets >150,000 111 14.1 40 18.1 1 3 18.8 148 14.9 1 40 to 150,000 441 56 125 56.6 0.22 0.78 0.52 1.18 5 31.3 561 56.6 0.09 0.44 0.1 1.86 <40,000 235 29.9 56 25.3 0.66 0.42 1.05 8 50 283 28.5 1.39 0.36 5.33 Bicarbonate ≥22 623 82.8 139 65.9 <0.001 1 2 12.5 760 80.3 <0.001 1 <22 129 17.2 72 34.1 2.5 1.77 3.52 14 87.5 187 19.7 28.45 6.41 126.26 Creatinine ≤1.3 666 92 155 73.5 <0.001 1 4 25 817 88.9 <0.001 1 >1.3 58 8 56 26.5 4.15 2.76 6.23 102 75 12 11.1 24.02 7.61 75.9 Troponin-I ≤ 0.04 59 84.3 34 52.3 <0.001 1 4 30.8 89 73 0.003 1 >0.04 11 15.7 31 47.7 4.89 2.18 10.96 9 69.2 33 27 6.07 1.75 21.05 Echo findings Normal 783 99.5 204 92.3 <0.001 1 13 81.3 974 98.2 0.004 NA Abnormal 4 0.5 17 7.7 16.31 5.43 49.01 3 18.8 18 1.8 AVB No 10 100 29 100 NA NA 8 100 31 100 NA NA Yes 0 0 0 0 0 0 0 0 Atrial Fibrillation No 9 90 23 79.3 0.65 1 5 62.5 27 87.1 0.14 1 Yes 1 10 6 20.7 2.35 0.25 22.34 3 37.5 4 12.9 4.05 0.68 23.9 Diastolic Dysfunction None 2 40 2 8.7 NA 2 33.3 2 9.5 1 Grade I 0 0 14 60.9 0.03 3 50 11 52.4 0.31 0.27 0.03 2.83 Grade II 3 60 6 26.1 1 16.7 8 38.1 0.12 0.007 2.17

A higher proportion of the patients who died were older than 35 years old (62.5%) when compared to 55.2% of the patients who survived. Patients with in-hospital mortality were more likely to be diabetics (p < 0.001) and hypertensive (p < 0.001) when compared to those who survived. Around 78% of the patients who died were dyspneic as opposed to 33.3% who survived (p-value: <0.02). A higher proportion of the patients (69.2%) who died had higher (>0.04) levels of cTn-I as opposed to 27% of the patients who survived. Patients with low serum bicarbonate on presentation had higher in-hospital mortality when compared to those with normal serum bicarbonate (87.5 vs. 11.1%, p < 0.001). Likewise, patients with in-hospital mortality had higher serum creatinine on presentation (75 vs. 25%, p < 0.001). Patients with higher in-hospital mortality had a higher percentage of abnormalities on ECHO (p = 0.004). Eighteen point eight percent of the patients who died were found to have abnormal findings on ECHO as opposed to 1.8% of the patients who survived (Table 2).

Characteristics of Dengue-infected patients stratified by length of stay

Most patients with higher LOS were older than 35-year when compared with those with lesser LOS (58.8 vs. 54.4%). DM (14.5 vs. 9.8%, p 0.04) and Hypertension (24.4 vs. 9%, p < 0.001) were more common in patients with higher LOS when compared with patients with lower LOS. Patients with raised cTn-I were more likely to have higher LOS when compared with those with negative biomarkers (47.7 vs. 15.7%, p < 0.00). Dengue-infected patients with myocarditis were 4.89 (OR = 4.89; [95% CI: 2.18–10.96]) times more likely to have higher LOS. Dengue infected patient with DM (OR = 1.56; [95% CI: 1.01–2.43]) and Hypertension (OR = 3.26; [95% CI: 2.20–4.83]) had more likelihood of higher LOS (Table 2).

Association of dengue-infected patients with a length of stay on multivariable analysis

Association of myocarditis with LOS was assessed by adjusting the results of multivariable analysis for age, gender, platelet count, echo findings, and DM. It was found that the association between raised cTn-I (aOR = 5.29; [95% I:2.16–12.96]) and any echocardiographic abnormality [aOR = 4.38; 95% CI: 1.26–15.27)] with patient’s LOS beyond three days persisted in the adjusted model and became stronger relative to the bivariate analysis as shown in Table 3. However, the association of age, gender, DM, and thrombocytopenia with increased LOS disappeared in the final adjusted model after controlling for potential confounders (Table 3).

Table 3

Association of myocarditis with morbidity and mortality (n = 1008). aOR = adjusted odds ratio; CI = confidence interval.

LENGTH OF STAY > 3 DAYS MORTALITY AOR 95% CI AOR 95% CI Age (Years)     ≤35 1 1     >35 0.66 0.24 1.81 0.22 0.04 1.34 Gender     Male 1 1     Female 1.24 0.55 2.77 2.82 0.68 11.67 Troponin levels     ≤0.04 1 1     >0.04 5.29 2.16 12.96 8.2 1.83 36.84 Diabetes Mellitus     No 1 1     Yes 0.67 0.27 1.68 1.48 0.34 6.49 Platelets     >150,000 1 1     40 to 150,000 0.41 0.13 1.32 0.28 0.04 1.95     <40,000 0.37 0.1 1.31 0.63 0.09 4.33 Echo Findings     Normal 1 1     Any cardiac abnormality 4.38 1.26 15.27 2.24 0.42 11.97 Association of Dengue-infected patients with mortality on multivariable analysis

After adjusting the results of multivariable analysis for age, gender, platelet count, echo findings, and DM, the result demonstrated a statistically significant association of raised cTn-I (aOR = 8.2; [95% CI: 1.83–36.84]), echocardiographic abnormality (aOR = 2.24; [95% CI: 0.42–11.97]) and female gender (aOR = 2.82; [95% CI (0.68–11.67]) with increased in-hospital mortality as shown in Table 3. Age and thrombocytopenia were not significantly associated with mortality (Table 3).

Discussion

There are several predictors of outcomes in dengue fever, such as extremes of age, hypertension, diabetes mellitus, nutrition status, and superadded infections [8]. In addition, altered mental status, and dyspnea at rest have been defined as independent predictors of outcomes in dengue illness [9

留言 (0)

沒有登入
gif