Circulating cardiac biomarkers and echocardiographic abnormalities in patients with scrub typhus: A prospective cohort study from a tertiary care center in North India

Ashok Kumar Pannu; Manoj Kumar Debnath; Navneet Sharma; Manisha Biswal; Rajesh Vijayvergia; Ashish Bhalla; Jyotdeep Kaur; Susheel Kumar

doi:10.4103/0972-9062.321754

RESEARCH ARTICLE

Year : 2021 | Volume : 58 | Issue : 3 | Page : 193-198

Circulating cardiac biomarkers and echocardiographic abnormalities in patients with scrub typhus: A prospective cohort study from a tertiary care center in North India

Ashok Kumar Pannu¹, Manoj Kumar Debnath¹, Navneet Sharma¹, Manisha Biswal², Rajesh Vijayvergia³, Ashish Bhalla¹, Jyotdeep Kaur⁴, Susheel Kumar¹
¹ Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
² Department of Medical Microbiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
³ Department of Cardiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
⁴ Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission	27-Oct-2019
Date of Decision	07-Aug-2020
Date of Web Publication	15-Feb-2022

Correspondence Address:
Navneet Sharma
Professor, 4th floor, F block, Department of Internal Medicine, PGIMER, Chandigarh
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/0972-9062.321754

Abstract

Background & objectives: Cardiac injury in scrub typhus is uncommonly reported. We studied the incidence and clinical significance of cardiac involvement among seventy consecutive adult patients of scrub typhus, using circulating cardiac biomarkers, including N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), troponin T, creatine kinase-muscle/brain isoenzyme (CK-MB) and 2D-echocardiography.
Methods: This was a hospital-based prospective cohort study conducted in the medical emergency of PGIMER, Chandigarh, India. Seventy consecutive patients aged 12 years and above with the diagnosis of scrub typhus were enrolled.
Results: Elevations of NT pro-BNP, troponin T, and CK-MB levels were observed in 70 (100%), 51 (72.8%), and 29 (41.4%) patients, respectively. Echocardiography detected reduced ejection fraction (EF) in 30 patients (42.8%) with mild reduction (EF 45-54 %) in 20 (28.5%) and moderate reduction (EF 30-44%) in 10 (14.3%). The age showed a significant difference with EF (p-value 0.003), and the patients with moderate reduction were younger (mean age of 20.7 ± 5.6 years). Pericardial effusion was found in nine patients (12.9%). Increased circulating levels of all the three cardiac biomarkers showed statistically significant association with a systolic dysfunction on echocardiography, and elevated CK-MB level further predicted a longer duration of hospital stay (p-value 0.002). No statistically significant association was observed between cardiac biomarkers or reduced EF and mortality.
Interpretation & conclusion: Cardiac injury is a common condition among patients with scrub typhus admitted in a medical emergency; however, it does not influence in-hospital mortality.

Keywords: Scrub typhus; Orientia tsutsugamushi; Heart failure; Cardiac injury; Echocardiography; ECG; N-terminal pro-B-type natriuretic peptide; Troponin T; CK-MB.

How to cite this article:
Pannu AK, Debnath MK, Sharma N, Biswal M, Vijayvergia R, Bhalla A, Kaur J, Kumar S. Circulating cardiac biomarkers and echocardiographic abnormalities in patients with scrub typhus: A prospective cohort study from a tertiary care center in North India. J Vector Borne Dis 2021;58:193-8

How to cite this URL:
Pannu AK, Debnath MK, Sharma N, Biswal M, Vijayvergia R, Bhalla A, Kaur J, Kumar S. Circulating cardiac biomarkers and echocardiographic abnormalities in patients with scrub typhus: A prospective cohort study from a tertiary care center in North India. J Vector Borne Dis [serial online] 2021 [cited 2023 Mar 29];58:193-8. Available from: http://www.jvbd.org//text.asp?2021/58/3/193/321754

Introduction

Scrub typhus is the most important human rickettsial infection worldwide. It affects about one million new cases each year around the globe with a mortality rate of up to 10%, which is higher than many other tropical acute febrile illnesses including malaria, dengue, leptospirosis, and enteric fever^[1],[2]. The disease is endemic in parts of Asia, Australia, and islands in the Indian and Pacific Oceans; however, increasingly being reported in (previously nonendemic) areas of Africa, France, the Middle East, and South America^[3],[4]. In India, scrub typhus was earlier known to be prevalent in the foothills of Himalayas; however recent outbreaks have occurred in many other states^[1],[5].

Scrub typhus is an acute zoonotic disease caused by Orientia tsutsugamushi, which is transmitted to humans by the bite of the larva of the trombiculid mites known as ‘chiggers.' The clinical presentation of scrub typhus varies from an acute febrile illness with nonspecific symptoms to life-threatening organ dysfunction such as acute respiratory distress syndrome, acute kidney injury, acute liver injury, acute brain dysfunction, disseminated intravascular coagulation, and shock^{[1],[2],[6],[7],[8]}. Scrub typhus with cardiac involvement is uncommonly reported and is limited to case reports, case series, and only two prospective studies so far to the best of our knowledge^[9],[10]. To date, the spectrum of cardiac dysfunction in scrub typhus and its early determinants are not clear. Moreover, the expanding geographic distribution of the disease itself mandates awareness of its cardiac manifestation.

In the present study, we aimed to prospectively investigate the spectrum and frequency of cardiac manifestations in scrub typhus and to evaluate clinical outcomes using noninvasive tools such as 2D-echocardiography and circulating cardiac biomarkers including N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), troponin T, creatine kinase-muscle/brain isoenzyme (CK-MB).

Material & Methods

Study population

This was a hospital-based prospective cohort study conducted in the Postgraduate Institute of Medical Education and Research, Chandigarh, India, from January 2017 to July 2018. Our hospital’s catchment area includes a large area in northern India, which is considered a high O. tsutsugamushi infection transmission region.

Case definition

Patients who were 12 years and older and presented to the medical emergency with a diagnosis of scrub typhus were included in the study. The diagnosis was made based on (1) undifferentiated acute febrile illness with suggestive clinical features and (2) IgM antibodies against O. tsutsugamushi positive by enzyme-linked immunosorbent assay (In Bios international Inc, Washington USA) and/or polymerase chain reaction for O. tsutsugamushi positive in blood or from a biopsy of the eschar tissue. We excluded patients who had a previous cardiac disease like coronary artery disease, cardiomyopathy, cardiac arrhythmia, rheumatic heart disease, and patients who were coinfected with dengue, malaria, leptospirosis, enteric fever, influenza or viral encephalitis.

Data collection

The number of patients enrolled during the study period determined the sample size. A clinical research form on enrolment, including a detailed history and a physical examination (especially eschar or skin rash), was completed. The basic laboratory tests including complete blood count (hemoglobin, white blood cell count, platelet count), serum electrolytes, renal function tests (blood urea, serum creatinine), liver function tests (bilirubin and liver enzymes), 12-lead electrocardiogram (ECG), chest X-ray, abdominal ultrasonography as a part of the routine evaluation were performed at admission. Further investigations or diagnostic procedures (including more radiological imaging, arterial blood gas analysis, etc.) were performed when judged to be appropriate.

Management of the patients was in no way altered as part of their enrolment in the study and followed standard treatment protocols. All cases were followed up until discharge or death. The outcome and the duration of hospital stay were recorded. Assessment of the disease severity and the outcome’s prediction was done using critical illness severity scoring systems such as Sequential Organ Failure Assessment (SOFA), and Multi-Organ Dysfunction Score (MODS) recorded on admission and every 24 hours until discharge or death^[11],[12].

Evaluation of cardiac injury

Details regarding the cardiac symptoms, vital signs, and cardiopulmonary auscultation (especially third heart sound and lung crackles) were noted using a structured proforma. The ECGs were analyzed for heart rate, rhythm, abnormal intervals, wave(s) abnormalities, and ST-T changes, among others.

Echocardiography (using EDGE-Sonosite Inc. USA machine) was performed by a trained cardiologist in all the patients to determine left ventricular ejection fraction (EF), stroke volume (SV), regional wall motion abnormality, and pericardial effusion. Systolic dysfunction was defined through estimating EF, a ratio of SV to end-diastolic volume. EF <55% was taken as reduced EF, with 45-54% as mild and 30-44% moderate reduction. Diastolic dysfunction was determined using mitral valve inflow velocities (e.g., E<A) based on pulse wave Doppler analysis.

Circulating levels of cardiac biomarkers, NT-pro- BNP (using COBAS from ROCHE diagnostics; normal level, <125 pg/ml), troponin T (by electrochemiluminescence immunoassay using COBAS from ROCHE diagnostics; normal level, <14 pg/ml) and CK-MB (using Beckman Coulter AU analyzers; normal level, <25 U/L) were determined.

Statistical analysis

We used Statistical Package for the Social Sciences (SPSS), version 24.0 for data analysis, and recorded categorical variable as to number (N) and percentage (%), and continuous data as mean + standard deviation (SD) or median with interquartile range (IQR). The one-way analysis of variance test was used to compare the differences between the groups based on EF, and the independent t-test analyzed the mean length of stay in the hospital between the two groups. All tests were two-sided with a 5% level of significance (p-value ≤0.05) and a 95% confidence interval.

Ethical statement

The Institutional Ethics Committee approved the study (No.: INT/IEC/2017/269). We obtained written, informed consent from all study participants.

Results

The spectrum of cardiac injury

This study included 70 patients with 40 males and 30 females. The most frequent cardiopulmonary complaint was shortness of breath (70%), and the most common finding was tachycardia (95.7%). Cardiopulmonary auscultation revealed lung crackles in 32 patients (45.7%) and third heart sound (S3) in three patients (4.2%). Mean arterial pressure was <70 mmHg in 23 patients (33.9%), in whom five patients had a value of <60 mmHg.

In this cohort, most patients (N=67) had an abnormal ECG, and the majority of them had nonspecific changes, the commonest being sinus tachycardia (95.7%). 28.5% (N=20) patients had mild reduction in EF and 14.3% (N=10) had moderate reduction. On pulse wave Doppler analysis, the ratio of the early (E) to late (A) ventricular filling velocities (the E/A ratio), seven patients (10%) had E=A, and 1 (1.4%) had E<A. Another abnormality, pericardial effusion, was present in nine patients (12.9%). The serum NT-pro-BNP levels were elevated in all patients, whereas troponin T and CK-MB elevations occurred in 51 (72.8%) and 29 (41.4%) patients, respectively. In three patients, CK-MB levels were three times elevated than the upper limit of the normal value.

Baseline characteristics with normal EF and reduced EF

Regarding clinical, hematological, and biochemical parameters, only the age showed a significant difference with EF >55%, EF <45–54%, and EF <45% (p-value 0.003). Patients with moderate EF reduction had a mean age of 20.7 ± 5.6 years [Table 1].

Table 1: Baseline characteristics with normal EF and reduced EF in scrub typhus patients (N=70).

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Elevation of all the three cardiac biomarkers showed a statistically significant difference with the reduction in EF (p- values for troponin T, NT-pro-BNP, and CK-MB were 0.001, 0.0001, and 0.001, respectively). A statistically significant negative correlation was found between NT-pro-BNP levels and the SV (Spearman’s r, 0.272; and p-value, 0.023). When critical illness scoring systems SOFA and MODS were analyzed, a statistically significant difference was observed only between CK-MB and SOFA Day two score (p-value 0.038).

Outcomes

In this cohort (N=70), five patients died. The mean duration of hospital stay was 10.5 ± 5.3 days. The reduced EF was not associated with either the mortality or hospital stay. Regarding the relationship between the serum cardiac biomarkers and outcome, the patients with low CK-MB levels (<25U/L) had a much shorter hospital stay as compared to those with levels >25U/L (p-value 0.002) [Table 2]. A similar pattern was observed with troponin T levels (>14 pg/ml) but did not reach the level of statistical significance (p-value 0.054).

Table 2: Cardiac biomarkers in relation to the length of hospital stay in scrub typhus patients (N=70).

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Discussion

Cardiac involvement in scrub typhus is traditionally hallmarked by heart failure. The proposed mechanism is endothelial dysfunction due to either direct O. tsutsugamushi-related infection or an immune-mediated inflammation of the endothelium of the small cardiac vessels^{[13],[14],[15]}. Most clinical features of heart failure (dyspnea, oxygen desaturation, tachycardia, lung crackles, and pulmonary edema) are nonspecific. They often overlap with manifestations of either acute respiratory distress syndrome or renal failure^[12]. This, along with a low index of clinical suspicion and lack of screening (with cardiac biomarkers or echocardiography), makes the cardiac dysfunction go unrecognized in these patients. Specific cardiac findings such as an S3, murmurs, or pericardial rubs are rarely appreciated^[9],[10]. In this cohort of 70 patients, an audible S3 was present only in three patients even when it was explicitly looked for.

An ECG serves as a noninvasive, readily available, and inexpensive tool for screening and early diagnosis in cardiology; however, electrocardiographic abnormalities may not be diagnostic in many cases. Among our study patients, sinus tachycardia was the most common abnormality, as was seen in other studies, albeit with a much lower frequency^[9],[10]. The ST-segment changes were observed in 8.5% of patients, whereas Karthik et al. and Thipmontree et al. reported such changes in 12.3% and 3.85%^[9],[10]. In contrast to the previous studies, T wave inversion was a common abnormality (65.7%) in our study; however, cardiac arrhythmias such as atrial fibrillation, supraventricular tachycardia, and atrioventricular block were not seen [Table 3]^[9],[10].

Table 3: Comparative study of electrocardiography and echocardiography findings and serum cardiac biomarker elevation in scrub typhus.

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Echocardiography is the crucial noninvasive test for bedside evaluation of impaired cardiac function in suspected myocardial involvement. A reduced EF (<55%) was observed in 30 patients (42.8%). The comparative figure from Karthik et al. was 30.9% with EF <50% [Table 3]^[10]. Diastolic dysfunction was seen only in 1 (1.42%) patient in this cohort, whereas it was more commonly observed (22.2%) by Karthik et al.^[10]. They postulated that regional wall motion abnormalities were due to focal myocarditis which was seen in 14.8% of their patients. These were not observed in our patients. Pericardial effusion was detected in 50.0% of their cases than 12.9%, as seen in our study^[10]. Pericardial involvement is also underreported in scrub typhus patients given that routine screening is not performed, and often manifests as mild to moderate effusion without cardiac tamponade^[10]. The proposed mechanism is a direct infection, immune-mediated inflammation of the pericardium, or as a component of capillary leak syndrome^[16],[17].

We noted that systolic dysfunction was more marked in younger patients. This finding may favor an immunemediated myocardial injury like in viral myocarditis^[18]. Circulating Troponin T levels indicate an acute myocardial injury^[19]. Our study found that 72.8% of patients with scrub typhus had elevated levels, however, without a significant relationship with the critical illness scoring systems (SOFA or MODS), duration of hospitalization, or mortality.

On the contrary, serum CK-MB, another marker of myocardial injury, was elevated in 41.4% of our patients, with a significant relation to high SOFA score on day two, and longer stay duration. Karthik et al. demonstrated increased serum cardiac markers (Troponin T and CK-MB) in 61.7% of cases correlated to hospital stay but not to death. A separate analysis with each marker was not performed in that study^[10].

NT-pro-BNP is an excellent rule out marker in dyspneic patients with suspected HF with reduced or preserved EF, especially in high-risk patients. However, the false elevation may occur with advanced age, obesity, renal insufficiency, anemia, sepsis, transfusion-associated circulatory overload, and overzealous fluid resuscitation with fluid overload^[20],[21]. The increased circulating NT-pro-BNP in all our patients can be explained with a subclinical myocardial dysfunction or the presence of one of the partially confounding factors. None of the previous studies have used NT-pro-BNP in evaluating cardiac injury in scrub typhus patients. All three cardiac biomarkers predicted systolic dysfunction on echocardiography, and increasing NT-pro-BNP levels further served as a proxy marker of reducing SV.

Conclusion

This study’s overwhelming impression is that cardiac involvement in scrub typhus is common. Elevated cardiac markers predict a reduced EF on echocardiography, and additionally, an extended hospital stays with increased CK-MB. Cardiac injury is not associated with a higher risk of in-hospital mortality. Data from larger populations and multiple centers are warranted to confirm cardiac injury outcomes and a beneficial role of ‘point-of-care’ echocardiography and cardiac biomarkers to evaluate dyspnea in scrub typhus patients in a medical emergency.

Conflicts of Interest: None

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