Barath Prashanth Sivasubramanian1*
Abul Hasan Shadali Abdul Khader2Diviya Bharathi Ravikumar3
Francis Vino Dominic Savio4*
Umabalan Thirupathy5Varshini Thiruvadi6Rhea Prasad3Hema Thokala7
Husna Qadeer3Dhiraj Poragal Venkataperumal3Ashima Gupta8Nagaraj Sanchitha Honganur9
Raghavendra Tirupathi10- 1Resident in the Department of Internal Medicine, Northeast Georgia Medical Center, Gainesville, GA, United States
- 2Department of Internal Medicine, Government Kilpauk Medical College, Chennai, India
- 3Department of Internal Medicine, Employee’s State Insurance Corporation (ESIC) Medical College and Postgraduate Institute of Medical Science and Research, Chennai, India
- 4Department of Internal Medicine, Tianjin Medical University, Tianjin, China
- 5Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA, United States
- 6Department of Internal Medicine, Thanjavur Medical College, Thanjavur, Tamil Nadu, India
- 7Department of Internal Medicine, Stavropol State Medical University, Stavropol, Stavropol Krai, Russia
- 8Department of Internal Medicine, Dr Panjabrao Deshmukh, Memorial Medical College, Amravati, Maharashtra, India
- 9Department of Internal Medicine University of Colorado Health/Parkview Medical Center, Pueblo, CO, United States
- 10Infectious Diseases, Keystone Health, PA, United States
Scrub typhus, a zoonotic disease caused by Orientia tsutsugamushi and transmitted by chiggers, predominantly affects the Asia-Pacific region. Complications of Scrub Typhus involve multiple systems, including cardiovascular (pericarditis, arrhythmia, myocarditis), respiratory (acute respiratory distress syndrome), hepatic (hepatitis), and renal (azotemia). In this review, we comprehensively focused on the cardiac manifestations caused due to scrub typhus. Scrub typhus-induced pericarditis should be suspected in patients residing in endemic regions presenting with fever, thrombocytopenia, and pericardial effusion. If undetected, it frequently leads to cardiomegaly, pericardial effusion, and congestive heart failure. Heart failure with scrub typhus commonly occurs following myocardial inflammation, particularly in patients with pre-existing cardiac disorders. Scrub typhus myocarditis is a relatively rare, but serious cardiac complication with a high mortality rate of up to 24.0%. Arrhythmias arise due to the involvement of the interventricular septum, coronary artery, or cardiac valves causing variable ECG findings including sinus arrhythmia, T wave changes, and QTc interval prolongation. Atrial fibrillation due to scrub typhus is associated with a 1.3 fold increase in 3-month mortality. These cardiac complications are mainly assessed using electrocardiography (ECG) and echocardiography. Serology is the primary diagnostic tool for O. tsutsugamushi. While the Scrub Typhus Detect IFA test offers 100% sensitivity, the Weil Felix test is specific and cost-effective. Nested PCR and ELISA are effective for early detection but are limited to resource-rich settings. Diagnostic difficulties arise from nonspecific symptoms and current testing limitations. Vaccine development using extracellular vesicles, nanoparticles, and subunit vaccines shows promise. Combined therapy with doxycycline and azithromycin is recommended for cardiac complications, alongside guideline-directed therapy. The review underscores the need for heightened clinical awareness and prompt management of scrub typhus, especially in endemic regions. It also highlights the necessity for further research into the pathogenesis of cardiac involvement and the development of more effective diagnostic tools and treatments.
Introduction
Scrub typhus is a zoonotic illness caused by Orientia tsutsugamushi, transmitted by the bite of trombiculid mite larvae (chiggers). The disease is most frequently reported within the “tsutsugamushi triangle” of the Asia-Pacific region, which encompasses more than 8 million km², including Thailand, India, China, Korea, Philippines, Taiwan, Sri Lanka, and extending from the Russian Far East in the north, to Pakistan in the west, Australia in the south, and Japan in the east (1). The pathophysiology of O tsutsugamushi involves vasculitis due to the infection of endothelial cells, leading to perivascular infiltration of T cells and monocytes or macrophages. Subsequently, a wide range of inflammatory responses occurs, with endothelial and non-endothelial cells producing various cytokines. These cytokines can have both beneficial effects, such as antimicrobial activity, and detrimental effects, causing tissue destruction in the infected host. This immune response’s dual nature can lead to severe complications such as hepatitis, renal failure, meningoencephalitis, and respiratory failure, including acute respiratory distress syndrome (ARDS) and myocarditis (2). The bacterial dissemination and replication during early infection need to be better understood (3). Vascular involvement is hypothesized to occur by downregulating the expression of glycoprotein-96 in the endothelial cells and phagocytes and by neutralizing the host’s immune response (4). Orientia infection is also proposed to affect CCR2, which drives blood monocytes into the lung, accelerating bacterial replication and the development of inflammation of the pulmonary interstitium (5). C-type lectin receptors, CCR7/dendritic cell-mediated mechanisms are also involved in immune dysregulation in scrub typhus (3, 6, 7). TNF receptors played an intrinsic role in CD8+ T cell activation, revealing the protective immunity of TNF against O. tsutsugamushi infection (8). Scrub typhus can increase several interleukins (IL-1alpha/beta, IL-4, IL-6, IL-7, IL10, IL-11, IL-18, and IL-24), chemokines (CXCL8, CCL2/MCP1, CCL5/RANTES, and CCL17), growth factors (NODAL, CNTF, and CSF2/GM-CSF), and TNFSF13B (9, 10). This can disrupt the B/T cell microenvironment and dysregulation of B cell responses during active infection (11). The cytokine signatures can be used as depletion targets in future experiments (12).
Scrub typhus is known to produce several cardiotoxic, hepatotoxic, and nephrotoxic metabolites (13). The incidence of complicated scrub typhus increases with delayed diagnosis and treatment of scrub typhus (14). Untreated infections can cause multi-organ involvement and raise the cost of treatment (15). The most common complications are hepatitis (40.5%), thrombocytopenia (28.4%), acute respiratory distress syndrome (20.5%), acute kidney injury (19.2%), meningitis (16.4%), shock (16.2%), and myocarditis (15.5%) (16, 17). Scrub typhus can persist for longer durations in the affected organs (18). Cardiac involvement due to scrub typhus is attributed to macrophage activation, immune-mediated or direct invasion of cardiomyocytes, and electrolyte alterations (4, 19–22). Table 1 depicts the Cardiac manifestation of scrub typhus.
Table 1. Cardiac manifestation of scrub typhus.
Several studies are being published in the native languages of endemic areas and studies that rely on national surveillance systems often face missing data due to unreported cases. Most studies are conducted on a small sample size with a single-center design. Due to a paucity of literature on cardiovascular compilations, there is a delay in timely diagnosis (23, 24). Scrub typhus is a rapidly emerging public health threat but no national protocols for prevention exist in Southeast Asia (25).
This article aims to provide a comprehensive review of the literature on the cardiac manifestation of scrub typhus to aid clinicians in timely diagnosis by ordering the ideal tests and optimal treatment modalities.
Epidemiology
Scrub typhus is endemic to a vast area known as the “tsutsugamushi triangle,” encompassing over 8 million km² of the Asia-Pacific region. This includes countries like Thailand, India, China, Korea, the Philippines, Taiwan, and Sri Lanka, stretching from the Russian Far East in the north to Pakistan in the west, Australia in the south, and Japan in the east. Within this region, specific locations like the northeastern states of India, Fujian province in China, the northern region of Thailand, and the southernmost part of Taiwan exhibit higher disease prevalence (1, 16). In South Korea, scrub typhus is most common in the southern and western regions, with a peak incidence in the later months of the year (26). The disease is also concentrated in the western province of Sri Lanka and limited to northern Queensland, Australia (27, 28). Epidemiology across various countries with respective prefectures and seasonal pattern have been described in the below.
The disease poses a significant public health threat, with an estimated one million cases annually. While primarily concentrated within the tsutsugamushi triangle, sporadic cases have been identified outside this region, underscoring the importance of understanding its global distribution (1) (Table 2).
Table 2. Epidemiological distribution of scrub typhus.
Pericarditis
Pericarditis is an additional noteworthy cardiac complication linked with scrub typhus. It frequently leads to cardiomegaly and, if untreated, can progress to pericardial effusion and congestive heart failure (26). Recent studies by Karthik et al. and Chin et al. have observed pericardial effusion in 51% and 20% of their respective patient populations. However, there is no mention of the development of cardiac tamponade in the studies (27, 28). In patients residing in endemic regions presenting with fever, thrombocytopenia, and pericardial effusion, clinical suspicion of scrub-typhus pericarditis should be taken into consideration (29). In certain cases, perimyocarditis can also occur and poses a diagnostic challenge due to its nonspecific presentation (30).
The diagnosis entails confirming the presence of pericardial effusion and serological tests such as the immunofluorescence assay (IFA) or the IgM enzyme-linked immunosorbent assay (ELISA) (26). The recently developed tool of PCR-based detection of tissue or tissue fluid can also aid in the diagnosis of scrub typhus (26, 29). Other supportive findings include an increase in inflammatory markers (erythrocyte sedimentation rate/C-reactive protein), ST-elevation in the anterior leads of the ECG, and a hypervascular epicardial region observed in CT angiography (30). Treatment options consist of doxycycline and azithromycin as an alternative if any side effects develop with doxycycline (29). Timely suspicion and appropriate management are crucial for achieving clinical improvement and reducing mortality (26).
Heart failure
Cardiac failure in patients with scrub typhus commonly occurs following myocardial inflammation. Younger patients often had a moderate reduction in ejection fraction and patients with predisposed cardiac disorders had a higher risk of developing heart failure. The presentation of heart failure characterized by dyspnea and features of fluid overload, may or may not be present (31–36). Even rare presentations such as Takotsubo cardiomyopathy and acute cor pulmonale with predominant lung involvement are seen with scrub typhus (31, 37). Due to atypical presentation and absence of physical signs, a high index of suspicion is necessary to diagnose heart failure before the development of cardiogenic shock (14, 38, 39). This warrants the identification of scrub typhus, chest X-ray, BNP (or NT-proBNP), and echocardiogram workup in suspected patients (28, 36, 40). 18.5% of patients with scrub typhus had detectable features of congestive heart failure on Chest X-ray (40). An echocardiogram is recommended to assess cardiac chamber size, wall thickness, and ventricular function in suspected myocarditis (41). Patients with CK-MB >25 U/L had a significantly longer length of hospital stay (36). If the diagnosis is uncertain, an endomyocardial biopsy can be obtained, but we exercise caution in patients with heart failure to further prevent the development of cardiogenic shock (42).
Management of acute heart failure from scrub typhus includes hemodynamic monitoring, stabilization with fluid resuscitation, vasopressor support, GDMT-guided therapy, and appropriate antibiotics such as doxycycline (31, 34, 42–44). As glucocorticoid is often used in severe sepsis, low doses of the same can be used in life threatening infections (45). One study reported a dramatic improvement in scrub typhus when steroids and chloramphenicol were used together (46). In our hospital, we have observed prompt improvements with the use of steroids for refractory shock (severe myocarditis), impending adult respiratory distress syndrome, or repeated seizures (severe encephalitis). However, as steroids inhibit the development of immunity against scrub typhus, the duration of use should be minimized (47). ECMO has also been effective in treating patients with complications (14). A repeat echo, 2 weeks following recovery is recommended to assess the resolution of Ejection Fraction and heart enlargement (31, 35, 44).
Arrhythmia
During acute infection, arrhythmia occurs due to the involvement of the interventricular septum, coronary artery, or cardiac valves (48). Table 3 depicts different ECG findings encountered in Scrub Typhus.
Table 3. ECG findings encountered in Scrub Typhus.
Atrial fibrillation
We focused on atrial fibrillation due to scrub typhus because it is a poor prognostic factor, with a 1.3-fold increase in 3-month mortality associated with new-onset AF (49). About 1% of patients with scrub typhus are found to have new-onset AF and the majority (87.2%) were >60 years of age. Regardless of occurrence, these patients were also more likely to have a previous diagnosis of cardiovascular disease, with a 1.67 times higher risk in patients with prior hypertension, a 1.9 times higher risk in ischemic heart disease, and a 1.5 times higher risk of heart failure in developing AF (49–51). Atrial fibrillation was seen in patients with an older age, male sex, fever, leukocytosis, and abnormal renal and liver functions (50, 51). However, the management of atrial fibrillation remains the same. In patients with the acute phase of infection, it is important to perform serial ECG monitoring (52) and in patients with suspected atrial fibrillation baseline cardiac enzymes (mainly CK MB) and Echocardiogram are needed. These will aid in identifying myocarditis as Paroxysmal AF is a strong predictor of myocarditis (70% sensitivity and 84% specificity) (28).
For treatment of atrial fibrillation, we recommend taking appropriate measures to maintain hemodynamic stability including ICU admission (52). Achieving rate control is key in the treatment through the use of agents like calcium channel blockers and/or beta-blockers. If rate control is hard to achieve or the patient is symptomatic, attain rhythm control through cardioversion or antiarrhythmic agents (amiodarone, flecainide, propafenone, dofetilide, and ibutilide) (53). Prompt treatment of scrub typhus with oral or intravenous antibiotics (doxycycline, azithromycin, or rifampicin) prevents serious cardiac complications (48, 52, 54). In patients with hemodynamic instability, intravenous antibiotics are preferred to achieve therapeutic levels (55). In addition to this, monitoring the metabolic panel is essential to prevent further complications (52).
Myocarditis
Myocarditis is defined as the inflammation of the cardiac muscle that causes chest pain, palpitations, and heart failure and is often accompanied by changes in the electrocardiogram, and elevated levels of inflammatory and cardiac biomarkers (56). Myocarditis is relatively rare and has been reported in only a few cases of scrub typhus and varies in severity from mild to fulminant, with some cases requiring mechanical circulatory support (14, 30, 44–46). The incidence of myocarditis in scrub typhus varies and has been reported to range from 8% to 14% (27, 28, 57–63) and a recent systematic review indicated an incidence of 4.3% (23, 27, 28, 62). Scrub typhus myocarditis is a serious cardiac complication with a mortality rate as high as 24.0% (23). Certain risk factors have been identified that can increase the risk of acute myocarditis, including paroxysmal atrial fibrillation (OR= 2.85; p= 0.02), elevated levels of total bilirubin (OR= 1.2; p= 0.04), and a shorter duration of symptoms before presentation (mean duration of illness= 6.8d vs 8.3d OR= 0.69; p= 0.04) (28, 30). The other risk factors that contribute to a poor prognosis with scrub typhus include liver disease (OR= 62.70; p=0.011), elevated C-reactive protein (OR= 122.69; p= 0.002), elevated bilirubin levels (RR= 9.28; p= 0.02), and elevated creatinine levels (RR= 43.9; p= 0.003) (28, 64). Identifying and acknowledging these risk factors promptly facilitates risk stratification and enables timely management (28, 64). The exact mechanism of myocarditis in scrub typhus is not well understood, and further research is needed for better understanding (14).
Patients with myocarditis can present with nonspecific symptoms like fever, myalgia, palpitations, and exertional dyspnea or even with cardiogenic shock and sudden cardiac death (65, 66). Thus, in cases of systemic infection with scrub typhus and concomitant new cardiovascular dysfunction or elevated cardiac enzymes, myocarditis should be suspected (45). Various tests like ECG, echocardiography, endomyocardial biopsy, and cardiac MRI aid in the diagnosis of acute myocarditis in scrub typhus (27, 44, 45). ST abnormalities on ECG may serve as an initial manifestation in the majority of patients (44). In a prospective study, ECG changes such as T wave inversion (p= 0.02) and QRS changes (p< 0.001) correlated with the occurrence of myocarditis (27). Cardiac biomarker- Troponin T is utilized as the most sensitive biomarker to indicate myocyte injury in patients with suspected myocarditis. The diagnosis of myocarditis is considered if myocardial injury coincides with global myocardial dysfunction (27). Echocardiography to detect impaired left ventricular function is needed in suspected cases of myocarditis (27). Endomyocardial biopsy has proven helpful in establishing the diagnosis in certain cases, as highlighted in a recent case report by Park et al. (14, 42, 67). A special indication of endomyocardial biopsy includes patients who develop acute decompensated heart failure of unknown etiology (less than 2 weeks in duration) (68). This technique has its limitations, such as invasiveness in hemodynamically unstable patients, difficulties in acquiring adequate specimens, and low sensitivity (45). Recently, cardiac MRI has been increasingly utilized for the diagnosis and prognostic assessment of myocarditis. This imaging modality offers three key advantages- it indirectly assesses cardiac function, aids in guiding myocardial biopsy at suitable sites, such as focal regions identified on the cardiac MRI, and facilitates the distinction between myocarditis and myocardial infarction based on the delayed gadolinium enhancement pattern in the myocardium (45, 69). Treatment for scrub typhus-induced myocarditis is doxycycline 100 mg IV or orally twice daily for 7-14 days and it has demonstrated efficacy in multiple cases (14, 44, 45). Interestingly, in certain severe cases, the addition of intravenous chloramphenicol to doxycycline is necessary (66). Low-dose glucocorticoids have been used in conjunction with antibiotics for severe myocarditis in a few cases with improvement (17, 47). However, this remains controversial as steroids inhibit the development of immunity against scrub typhus, and increase the risk of scrub relapse, and post-typhus asthenia. Also, in-vitro studies have shown steroids do not increase bacteria counts yet further in vivo research is warranted to support this line of management (70). In cases of fulminant progression that does not respond to medical management, the successful and prompt implementation of VA ECMO has proven to be beneficial (14, 46).
Myocardial ischemia
Scrub typhus can cause ischemic events through endothelial dysfunction and increase proinflammatory mediators which further worsens this event. It can also cause systemic vasculitis or can also cause plaque stability (71). Patients who have high-risk factors for acute coronary syndrome can also develop myocardial ischemia during the illness. Men and patients of 35-49 years of age had a 2-fold increased risk of developing acute coronary syndrome. The risk of ACS was also associated with diabetes (adjusted HR =2.77, 95% CI 2.04 to 3.76), hypertension (adjusted HR 1.88, 95% CI 1.38 to 2.76), and previous coronary artery disease (adjusted HR=1.53, 95% CI 1.03 to 2.27). However, they also remain independent risk factors of ACS after adjusting for covariates (72). During 6 month follow-up, patients who had scrub typhus had a 3-fold significant increase in the risk of developing ACS (95% CI 1.47 to 7.70) (72). As the pathogenesis involves systemic vasculitis, young patients have presented with no atherosclerotic blockage on coronary angiography but exhibit symptoms of acute coronary syndrome. Additionally, they show elevated cardiac enzymes and EKG changes (73). There are also cases of scrub typhus where thrombotic occlusion was identified and percutaneous intervention where necessary to stabilize the patient (74, 75). We recommend treating patients with appropriate antibiotics and depending on coronary angiography findings further management should be planned.
Endocarditis
BCNIE (blood culture-negative infective endocarditis) can manifest in up to 31% of all patients with infective endocarditis with significant diagnostic and therapeutic difficulties. Scrub typhus-induced endocarditis is extremely rare and presents as blood-culture negative IE (76). However, based on clinical suspicion and endemicity in the region, clinicians should consider workup for scrub typhus as a possible etiology (77). In a case report by Yu et al. in 2016, chloramphenicol (1g q12h iv drip for 10 days) may be appropriate for scrub typhus-associated infective endocarditis. However, further large-scale prospective randomized controlled trials are necessary to validate this finding (77).
Diagnostic methods
Serology is the primary diagnostic tool for O. tsutsugamushi infection. IgM antibody titer increases by the end of the 1st week of the infection, while IgG antibody peaks by the end of the 2nd week. The Weil-Felix test is the most affordable serological test to detect antibodies for various Proteus species. A titer of 1:320 or above, or a fourfold increase from 1:50, is considered positive (76). However, the test has a low sensitivity of 33% at a breakpoint titer of 1:80 but with 100% specificity and positive predictive value (78, 79). Indirect immunofluorescence antibody (IFA) is an expensive, specialized test to confirm infection before seroconversion (80, 81). The lateral flow rapid test and Scrub Typhus Detect use recombinant 56-kDa antigen and have shown a strong potential for diagnosing scrub typhus patients with 100% sensitivity and 92% specificity for IgM. This prototype product can help clinicians diagnose patients rapidly, accurately, and easily, allowing them to provide timely care (82). Some commercial laboratories in India offer the immunochromatographic test (ICT) that serves as a rapid diagnostic test, with the advantage of being inexpensive (83). Replacing fluorescein with peroxidase, indirect immunoperoxidase eliminates the need for a fluorescent microscope, making it beneficial in a resource-poor setting (84). Western immunoblot assay is an effective serodiagnostic tool for large-scale screening and confirming serologic diagnosis. It uses sodium dodecyl sulfate-gel electrophoresed and electro-blotted antigens and helps analyze cross-reactive strains (80). The most abundant and immunodominant protein is employed in a recombinant protein-based enzyme-linked immunosorbent assay, which has been developed to detect Orientia-specific antibodies in serum. Four prototype strains of Karp were used to generate three recombinant protein antigens, namely TA763 (r56C1), Kato (r56Kt), and Gilliam (r56Gm) Orientia. Chimeric proteins were compared to titers of serum samples against Karp, Kato, Gilliam, and TA763 strains. These new proteins had similar reactivity to parent proteins and were recognized by 14 Orientia strains, making them useful for diagnosis and vaccination. Chimeric C1 was identified as a potential substitute for parent proteins to diagnose Orientia infection and as a vaccine candidate with broad protective efficacy (81). It can be regarded as an enhanced, practical, and affordable substitute for the gold standard IFA in rapid diagnosis and seroprevalence (85). A cell-based ELISA technique was used to test serum samples from ST-positive rats and monoclonal antibodies. The accuracy, sensitivity, and specificity of this technique were 96.3%, 98.6%, and 84.6%, respectively. The results were consistent with those of immunofluorescence assays. This technique is safe, easy to operate, and does not require specialized equipment (86). Rickettsial culture can be obtained from buffy coats of heparinized blood, defibrinated whole blood, plasma, and skin biopsy. Different methods, such as MRC 5 cells, Vero cell culture, BHK21, etc., are used for this purpose, with Vero or L929 cells enabling quicker and more effective isolation (87). The average time required for culture isolation of Rickettsia species is four weeks (88). However, bacterial culture for O. tsutsugamushi is a tedious process requiring biosafety level 3 containment and significant technical expertise. Due to its complexity, it is primarily used for research purposes in reference laboratories.
Polymerase Chain Reaction (PCR) molecular detection using skin rash, lymph node, or blood samples is an efficient and sensitive method for diagnosing scrub typhus. Real-time PCR assays based on GroEL provide a more quantitative result, while nested PCR is one hundred times more sensitive than single PCR (76, 89, 90). Combined with IFA, nested PCR has a sensitivity of 82.2% and specificity of 100% (91) and other studies also show similar findings (87, 92, 93).
A tool was created to distinguish severe fever with thrombocytopenia syndrome (SFTS) from scrub typhus. It uses low CRP, thrombocytopenia, and leukopenia as variables. A score of >=2 has a specificity of 96.1% and a sensitivity of 93.1% for SFTS (89). Recently, the highly conserved O. tsutsugamushi 60 kDa GroEL chaperonin produced by E. coli was the focus of an immunochromatographic antigen detection test kit (ICT AgTK). Polyclonal antibodies, including a rGroEL-specific monoclonal antibody, were used as antigen detection reagents. In in-house validation studies, the test showed potential with a sensitivity, specificity, and accuracy of 85%, 100%, and 95%, respectively, compared to the combined clinical characteristics and standard IFA. This test holds promise for on-the-spot and early diagnosis of scrub typhus (90). In a recent report by Zuan Zhan et al, metagenomic next-generation has been used to diagnose scrub typhus in a patient with fever, multiorgan dysfunction, and negative serology (94). It has the advantage of having the ability to diagnose scrub typhus early in the course of illness (95). The investigations are summarized in Table 4.
Table 4. Summary of the investigations.
Treatment
The increase in outbreaks both within and outside the Tsutsugamushi Triangle, the emergence of antibiotic-resistant strains of Orientia, and the emergence of new Orientia species (101). During the 1990s, genotypes in Thailand that were resistant to chloramphenicol and doxycycline were identified (101, 102). The strains AFSC-3 and AFSC-4 of the pathogen are identified as resistant to doxycycline (102). Proposed mechanisms to explain resistance include dormant organisms within patients subjected to repeated or long-term exposure to antibiotics. Additionally, the supplementation of poultry feed in Thailand with antibiotics may result in the development of drug-resistant strains of chiggers. The ingestion of antibiotics by mites during their feeding on their rodent host, which frequently consumes grain designated for poultry, is a plausible consequence (101). The occurrence of treatment failures has also prompted reports of potential doxycycline resistance in India and South Korea (103). It is important to note that the prophylactic administration of doxycycline has failed to prevent breakthrough infections and can lead to the emergence of resistant strains (101). Despite this, there is no evidence of extensive presence or prevalent distribution of scrub typhus strains that are resistant to antibiotics (101).
Monotherapy vs combination therapy?
When it comes to treating cardiac complications, our recommendation aligns with Varghese et al. The study by Varghese et al. was a prospective, multicenter, randomized trial with a large sample size, and concluded that combination therapy with azithromycin and doxycycline is better than monotherapy when it comes to severe sepsis and organopathies (104). We recommend combination therapy, especially in patients with multiple organ involvement and in those with multiple comorbidities that further increase their risk for cardiac complications (104). In patients who have not yet developed cardiac complications but are from endemic regions of scrub typhus and have an eschar on presentation, we recommend empirical therapy (103) as either a monotherapy or as a combination therapy (47, 104). In regions where doxycycline resistance is not a concern, drugs such as doxycycline, rifampicin, or azithromycin can be used (47). Rifampicin and doxycycline combination therapy showed more effectiveness and longer fever clearance than monotherapy (105). Since rifampicin is an integral part of antitubercular therapy, it should be kept as a last resort. In pregnant women, azithromycin is preferred over doxycycline. For the treatment of nonpregnant adults, oral doxycycline is comparable to iv azithromycin in treating scrub typhus (106). When treating an undifferentiated fever in clinic practice, cefotaxime is not a preferred therapy for scrub typhus. This is because when used in combination therapy, it has demonstrated an antagonistic effect with azithromycin and doxycycline. The reason behind the antagonism is not well understood (47). Table 5 depicts commonly used antimicrobial agents in scrub typhus infection.
Table 5. Commonly used antimicrobial agents in scrub typhus infection (123).
The next step in treatment and prevention
Traditional ayurvedic and Chinese phytochemicals containing compounds (ZINC8214635, ZINC32793028, ZINC08101133, ZINC85625167, ZINC06018678, and ZINC13377938) have demonstrated successful inhibition of Orientia tsutsugamushi (107). Newer compounds and antibiotic discovery are underway. The CDC recommends avoiding contact with infected chiggers (25). General measures against vectors include minimizing exposure through clothes avoiding walking through dense vegetation, sitting in bare ground or grass, and use of insecticides and insect repellants. Appropriate clothing to avoid getting bitten in sun-exposed areas. Personal hygiene is advised and removal of clothing and thorough cleaning of skin and clothes with detergent can reduce the risk of infection. Postexposure prophylaxis with doxycycline is currently not recommended (1, 108). However, prophylactic medications of doxycycline, chloramphenicol, or tetracycline are provided in the endemic areas (single dose every 5 days for a total of 35 days) (1, 109). Measures to control rodents that attract these vectors are also recommended (108).
Vaccines
The existence of numerous strains of Orientia tsutsugamushi hinders the development of a broad and lasting immune response. Efforts to prepare a vaccine have been ongoing since World War II. A recent study has highlighted that the CD-1 outbred mice model proves valuable for understanding host susceptibility and facilitating future vaccine studies (110). Table 6 depicts the evolution of vaccines for scrub typhus. Field trials and large-scale attempts, such as the Tyburn operation and studies by the Japanese, were not fruitful, each demonstrating setbacks, particularly the waning of immunity or the acquisition of a fatal infection post-vaccination (112–115). Vaccine preparation has been attempted through formalin-inactivated pathogens, live attenuated strains, irradiated strains, and using antibiotics and live vaccines together. However, all these strategies have failed to provide either long-term immunity for homologous strains or any immunity against heterologous strains (115–122). This encouraged a shift towards the development of subunit vaccines (112).
Table 6. Evolution of vaccines for scrub typhus.
Over the last two decades, the focus on scrub typhus subunit vaccine involved the production of recombinant proteins (kDa antigens) and their incorporation into DNA vaccine candidates through cloning (124, 125). Research on the 56-kDa protein of Rickettsia tsutsugamushi explored TSA56 (56-kDa type-specific antigen), a key outer membrane protein, as a potential vaccine candidate for generating immunity against scrub typhus. Kp r56 showed strong immunogenicity, triggering immune responses and IFN-γ production (126). The plasmid DNA vaccine pKarp56, pKarp110, 47 kDa gene fragment, and the fused antigen Sta56-47 demonstrated the ability to elicit robust immune responses (124, 127–129). Additionally, a novel recombinant antigen derived from the conserved regions of the 56 kDa type-specific antigen (cTSA56) provided superior protection against both homologous and heterologous genotypes (130). Recent studies also explored the protective effects of ScaA immunization and Zinc oxide nanoparticles (ZNPs) as a novel vaccine carrier system for O. tsutsugamushi (131, 132). Subsequently, dual-antigen subunit vaccine nanoparticles (47 kD and 56 kD) also highlight their potential as a promising vaccine strategy (133).
The intranasal rec56 vaccines elicited a higher IgG response than the intramuscular route (134). Supporting this, Park et al. demonstrate the development of an intranasal vaccine targeting Orientia tsutsugamushi’s outer-membrane protein (OMPOT), intranasal vaccination boosts cell-mediated and protective immunity in pulmonary compartments (135). A model vaccine, utilizing extracellular vesicles (EVs) derived from Salmonella expressing DNA sequences of full-length Ot proteins (TSA56, ScaA, ScaC, ScaD, and ScaE), showed promising results. Inoculation with EVs from TSA56-expressing cells protected mice from Salmonella-induced illness, suggesting the potential for scrub typhus immunizations based on T-cell immune response (136).
Conclusion
We conducted a review of the literature to raise awareness on cardiac complications of scrub typhus. Our review is limited to strain-specific epidemiological patterns and treatment options based on disease severity. The early identification of at-risk cases is key to managing these complications, particularly patients from endemic regions presenting with eschars. IFA is the gold standard for investigation and rapid ICT kits are invaluable in resource-limited areas. The approach to the individual cardiac complications is decided based on the presentation and investigations such as ECG and echocardiography findings of the patients. We recommend combined therapy with doxycycline and azithromycin for treating cardiac complications in addition to the guideline-directed therapy for the cardiac event. Vaccine development using extracellular vesicles, nanoparticles, and subunit vaccines containing recombinant proteins has demonstrated potential. However further research is needed to design a vaccine that can provide a long-lasting immunity against scrub typhus.
Author contributions
BS: Writing – original draft, Writing – review & editing. AA: Writing – review & editing, Writing – original draft. DR: Writing – review & editing, Writing – original draft. FD: Writing – original draft, Writing – review & editing. UT: Writing – review & editing, Writing – original draft. VT: Writing – review & editing, Writing – original draft. RP: Writing – original draft. HT: Writing – original draft. HQ: Writing – original draft. DP: Writing – original draft. AG: Writing – original draft. NH: Writing – original draft. RT: Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: scrub typhus (tsutsugamushi disease), Orientia species, cardiac complications, pericarditis, myocarditis, arrhythmia, heart failure, mite-borne disease
Citation: Sivasubramanian BP, Abdul Khader AHS, Ravikumar DB, Dominic Savio FV, Thirupathy U, Thiruvadi V, Prasad R, Thokala H, Qadeer H, Venkataperumal DP, Gupta A, Honganur NS and Tirupathi R (2024) Comprehensive review on cardiac manifestation of scrub typhus. Front. Trop. Dis 5:1375087. doi: 10.3389/fitd.2024.1375087
Received: 01 February 2024; Accepted: 22 July 2024;
Published: 20 September 2024.
Edited by:
Suzanne Donovan, University of California, Los Angeles, United StatesReviewed by:
Yohei Sato, Jikei University School of Medicine, JapanJirko Kühnisch, Charité University Medicine Berlin, Germany
Copyright © 2024 Sivasubramanian, Abdul Khader, Ravikumar, Dominic Savio, Thirupathy, Thiruvadi, Prasad, Thokala, Qadeer, Venkataperumal, Gupta, Honganur and Tirupathi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Barath Prashanth Sivasubramanian, barathprashanth18196@gmail.com; Francis Vino Dominic Savio, francis.vino@gmail.com