Introduction

With one million people affected and over a billion people at risk of infection, Scrub typhus is Asia’s leading cause of treatable non-malarial febrile illness.(1–3) Also called the tsutsugamushi disease, it is caused by the gram-negative bacteria Orientia tsutsugamushi, endemic to many countries in eastern and Southeast Asia and northern Australia.(1,4–6) It has a seroprevalence ranging between 9.3%-27.9% in Asia and an 18%-23% seroprevalence across India.(3,7,8)

Scrub typhus is transmitted via arthropods, primarily through bites of trombiculid mites in the wild, and usually infects vertebrates such as small mammals and birds.(5,9)However, humans become accidental hosts when the primary vectors are unable to find their animal hosts. People surviving in areas such as forests and near mite-infested undergrowth are prone to be infected due to bites, which leads to the multiplication of the pathogen at the site of inoculation, further inducing local and systemic manifestations of infection. (4,9)

The average case-fatality rate of scrub typhus in India is around 7%, which increases up to 40% with organ involvement, including myocarditis, shock, and multiorgan dysfunction syndrome. About 81.7% of scrub typhus cases are predominantly reported from rural areas in India.(10,11) In South India, the mortality rate is 9% with antibiotic treatment. However, it is as high as 70% in those without prompt treatment.(12) Around 6.07% of seroprevalence has also been reported in the tribal belts of the Nilgiris district in south India. (13)

Scrub typhus remains underdiagnosed in India, despite its higher prevalence and mortality rates. (10) Located near forest and foothill areas of Coimbatore in south India, our hospital receives around 75 scrub typhus patients annually with varying clinical features and outcomes. Therefore, to prevent case fatality rates and morbidity, it is necessary to identify predictors of outcome in scrub typhus cases. Different predictors of outcomes in south India included duration of illness, clinical features such as altered sensorium, shortness of breath, heart rate, systolic blood pressure, acute respiratory distress syndrome (ARDS), nervous system dysfunction, etc., and ventilatory support.(2,14) Positive clinical outcomes in response to earlier initiation of antibiotic treatment have been reported previously.(15,16) However, this factor was not evaluated in South India. Therefore, this study assessed the influence of the time of initiation of antibiotics treatment on clinical outcomes such as the duration of hospitalization and the need for oxygen in scrub typhus patients. We also observed the clinical profile of this cohort of scrub typhus patients and assessed the influence of various factors on the duration of hospitalization.

Materials and Methods

This was a retrospective study conducted on patients diagnosed with scrub typhus at a tertiary care hospital in south India. The study was approved by the Institutional Human Ethics Committee (IHEC, PSG/IHEC/2022/Appr/Exp/284), dated December 14, 2022. The need for written informed consent from patients was waived off due to the retrospective nature of the study, and all the data were anonymized before analysis.

This study location is situated close to forest and foothill areas in Tamil Nadu constituting a vulnerable area for infection and hence, diagnosis of higher cases of scrub typhus. The study included case records of scrub typhus patients above 18 years old and excluded patients who were discharged against medical advice. The diagnosis was confirmed using immunoglobulin M (IgM) enzyme-linked immune sorbent assay (ELISA) (Scrub Typhus Detect™ IgM ELISA, Inbios International). The cut-off was set at a titer value of 0.5OD with a sensitivity of 98.5% and specificity of 96.3%.

The data was collected from patient records between January 2021 to November 2022. Demographics, comorbidities, clinical features of patients, duration of illness, time of antibiotic initiation, and biochemical parameters such as platelet count, serum alanine transferase (ALT), and serum aspartate transferase (AST) levels were recorded for analysis.

Statistical analysis

The data was analyzed using SPSS software. Categorical data was presented as frequency and percentages, and continuous data as mean (standard deviation, SD) or median (minimum, maximum). Mann-Whitney U test was employed for data analysis due to the non-normal distribution of data. Chi-square tests were employed to analyse for association between various parameters. A p-value less than 0.05 was considered statistically significant.

Results

Demographic data

A total of 143 eligible records from January 2021 to November 2022 were retrieved and analyzed. The mean (SD) age of the patients was 49.71 (15.26) years, and the number of men and women cases was comparable (49.7%, n=71, and 50.3%, n=71, respectively). Most patients were from rural areas (65%, n=93).

Clinical characteristics:

The patients presented with comorbidities such as diabetes mellitus (22.4%, n=32), hypertension (14.7%, n=21), ischemic heart disease (3.5%, n=5), and chronic kidney disease (2.8%, n=4). The distribution of the symptoms and the duration of illness is presented in Table 1. Most patients presented with fever (98.6%, n=141) and breathlessness (38.5%, n=55), followed by symptoms such as cough, headache, vomiting, etc. The duration of illness was greater than 5 days for 62.9% (n=90) of patients and the mean duration of hospitalization was 5.7±3.59 days. The patients were either treated with 500mg Azithromycin or 100mg Doxycycline twice a day for 7 days. Eighty-nine (63.12%) patients received antibiotic treatment within 24 hours of admission. The patients were discharged after at least 24 hours of afebrile period and the treatment with antibiotics was continued for 7 more days. No major adverse events were reported by the patients.

Other signs presented by most of the patients were abnormal alanine transaminase (SGOT, 84.6%, n=121) and aspartate transaminase (SGPT, 91.6%, n=131) levels, thrombocytopenia (65.7%, n=94), and pneumonia (30.8%, n=44). Fewer patients demonstrated eschars or rash (10.5%, n=15) and meningoencephalitis (3.5%, n=5). Only 26.6% (n=38) of patients required oxygen. The duration of hospital stay was less than 5 days for most of the patients (60.8%, n=87). Out of 143 patients, eight of them were additionally found to be infected with hepatitis A (2.8%, n=4), dengue (2.1%, n=3), and COVID-19 (0.7%, n=1).

Among 143 patients, 89 (63.12%) were started on either of the antibiotics within 24 hours of admission and their mean duration of hospitalization was 5.5±3.75 days.

Factors influencing outcomes like duration of hospitalization and oxygen requirement

Upon assessing for the association between clinical symptoms with parameters like area of residence and duration of hospital stay, we found that the symptoms were not associated with the patient’s area of residence (Table S1).

Breathlessness (p=0.000) and loose stools (p=0.035) were significantly associated with the duration of hospitalization less than 5 days (Table 2).

Among the comorbidities, hypertension (p=0.021) (Table 3), and among the different signs manifested by the patients, pneumonia (p=0.000) was significantly associated with the duration of hospitalization (Table 4).

The duration of hospitalization was also influenced by the oxygen requirement in scrub typhus patients (p<0.001) (Table 5).

The duration of illness/ infection was significantly associated with the initiation of antibiotics within 24 hours of admission (Χ²=4.571, p=0.033) (Table S2). However, the early initiation of antibiotics within 24 hours of admission did not influence the duration of hospitalization (Χ²=1.017, p=0.313) (Table S3).

Discussion

Scrub typhus is a serious public health issue, predominantly reported in the rural areas of many countries in the Asia-Pacific region like Korea, Japan, China, Taiwan, India, Indonesia, Sri Lanka, and the Philippines.(1) Though the disease was reported to be rare for several decades, a re-emergence has been reported in different states in India including Tamil Nadu, Kerala, Himachal Pradesh, Karnataka, Rajasthan, etc.(14,17,18) During colder seasons, scrub typhus accounts for up to 50% of all hospital admissions for undifferentiated fever in south India. (12) Presenting as acute febrile illness associated with headache, cough, altered sensorium, and shortness of breath, symptoms of scrub typhus develop after 9-12 days of bite, with an eschar at the site of inoculation.(16,19) Various factors, such as duration of illness, altered sensorium, ventilatory support, central nervous system dysfunction, myocarditis, acute kidney injury, hepatitis, acute respiratory distress syndrome (ARDS), etc., were reported as predictors of mortality. (14,20) Depending on the treatment initiation, a wide range of case fatality rates between 6%-70% has been reported in India, in addition to a high proportion of scrub typhus cases in south India (55.5%) alone.(10,19) This prompts the necessity to identify the influence of the time of initiation of treatment and other factors on clinical outcomes so that early treatment initiation could prevent mortality and morbidity in these patients.

In the present study mean duration of hospital stay in scrub typhus patients was 5.7 (3.59) days, which was lower than that reported by other studies in India, which ranged between 7-10 days.(21,22) This difference in the duration of hospital stay could be attributed to the stage of the disease when the patients sought medical help. In the present study, patients predominantly presented with fever, and the majority of them did not develop an eschar or other complications such as breathlessness, pneumonia, etc. But, in the other studies conducted in India, most of the patients presented with eschar and had complications like lymphadenopathy, hepatitis, and acute respiratory failure, and physical examination, revealed hepatomegaly, splenomegaly, and even cerebellar dysfunction.(21–23)

In the present study, we found that early treatment initiation influenced the duration of illness, however, it did not impact the duration of hospitalization. Patients who were initiated on early antibiotic treatment experienced a shorter duration of illness but did not sufficiently impact their stay in the hospital. Delay in treatment initiation within 24 hours of diagnosis has previously been reported as a significant risk factor for negative outcomes in a seven-year follow-up study conducted in Taiwan.(16) This contradiction could be attributed to patients reporting to the hospital at earlier stages of the disease as evidenced by the lower number of cases who presented with eschar leading to earlier diagnosis and therefore, a 0% mortality rate. Additionally, the patients in this study were initiated either on azithromycin or doxycycline, which have been prescribed as the first-line treatment of scrub typhus. This effectiveness of antibiotics used for the treatment could also have contributed to a non-significant difference in the duration of hospital stay, between groups initiated on antibiotics within and after 24 hours of admission. A recent double-blind, randomized, controlled study conducted across seven centres in India reported superior efficacy of combination therapy involving intravenous doxycycline and azithromycin than monotherapy with either drug alone.(19) Therefore, improvement in treatment approaches could further help in a better prognosis for scrub typhus.

The clinical symptoms that influenced the length of stay in the hospital were breathlessness and loose stools. In this study, more patients with these symptoms had a duration of hospitalization of more than 5 days. Several recent case reports have identified atypical cases of scrub typhus with breathlessness accompanying cryptogenic organizing pneumonia and gastrointestinal presentations including diarrhea.(24–26) These unusual presentations could increase the chance of misdiagnosis, prompting the diagnostic work-up for scrub typhus in patients from endemic locations. (24–26)

Additionally, the length of hospitalization in the present study was also influenced by the presence of comorbid hypertension and other signs of disease progression like pneumonia, which naturally increased the duration of hospitalization to more than 5 days. Pneumonia has previously been reported as predictor of severe scrub typhus. (27)

Limitations:

Some of the limitations of the study include its retrospective design, which may have introduced selection bias and confounding factors, in addition to the small sample size, and lack of a control arm. Furthermore, prospective studies must be conducted in other endemic areas in India to determine the influence of the time of antibiotic initiation on clinical outcomes.

Conclusion

This study's findings revealed that the time of initiation of antibiotic treatment did not influence the clinical outcome in terms of the duration of hospitalization. Further prospective studies need to be conducted to obtain a generalizable result. Unusual presentations such as loose stools and breathlessness significantly influenced the duration of hospitalization, along with comorbid hypertension and pneumonia.

References

1. Xu G, Walker DH, Jupiter D, et al. A review of the global epidemiology of scrub typhus. PLoS Negl Trop Dis. 2017 Nov 3;11(11).
2. Kore VB, Mahajan SM. Recent Threat of Scrub Typhus in India: A Narrative Review. Cureus. 2022 Oct 9;14(10).
3. Bonell A, Lubell Y, Newton PN, et al. Estimating the burden of scrub typhus: A systematic review. PLoS Negl Trop Dis. 2017 Sep 25;11(9):e0005838.
4. Rajapakse S, Rodrigo C, Fernando D. Scrub typhus: pathophysiology, clinical manifestations and prognosis. Asian Pac J Trop Med. 2012 Apr;5(4):261–4.
5. Luce-Fedrow A, Lehman ML, Kelly DJ, et al. A Review of Scrub Typhus (Orientia tsutsugamushi and Related Organisms): Then, Now, and Tomorrow. Trop Med Infect Dis. 2018 Jan 17;3(1):8.
6. Jiang J, Richards AL. Scrub Typhus: No Longer Restricted to the Tsutsugamushi Triangle. Trop Med Infect Dis. 2018 Jan 25;3(1).
7. Singh S, Patel SS, Sahu C, et al. Seroprevalence trends of Scrub typhus among the febrile patients of Northern India: A prospective cross-sectional study. J Family Med Prim Care. 2021;10(7):2552.
8. Jacob SM, Sekkizhar G, Kanagasabai S, et al. Seroprevalence and clinical manifestations of scrub typhus infection in Chennai city: A cross-sectional study. Int J Health & Allied Sci. 2023;7(3):201.
9. Elliott I, Pearson I, Dahal P, et al. Scrub typhus ecology: a systematic review of Orientia in vectors and hosts. Parasites & Vectors 2019 12:1. 2019 Nov 4;12(1):1–36.
10. Devasagayam E, Dayanand D, Kundu D, et al. The burden of scrub typhus in India: A systematic review. PLoS Negl Trop Dis. 2021 Jul 1;15(7).
11. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention. 2020 [cited 2023 Mar 24]. Scrub Typhus. Typhus Fevers. Available from: https://www.cdc.gov/typhus/scrub/index.html
12. Trowbridge P, Divya P, Premkumar PS, et al. Prevalence and risk factors for scrub typhus in South India. Trop Med Int Health. 2017 May 1;22(5):576–82.
13. Paulraj PS, Renu G, Ranganathan K, et al. First seroprevalence report of scrub typhus from the tribal belts of the Nilgiris district, Tamil Nadu, India. Indian J Med Res. 2021 Apr 1;153(4):503–7.
14. Varghese GM, Trowbridge P, Janardhanan J, et al. Clinical profile and improving mortality trend of scrub typhus in South India. Int J Infect Dis. 2014 Jun 1;23:39–43.
15. Veerappan I, Ramar R, Palanisamy S. Antibiotic Response to Pediatric Scrub Typhus in South India: Is Clinical Failure to Azithromycin to be Worried? J Trop Pediatr. 2021 Jan 29;67(1).
16. Lim HK, Wang JM. Scrub Typhus: Seven-Year Experience and Literature Review. J Acute Med. 2018 Sep 1;8(3):99–108.
17. Kumar D, Jakhar S. Re-emerging trends of scrub typhus disease in Southern Rajasthan (India): A Global Public Health Problem. J Vector Borne Dis. 2023;0(0):0.
18. Ranjan J, Prakash JAJ. Scrub typhus re-emergence in India: Contributing factors and way forward. Med Hypotheses. 2018 Jun 1;115:61–4.
19. Varghese GM, Dayanand D, Gunasekaran K, et al. Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus. NEJM. 2023 Mar 1;388(9):792–803. https://doi.org/101056/NEJMoa2208449. 
20. Gaba S, Gupta M, Singla N, et al. Clinical outcome and predictors of severity in scrub typhus patients at a tertiary care hospital in Chandigarh, India. J Vector Borne Dis. 2019 Dec 1;56(4):367.
21. Premraj SS, Mayilananthi K, Krishnan D, et al. Clinical profile and risk factors associated with severe scrub typhus infection among non-ICU patients in semi-urban south India. J Vector Borne Dis. 2018 Mar 1;55(1):47–51.
22. Verma SK, Gupta KK, Arya RK, et al. Clinical and biochemical profile of scrub typhus patients at a tertiary care hospital in Northern India. J Family Med Prim Care. 2021;10(3):1459.
23. Pathania M, Amisha, Malik P, et al. Scrub typhus: Overview of demographic variables, clinical profile, and diagnostic issues in the sub-Himalayan region of India and its comparison to other Indian and Asian studies. J Family Med Prim Care. 2019;8(3):1189.
24. Khanna S, Talwar D, Kumar S, et al. Scrub typhus presenting as cryptogenic organizing pneumonia in a young female: A first case report. J Family Med Prim Care. 2022;11(9):5667.
25. Guleria VS, Sharda C, Sood AK, et al. Scrub typhus: Atypical presentation in sub Himalayan region. Med J Armed Forces India. 2018 Apr 1;74(2):180.
26. Lee CH, Lee JH, Yoon KJ, et al. Case Report: Peritonitis in Patients with Scrub Typhus. Am J Trop Med Hyg. 2012 Jun 6;86(6):1046.
27. Agarwal VK, Reddy GKM, Krishna MR, et al. Predictors of scrub typhus: a study from a tertiary care center. Asian Pac J Trop Dis. 2014 Sep 1;4(S2):S666–73.