Patient Profile:

42 years old male presented with

• Fever, respiratory distress, and general
• No significant past medical
• Social History: No history of recent travel, exposure to tick bites, or contact with  Non-smoker, occasional alcohol use.

Clinical Presentation:

• The patient presented to the ER with a history of high- grade fever for 4 days, severe fatigue, and progressive shortness of breath.
• Initial physical examination revealed tachypnea, tachycardia, and  The patient was febrile with a temperature of 102.5°F.
• Eschar was noted on the skin

Investigations:

• Complete Blood Count (CBC):- revealed severe thrombocytopenia (15000) with mildly elevated liver

(ABG): revealed type 1 respiratory failure

• Chest X- ray: Bilateral diffuse infiltrates consistent with Acute Respiratory Distress Syndrome (ARDS).
• Scrub Typhus IgM ELISA: Positive
• Blood Cultures: Negative

Treatment:

• Initial Management:
  • The patient was started on high-flow nasal cannula (HFNC) due to severe hypoxemia with a FiO2 requirement of 70%
  • Intravenous fluids were administered cautiously due to the risk of fluid overload in the setting of
  • Empirical antibiotic therapy was initiated with **Azithromycin (500 mg once daily) and Doxycycline (100 mg twice daily)** for dual coverage against scrub

• Supportive Care:
  • There was a improvement in oxygenation, allowing for a gradual reduction in FiO2requirements and subsequently tapered from
  • Platelet transfusion was not initially required as there was no evidence of active bleeding but in due course Day 3 and Day 4 his platelets dropped to less than 10000 which required platelets .
  • Liver function tests and platelet counts were monitored

Outcome:

• Day6, the patient’s respiratory status improved  He was weaned off HFNC to nasal cannula with 4L/min of oxygen. Platelet counts started to recover (85,000 cells/µL), and liver function tests showed normalization of transaminases.
• The patient was eventually transferred out of the ICU to a general ward for continued

Discussion:

Scrub typhus, a life-threatening zoonotic bacterial  infection caused by Orientia tsutsugamushi and transmitted by trombiculid mite larvae, is a public health challenge that extends beyond the so-called Tsutsugamushi Triangle, the region where this infection has traditionally been endemic in Asia and Northern Australia. A billion people are estimated to be at risk in endemic regions, with an estimated 1 million cases and 150,000 deaths annually. Scrub typhus typically presents as an acute febrile illness that may be associated with headache, cough, shortness of breath, and altered sensorium. An eschar at the site of the mite bite serves as a highly distinctive diagnostic clue. When this infection is untreated, the median case fatality is approximately 6% but can reach 70% in severe disease. Severe disease (including multiorgan dysfunction and shock) develops in approximately one third of hospitalized patients and can lead to death in approximately a quarter of cases despite therapy.

Historically, scrub typhus has been treated with doxycycline or chloramphenicol. However, data from sufficiently powered, randomized, controlled trials are lacking, particularly for severe scrub typhus. In recent years, chloramphenicol has been used less frequently because of its toxicity profile, and oral azithromycin is increasingly used for mild scrub typhus. A small, prospective, open-label, randomized trial in South Korea involving patients with mild scrub typhus showed that single-dose azithromycin (500 mg) was as effective as doxycycline (200 mg) daily for a week.

Intravenous Treatment for Scrub Typhus (INTREST) clinical trial was conducted to compare the efficacy and safety of three 7- day intravenous antibiotic treatments (doxycycline, azithromycin, or a combination of both) in patients with severe scrub typhus and concluded that combination therapy with intravenous doxycycline and azithromycin was superior to monotherapy with either drug with respect to the primary composite outcome of death at day 28, persistent complications at day 7, and persistent fever at day 5 in both the modified intention-to-treat and per-protocol populations. The superiority of combination therapy was mainly due to a reduced incidence of persistent complications at day 7, when the frequencies of respiratory, renal, hepatic, and central nervous system complications were lower in the combination- therapy group than in either of the monotherapy groups.

Severe scrub typhus is associated with substantial complications and death. Common manifestations resulting in organ involvement include acute respiratory  distress syndrome, hepatitis, shock, meningoencephalitis, and renal failure.

Why a combination of doxycycline and azithromycin should be more clinically effective in the treatment of severe scrub typhus than either of the drugs alone is a matter of speculation. Through different  mechanisms, the  two drugs inhibit messenger RNA translation at the bacterial ribosome. Azithromycin binds the 23SrRNA of the 50S ribosomal subunit at the polypeptide exit tunnel, and doxycycline prevents aminoacyl-tRNA binding to the 30S ribosomal subunit. The combination of the two drugs may result in a more complete blockade of  protein synthesis with a consequently greater effect against O. Tsutsugamushi. Better bacterial control during the critical first week of infection may result in prevention and faster resolution of severe manifestations of illness.

Conclusion:

This case highlights the importance of early recognition  and aggressive management of scrub typhus, particularly in patients presenting with severe complications like ARDS and thrombocytopenia. The patient responded well to the combination of azithromycin and doxycycline, coupled with intensive supportive care. There is some clinical support for the use of dual therapy in severe cases of scrub typhus. Dual therapy offers significant advantages over monotherapy, particularly in high-risk or critically ill patients.

References:

1. Weitzel T, Dittrich S, López J, et al. Endemic scrub typhus in South America. N Engl J Med 2016;375:954-961.
2. Xu G, Walker DH, Jupiter D, Melby PC, Arcari CM. A review of the global epidemiology of scrub typhus. PLoS Negl Trop Dis 2017;11(11):e0006062-e0006062.
3. Wangrangsimakul T, Elliott I, Nedsuwan S, et al. The estimated burden of scrub typhus in Thailand from national surveillance data (2003–2018). PLoS Negl Trop Dis 2020;14(4):e0008233-e0008233.
4. Li Z, Xin H, Sun J, et al. Epidemiologic changes of scrub typhus in China, 1952–2016. Emerg Infect Dis 2020;26:1091-1101.
5. Devasagayam E, Dayanand D, Kundu D, Kamath MS, Kirubakaran R, Varghese GM. The burden of scrub typhus in India: a systematic review. PLoS Negl Trop Dis 2021;15(7):e0009619-e0009619.
6. Roychowdhury S, Ghosh S, Majumder D, Mukhopadhyay P. A menace without specific feature — scrub typhus a reemerging disease. J Assoc Physicians India 2022;69:11-12.
7. Kundavaram AP, Jonathan AJ, Nathaniel SD, Varghese GM. Eschar in scrub typhus: a valuable clue to the diagnosis. J Postgrad Med 2013;59:177-178.
8. Tran HTD, Schindler C, Pham TTT, et al. Simple clinical and laboratory predictors to improve empirical treatment strategies in areas of high scrub typhus and dengue endemicity, central Vietnam. PLoS Negl Trop Dis 2022;16(5):e0010281-e0010281.
9. Taylor AJ, Paris DH, Newton PN. A systematic review of mortality from untreated scrub typhus (Orientia tsutsugamushi). PLoS Negl Trop Dis 2015;9(8):e0003971-e0003971.
10. Bonell A, Lubell Y, Newton PN, Crump JA, Paris DH. Estimating the burden of scrub typhus: a systematic review. PLoS Negl Trop Dis 2017;11(9):e0005838-e0005838.
11. Varghese GM, Janardhanan J, Trowbridge P, et al. Scrub typhus in South India: clinical and laboratory manifestations, genetic variability, and outcome. Int J Infect Dis 2013;17(11):e981-e987.
12. Griffith M, Peter JV, Karthik G, et al. Profile of organ dysfunction and predictors of mortality in severe scrub typhus infection requiring intensive care admission. Indian J Crit Care Med 2014;18:497-502.
13. Kim Y-S, Yun H-J, Shim SK, Koo SH, Kim SY, Kim S. A comparative trial of a single dose of azithromycin versus doxycycline for the treatment of mild scrub typhus. Clin Infect Dis 2004;39:1329-1335.
14. Phimda K, Hoontrakul S, Suttinont C, et al. Doxycycline versus azithromycin for treatment of leptospirosis and scrub typhus. Antimicrob Agents Chemother 2007;51:3259-3263.
15. Kabir KI, John J, Satapathy AK, Sahu S, Behera B, Padhy BM. Oral azithromycin versus doxycycline in the treatment of children with uncomplicated scrub typhus: a randomized controlled trial. Pediatr Infect Dis J 2022;41:224-229.
16. Wee I, Lo A, Rodrigo C. Drug treatment of scrub typhus: a systematic review and meta-analysis of controlled clinical trials. Trans R Soc Trop Med Hyg 2017;111:336-344.
17. El Sayed I, Liu Ǫ, Wee I, Hine P. Antibiotics for treating scrub typhus. Cochrane Database Syst Rev 2018;9:CD002150-CD002150.
18. Lee SC, Cheng YJ, Lin CH, et al. Comparative effectiveness of azithromycin for treating scrub typhus: a PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore) 2017;96(36):e7992-e7992.
19. Bhargava A, Kaushik R, Kaushik RM, et al. Scrub typhus in Uttarakhand & adjoining Uttar Pradesh: seasonality, clinical presentations & predictors of mortality. Indian J Med Res 2016;144:901-909.
20. Mukhopadhyay K, Chakrabarty S, Chatterjee C, Misra SC. Mortality and complications of scrub typhus in the paediatric population: a systematic review and meta-analysis. Trans R Soc Trop Med Hyg 2021;115:1234-1246.
21. Jain D, Nand N, Giri K, Bhutani J. Scrub typhus infection, not a benign disease: an experience from a tertiary care center in Northern India. Med Pharm Rep 2019;92:36-42.
22. 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;23:39-43.
23. Parnham MJ, Erakovic Haber V, Giamarellos-Bourboulis EJ, Perletti G, Verleden GM, Vos R. Azithromycin: mechanisms of action and their relevance for clinical applications. Pharmacol Ther 2014;143:225-245.
24. Nguyen F, Starosta AL, Arenz S, Sohmen D, Dönhöfer A, Wilson DN. Tetracycline antibiotics and resistance mechanisms. Biol Chem 2014;395:559-575.
25. Salje J. Cells within cells: Rickettsiales and the obligate intracellular bacterial lifestyle. Nat Rev Microbiol 2021;19:375-390.
26. Lee SM, Kwon HY, Im JH, et al. In vitro activity of tigecycline against Orientia tsutsugamushi. Yonsei Med J 2016;57:1034-1037.
27. Anderson KE, Dencker H, Mårdh PA, Akerlund M. Relationships between the concentrations of doxycycline in serum and in thoracic duct lymph after oral and intravenous administration in man. Chemotherapy 1976;22:277-285.
28. Neu HC. Clinical microbiology of azithromycin. Am J Med 1991;91:3A:12S-18S.
29. Cross R, Ling C, Day NP, McGready R, Paris DH. Revisiting doxycycline in pregnancy and early childhood — time to rebuild its reputation? Expert Opin Drug Saf 2016;15:367- 382.
30. Gaillard T, Briolant S, Madamet M, Pradines B. The end of a dogma: the safety of doxycycline use in young children for malaria treatment. Malar J 2017;16:148-148.

Dr Ramapriya
Critical Care
Kauvery Hospital, Chennai

Mentor:

Dr Vetriselvan P
Associate Consultant Critical Care Medicine
Kauvery Hospital, Chennai