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Background: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon, potentially fatal, hyperinflammatory syndrome that may rarely complicate the clinical course of Orientia tsutsugamushi disease (scrub typhus). Methods: We describe here the clinicopathological features, laboratory parameters, management, and outcome data of three adult patients (1 female, 2 males) with scrub typhus associated HLH from a tertiary center with a brief and concise review of international literature. Results: All three patients satisfied the HLH-2004 diagnostic criteria; one had multi organ dysfunction with “sky high” ferritin level; and all had a dramatic recovery following doxycyclin therapy. Literature review from January 1990 to March 2014 revealed that scrub typhus associated HLH were reported in 21 patients, mostly from the scrub endemic countries of the world. These included 11 females and 10 males with mean age of 35 years (range; 8 months to 81 years). Fifteen of 17 patients (where data was available) had a favorable outcome following early serological diagnosis and initiation of definitive antibiotic therapy with (N=6) or without (N=9) immunosuppressive/immunomodulator therapy. Mutation analysis for primary HLH was performed in one patient only, and HLH-2004 protocol was used in two patients. Conclusion: We suggest that HLH should be considered in severe cases of scrub typhus especially if associated with cytopenia (s), liver dysfunction, and coagulation abnormalities. Further studies are required to understand whether an immunosuppressive and/or immunomodulator therapy could be beneficial in those patients who remain unresponsive to definitive antibiotic therapy.
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2. Bode SF, Lehmberg K, Maul-Pavicic A, Vraetz T, Janka G, Stadt UZ, Ehl S. Recent advances in the diagnosis and treatment of hemophagocytic lymphohistiocytosis. Arthritis Res Ther 2012; 14(3):213. DOI: 10.1186/ar3843.
3. Gupta S, Weitzman S. Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy. Expert Rev Clin Immunol 2010; 6: 137–154.
4. Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with hemophagocytic syndrome. Lancet Infect Dis 2007; 7:814-822.
5. Cascio A, Giordano S, Dones S,Venezia S, Iaria C, Ziino O. Hemophagocytic syndrome and rickettsial diseases. J Med Microbiol 2011; 60:537-542.
6. Henter JI, Horne AC, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48:124-131.
7. Ho C, Yao X, Tian L, Li FY, Podoltsev N, Xu ML. Marrow assessment of hemophagocytic lymphohistiocytosis demonstrates poor correlation with disease probability. Am J Clin Pathol 2014; 141:62-71.
8. Diwan AG, Shewale R, Iyer S, Nisal A, Agrawal P. Triple trouble: macrophage activation syndrome in a case of severe leptospirosis and scrub typhus co-infection. JAPI 2014; 62:58-61.
9. Goswami D, Hing A, Das A, Lyngdoh M. Scrub typhus complicated by acute respiratory distress syndrome and acute liver failure: a case report from Northeast India. Int J Infect Dis 2013; 17 (8): e644-e645. DOI: 10.1016/j.ijid.2012.12.023.
10. Cascio A, Correnti P, Iaria C. Scrub typhus, acute respiratory distress, and hemophagocytic lymphohistiocytosis. Int J Infect Dis 2013; 17 (8): e662. DOI: 10.1016/j.ijid.2013.03.006.
11. Kwon HJ, Yoo IH, Lee JW, Chung NG, Cho B, Kim HK, et al. Life-threatening scrub typhus with hemophagocytosis and acute respiratory distress syndrome in an infant. J Trop Pediatr 2013; 59 (1):67-69.
12. Han DK, Baek HJ, Shin MG, Kim JW, Kook H, Hwang TJ. Scrub typhus-associated severe hemophagocytic lymphohistiocytosis with encephalomyelitis leading to permanent sequelae: a case report and review of the literature. J Ped Hematol Oncol 2012; 34 (7):531-533.
13. Hong JH, Cho HJ, Kim HM, Namgoong MK, Kwon O, Chun JK. A case of Epstein - Barr virus associated hemophagocytic lymphohistiocytosis after scrub typhus infection. Clin Pediatr Hematol Oncol 2012; 19 (1):49-52.
14. Jayakrishnan MP, Veny J, Feroze M. Rickettsial infection with hemophagocytosis. Trop Doct 2011; 41 (2):111-112.
15. Kim HW, Choi BS, Kim JH, Shin YM, Lee SJ, Kim SR, Jun JB. A case of death due to hemophagocytic lymphohistiocytosis accompanied by scrub typhus. Infect Chemother 2010; 42 (4):266-270.
16. Gopal GK, Anugrah C, Boorugu H. Scrub typhus associated macrophage activation syndrome. Trop Doct 2010; 40:249-250.
17. Valsalan R, Kosaraju K, Sohanlal T, Prem Kumar PS. Hemophagocytosis in scrub typhus. J Postgrad Med 2010; 56 (4):301-302.
18. Premaratna R, Williams HS, Chandrasena TG, Rajapakse RP, Kularatna SA, de Silva HJ. Unusual pancytopenia secondary to haemophagocytosis syndrome in rickettsioses. Trans R Soc Trop Med Hyg 2009; 103; 961-963.
19. Yang SH, Ho YH, Chu CH, Chu SY. Childhood scrub typhus in eastern Taiwan: ten-year experience from a medical center. Acta Pediatr Taiwan 2007; 48:332-336.
20. Miyakawa K, Ohsugi K, Kuriyama C, Sugahara S, Kikuchi A, Ohta M. Tsutsugamushi disease with hemophagocytosis complicated by parvovirus B19 infection. Nippon Naika Gakkai Zashi 2006; 95:2544-2546.
21. Takami A, Yamauchi H, Asakura H, Ishiyama K, Nakao S. Tsutsugamushi disease (scrub typhus)-associated hemophagocytic syndrome. Int J Hematol 2002; 75 (3):337-338.
22. Wada M, Yamane Y, Tsumori M, Kato Y. Tsutsugamushi disease-associated hemophagocytic syndrome. Rinsho Kenkyu 2001; 78:1173-1176.
23. Chen YC, Chao TY, Chin SC. Scrub typhus associated hemophagocytic syndrome. Infection 2000; 28:178-179.
24. Iwasaki H, Hashimoto K, Takada N, Nakayama T, Ueda T, Nakamura T. Fulminant Rickettsia tsutsugamushi infection associated with haemophagocytic syndrome. Lancet 1994; 343:8907:1236.
25. Kobayashi T, Takizawa H, Hiroshima K, Uruma T, Enokihara H, Okuyama A. A case of new type scrub typhus (tsutsugamushi disease) presenting with acute respiratory failure and hemophagocytic syndrome. Jpn J Thor Dis 1992; 30:447-452.
26. Paris DH, Day NPJ. Tropical Rickettsial Infections. In: Farrar J, Hotez P, Junghanss T, Kang G, Lalloo D, White NJ (editors). Manson’s Tropical Diseases: Expert Consult Online. 23rd edition, ELSEVIER, 2014, China.
27. Sahni SK, Rydkina E. Host cell interactions with pathogenic Rickettsia species. Future Microbiol 2009; 4:323-339.
28. Iwasaki H, Takada N, Nakamura T, Ueda T. Increased levels of macrophage colony stimulating factor, gamma interferon and tumour necrosis factor alpha in sera of patients with Orientia tsutsugamushi infection. J Clin Microbiol. 1997; 35: 3320-3322.
29. Brown GN, Shiraj A, Rogers C, Groves MG. Diagnostic criteria for scrub typhus: probability values for immunofluorescent antibody and Proteus OXK agglutinin titres. Am J Trop Med Hyg 1983; 32 (5):1101-1107.
30. Kamarasu K, Malathi M, Rajagopal V, Subramani K, Iagadeeshramasamy D, Mathai E. Serological evidence for wide distribution of spotted fevers and typhus fever in Tamil Nadu. Indian J Med Res 2007; 126:128-130.
31. Batra HV. Spotted fever and typhus fevers in Tamil Nadu. Indian J Med Res 2007; 126:101-103.
32. Bakshi D, Singhal P, Mahajan SK, Subramaniam P, Tuteja U, Batra HV, et al. Development of a real-time PCR assay for the diagnosis of scrub typhus cases in India and evidence of the prevalence of new genotype of O. tsutsugamushi. Acta Trop 2007; 104:63-71.
33. Prakash JA, Reller ME, Barat N, Dumler JS. Assessment of a quantitative multiplex 5' nuclease real-time PCR for spotted fever and typhus group rickettsioses and Orientia tsutsugamushi. Clin Microbiol Infect. 2009; 15 Suppl 2:292-293.
34. Delay in tetracycline treatment increases the risk of complications in Tsutsugamushi disease: data from the Japanese Diagnosis Procedure Combination database. Intern Med 2011; 50:37-42.
35. Park SW, Lee CS, Lee CK, Kwak YG, Moon C, Kim BN, et al. Severity predictors in eschar-positive scrub typhus and role of serum osteopontin. Am J Trop Med Hyg 2011; 85:924-930.
36. Lin TF, Ferlic-Stark LL, Allen CE, Kozinetz CA, McClain KL. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Canc 2011; 56(1):154–155.
37. Park HS, Kim DY, Lee JH, Lee JH, Kim SD, Park YH, et al. Clinical features of adult patients with secondary hemophagocytic lymphohistiocytosis from causes other than lymphoma: an analysis of treatment outcome and prognostic factors. Ann Hematol 2012; 91:897-904.