scrub typhus is endemic in many asian countries , including china , india , japan , korea , taiwan , and others regions in east and south east asia . a delay in the diagnosis and treatment can result in severe complications , including disseminated intravascular coagulation ( dic ) , acute respiratory distress syndrome ( ards ) , and hemophagocytic lymphohistiocytosis ( hlh ) . hlh is a rare but potentially fatal disease , characterized by a malfunction of natural killer t - cell function , activation and proliferation of lymphocytes or histiocytes with uncontrolled hemophagocytosis and cytokine overproduction . hlh phenotypically presents as 2 different conditions : primary ( phlh ) and secondary ( shlh ) . shlh has been associated with a variety of stimuli , such as infections , malignant neoplasia , and conditions characterized by immunosuprresion . the shlh associated with scrub typhus has been reported only in 4 cases ( table 1 ) . here , we report 3 additional cases from the southern part of china . reported cases of scrub typhus - associated hemophagocytic lymphohistiocytosis in children a 6-year - old boy was admitted to our hospital in the context of fever of unknown origin for 7 days ( august , 2009 ) . before admission , the boy was treated for 5 days with ceftriaxone for the presumptive diagnosis of sepsis . this boy lived in cang - nan county , which is a rural area in south of china where scrub typhus is considered endemic . on examination , a temperature of 39.7c was measured and a 1  0.5  cm necrotic cutaneous lesion was observed on the left shoulder ( figure 1a ) . ultrasound examination revealed splenomegaly extending 4.0  cm below the left costal margin at the lowest point . ( a ) a necrotic cutaneous lesion at the left shoulder area in case 1 . a bone marrow examination revealed hemophagocytosis ( figure 1b ) without any evidence of malignancy . a weil  felix agglutination test for the diagnosis of rickettsial infections revealed a high anti - oxk titer of 1:160 . the patients clinical profile and main laboratory values a final diagnosis of shlh associated with scrub typhus was proposed and the patient was treated with chloramphenicol ( 45  mg  kg d , divided every 8  h ) . his fever subsided immediately within 24  h. after 11 days of chloramphenicol treatment , the boy was discharged from hospital with a completely remission . a 4-year - old girl presented with a history of fever and cough for 9 days ( august , 2014 ) . before admission , she was treated for 3 days with azithromycin and 4 days with cefotaxime for the presumptive diagnosis of sepsis and pneumonia . this girl also lived in cang - nan county , which is a rural area in south of china in which scrub typhus is endemic . on examination , additionally , a 0.5  0.5  cm necrotic cutaneous lesion was found in the right opisthotic area . furthermore , she had an anemic appearance and disseminated ecchymosis was noticed on the facial region . ultrasound examination revealed splenomegaly , extending 2.0  cm below the left costal margin at the lowest point . a weil  felix agglutination test ( for the diagnosis of rickettsial infections ) revealed a high anti - oxk titer of 1:320 . a diagnosis of shlh associated with scrub typhus was proposed and the patient was treated with chloramphenicol ( 45  mg  kg d , divided every 8  h ) . the girl was afebrile 24  h after initiating the drug and cured after 9 days of chloramphenicol treatment . a 3-year - old girl presented with an 8-days history of fever with 2-days of vomiting ( july , 2013 ) . before the admission , a treatment for 2 days with meropenem was initiated for the presumptive diagnosis of meningitis and sepsis . a temperature of 40.3c was measured and a 0.5  0.5  cm necrotic cutaneous lesion at he left forearm was observed . ultrasound examination revealed splenomegaly extending 3.5  cm below the left costal margin at the lowest point . felix agglutination test for the diagnosis of rickettsial infections revealed a high anti - oxk titer of 1:320 . a diagnosis of shlh associated with scrub typhus was made after which the patient was treated with chloramphenicol ( 45  mg  kg d , divided every 8  h ) . her fever subsided immediately . after 13 days of chloramphenicol treatment , peripheral blood counts normalized completely leading to full recovery . two of 3 subject developed fever in the setting of upper respiratory tract infection during the follow - up period . a 6-year - old boy was admitted to our hospital in the context of fever of unknown origin for 7 days ( august , 2009 ) . before admission , the boy was treated for 5 days with ceftriaxone for the presumptive diagnosis of sepsis . this boy lived in cang - nan county , which is a rural area in south of china where scrub typhus is considered endemic . on examination , a temperature of 39.7c was measured and a 1  0.5  cm necrotic cutaneous lesion was observed on the left shoulder ( figure 1a ) . ultrasound examination revealed splenomegaly extending 4.0  cm below the left costal margin at the lowest point . ( a ) a necrotic cutaneous lesion at the left shoulder area in case 1 . a bone marrow examination revealed hemophagocytosis ( figure 1b ) without any evidence of malignancy . a weil  felix agglutination test for the diagnosis of rickettsial infections revealed a high anti - oxk titer of 1:160 . the patients clinical profile and main laboratory values a final diagnosis of shlh associated with scrub typhus was proposed and the patient was treated with chloramphenicol ( 45  mg  kg d , divided every 8  h ) . his fever subsided immediately within 24  h. after 11 days of chloramphenicol treatment , the boy was discharged from hospital with a completely remission . a 4-year - old girl presented with a history of fever and cough for 9 days ( august , 2014 ) . before admission , she was treated for 3 days with azithromycin and 4 days with cefotaxime for the presumptive diagnosis of sepsis and pneumonia . this girl also lived in cang - nan county , which is a rural area in south of china in which scrub typhus is endemic . on examination , additionally , a 0.5  0.5  cm necrotic cutaneous lesion was found in the right opisthotic area . furthermore , she had an anemic appearance and disseminated ecchymosis was noticed on the facial region . ultrasound examination revealed splenomegaly , extending 2.0  cm below the left costal margin at the lowest point . a weil  felix agglutination test ( for the diagnosis of rickettsial infections ) revealed a high anti - oxk titer of 1:320 . a diagnosis of shlh associated with scrub typhus was proposed and the patient was treated with chloramphenicol ( 45  mg  kg d , divided every 8  h ) . the girl was afebrile 24  h after initiating the drug and cured after 9 days of chloramphenicol treatment . a 3-year - old girl presented with an 8-days history of fever with 2-days of vomiting ( july , 2013 ) . before the admission , a treatment for 2 days with meropenem was initiated for the presumptive diagnosis of meningitis and sepsis . a temperature of 40.3c was measured and a 0.5  0.5  cm necrotic cutaneous lesion at he left forearm was observed . ultrasound examination revealed splenomegaly extending 3.5  cm below the left costal margin at the lowest point . felix agglutination test for the diagnosis of rickettsial infections revealed a high anti - oxk titer of 1:320 . a diagnosis of shlh associated with scrub typhus was made after which the patient was treated with chloramphenicol ( 45  mg  kg d , divided every 8  h ) . after 13 days of chloramphenicol treatment , peripheral blood counts normalized completely leading to full recovery . two of 3 subject developed fever in the setting of upper respiratory tract infection during the follow - up period . , the finding of a cutaneous lesion is essential for the diagnosis of this disease . however , it is sometimes difficult to be noticed at early stages because the lesion could appear at any ( hidden ) location ( figure 2 ) . all our patients presented with fever and a pathognomonic lesion . a high anti - proteus ox - k titer as observed by the weil all 3 cases presented with 5 out of 8 diagnostic hlh-2004 criteria ( table 2 ) . in our patients , a clear association was found between scrub typhus and hlh as demonstrated by the diagnosis of scrub typhus and the complete resolution of the hemophagocytic condition after successful treatment with chloramphenicol . only a minimal amount of evidence based on epidemiologic data can be found related to shlh cases with 20% of the cases initiated in relation to an infection . scrub typhus - associated hlh is even more rare , cascio et al reviewed 153 papers on shlh in zoonoses between 1950 and 2012 , and only 4 papers were associated with tsutsugamushi . the mortality rate of hlh as presented in the literature , ranged from 22% to 60% . the hlh-2004 guidelines are suitable for all patients with hlh , with or without evidence of genetic or familial disease , regardless of documented or suspected viral infections . dexamethasone , etoposide , and cyclosporin a are recommended as the initial therapy in this protocol . kleynberg and schiller et al emphasized the importance of etoposide for the treatment of ebv infection associated with hlh . according to the reported papers , 2 cases ( age 5 years , 2 months , respectively ) were treated with doxycycline and 1 case ( age 9 years ) was treated with doxycycline plus chloramphenicol with chemotherapy including etoposide , cyclosporine , dexamethasone , and methotrexate . it seems effective to treat the scrub typhus - associated hlh in children by doxycycline with or without chemotherapy . however , 1 member of the tetracycline family , doxycycline , is banned for use in children under the age of 8 years in china ( negative impact on bone growth and discoloration of permanent teeth ) . in addition , another case ( age 8 months ) treated by clarithromycin in association with etoposide resulted incomplete remission . however , in case 2 , 3-day azithromycin was administered before hospital admission and another case was treated with empiric roxithromycin for 7 days before doxycycline plus chloramphenicol was given . the effective use of macrolides for scrub typhus - associated hlh in children is questionable . our 3 cases were treated with chloramphenicol without chemotherapy , resulting in complete resolution of the disease . another 2 cases were found to be treated with doxycycline without chemotherapy also resulting in complete resolution . considering the severe toxic and side effect to children , the use of chemotherapy ( e.g. , etoposide ) in the treatment of scrub typhus - associated hlh in children may be unnecessary . the former is very rare and the latter is fully reversible once the drug is stopped . all our patients had blood counts checked twice weekly during treatment and once monthly after discharge until 1 year . no aplastic anaemia or bone marrow suppression was noticed . in the children under the age of 8 years , chloramphenicol may be the most desirable drug in the treatment of scrub typhus - associated hemophagocytic syndrome . six of the 7 known cases with confirmed diagnosis in < 10 days achieved complete resolution . only 1 case resulted in permanent neurological sequelae but this patient had its diagnosis confirmed only on the 19th day after onset . early diagnosis and treatment ( e.g. within 10 days of onset ) seem to be essential for preventing sequelae to appear based on this data . in summary , these case reports present the therapy for scrub typhus - associated hemophagocytic syndrome in children . with early diagnosis and treatment within a 10 days period after onset , chloramphenicol without the addition of chemotherapy as the treatment of scrub typhus - associated hlh in children under the age of 8 years may be an appropriate choice .
abstractscrub typhus is caused by orientia tsutsugamushi . any delay in diagnosis can result in delayed treatment and severe complications , including secondary hemophagocytic lymphohistiocytosis , which is rare but potentially fatal.in this paper , the authors present 3 cases of secondary hemophagocytic lymphohistiocytosis associated with scrub typhus , successfully treated with chloramphenicol without additional antineoplastic therapy . 
 all patients cured and achieved complete resolution.this report highlights the effectiveness of chloramphenicol without the need for chemotherapy in the treatment of scrub typhus - associated hemophagocytic lymphohistiocytosis in a pediatric population under the age of 8 years .