Scrub Typhus in Children at Chiang Mai University Hospital

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1 Original Article Scrub Typhus in Children at Chiang Mai University Hospital Virat Sirisanthana, M.D. Boonsom Poneprasert, M.D. Abstract During a one-year period from 1 January 1987 to 31 December 1987, there were 25 pediatric patients with the diagnosis of scrub typhus at Chiang Mai University Hospital. All were patients who came in with prolonged fever and defervesced within 72 hours after tetracycline or chloramphenicol therapy. Their age ranged from 1.5 to 14 years (mean 9.9 years). The male to female ratio is 2.6/1. There was no case between January and April. An average of 9.4 days elapsed between onset of fever and hospitalization. The average peak temperature during the first 24 hours of admission was 39.7 C. Headache, nausea and vomiting were present in 52-60% of the patients. About one fourth had history of upper respiratory tract infection and non-productive cough which subsided by the time of admission. There were 5 cases with abdominal pain and tenderness. Four cases had history of convulsion before admission. The most common physical findings besides fever were hepatomegaly, generalized lymphadenopathy and conjunctivitis. A maculopapular rash occurred in 10 cases. An eschar was found in 7 cases. Abnormal neurological signs were presented in 12 cases. They included nuchal rigidity, papilledema, drowsiness and abnormal cerebellar signs. On admission, leukocyte counts ranged from 6,050 to 25,200/mm 3 with an average of 11,462. Seven cases had decreased platelet count (one had platelet count less than 100,000 cells/mm 3 ). In two patients who had severe myalgia in the hospital, the serum creatinine phosphokinase levels were elevated (268 and > 1000 unit/l). Chest roentgenogram was done in 12 cases and found to be abnormal in 4 cases. Lumbar puncture was performed in 14 cases (12 with abnormal neurological findings, one with severe headache and vomiting and one with history of convulsion before admission). Cerebrospinal fluid (CSF) examination were abnormal in all 14 cases. The CSF white blood cell count ranged from 0 to 1,410 cells/mm,3 with an average of 299 cells/mm. 3 The protein in the CSF ranged from 50 to 364 mg %, with an average of 130 mg %. Seven cases had CSF glucose less than half of concurrent blood glucose. Weil-Felix test with Proteus OX-K was positive (defined as a fourfold rise in titer and/or the titer of 1: 160 or greater) in 15 cases. The fever subsided within an average of 38.4 hours after tetracycline or chloramphenicol administration...; I ljfn[jf) "nfu 'Ylrf" 1lll~fl~h~'WU1lJ1"1J11l'1'tillfl'HotiU~ '11,j if\ji ft~,r'uti'u~ 'W.u., UWfnJ H'ltl1~m1;} 'W.u. u.. 1l1fl1"1l1fi:IJ11n"llflltHl'i mu.:; bbyi'yl!jfll~'1l'i :IJ~11'Yl!Jl~!Jb!Jl!J.J1mJ, v 'l. ""<l. ""'I i/ 0<:{ n';jtftjljrwwlt'lff)llij~lj7m'jjvij'lfw 2532; 6:22,27. v 1~U~n'l11 lj ~--1l1llil'U~ IlJtl11f1lJ 'W.ft il--11'u~ 31 ti 'Ul1f1lJ 'W.ft ~H'''hUivifl~,,,~,,vrfuflniu;)uUlu'U"mvu 'f1v(" nh--1'wu1u1'llj'i11n'll'uml.vu--11'11~ 2511U H'''hul'I1~n~hu'UH'''hun~ 'eu',!--1ljl'ul'u lylu'i11"11'l1\lj'iltl--1'~;)1i) hfl~'u 9'~'Wu 1I'l~I~tl'vrU1 tetracycline 'I1~tl chloramphen,iij..., 0'1 _I'" OJ V'i'..::,...:II.. COlli'll tlol'l1illj'iltl--11nfllu'lyl'l--1lu'uufl\jiftlu l'un'll 72 'li1ilj--1 tllulj\ji--1i1\j1'\j1um u (tllulll'lu ~ ~"a '" gj, c::i gj <II 9.9U) IU'UI~fl~'lI1UlJli)f111IYlfl~':'ty--1(2.6: 1) 'ii"~" ~ ~ 'lj~u~ihu''u'li}--1iyltl'uljtl11fllj0--1iyltl'ullj}n~'u " ~ 11l'lU mhvif1l'l1~l'u~'~ljl'ul'u 91'Untl'Un;)~lJlfUflmvm:llnh--1'WU1U1m1 l'uli1mvuh'''hu~'~''--1llli\u ' "II. Department of Pediatrics. Faculty of Medicine, Chiang Mai University, Chiang Mai. 22

2 J Infect Dis Antimicrob Agents Vol. 6 No.1 Jan. - Mar INTRODUCTION Reports from the Division of Epidemiology, the Ministry of Public Health, Thailand, revealed that the number of cases of scrub typhus in Thailand increased from 17 cases in 1980 to 26, 42,99,104, 274 and 513 in 1981, 1982, 1983, 1984, 1985 and 1986 respectively. 1 The disease is caused by infection with Rickettsia tsutsugamushi. It is transmitted to human by the bite of infected larval trombiculid mites (chiggers). The mites transmit the rickettsia from one generation to the next through the egg (transovarial passage) and probably constitute the main reservoir of Rickettsia tsutsugamushi as well as serving as vectors. Chiggers are the only stage to feed on man and rat. The spectrum of clinical manifestations of untreated scrub typhus ranges from inapparent to severe, with mortality rates varying from zero to more than 30%.2 In Thailand, the first case was reported in The patient lived in Nakornpatom province. After that there were very few case reports, all of which were adults Although not many cases were reported from northern Thailand, our experience suggested that the disease was not uncommon, even in children. 12 This study was carried out to emphasize the importance of scrub typhus in pediatric patients. MATERIAL AND METHOD From 1 January 1987 to 31 December 1987, patients who came in with 5 days or more of high fever, no obvious site of infection in any organ system and who defervesced within 72 hours after tetracycline or chloramphenicol therapy were included in the study. The history was taken, and physical examination was performed on admission and during hospitalization. The following laboratory tests were performed: complete blood count (CBC), urine analysis, Weil-Felix test on acute and convalescent sera. Lumbar puncture was performed in cases with abnormal neurological signs or symptoms. Chest roentgenography, electrocardiography, Widal test, heterophil antibody determination, and cold agglutinin determination were performed when indicated. RESULTS Twenty-five patients were included in this study. All except one fit the criteria for inclusion. The other patient had a very high OX-K titer in the Weil Felix test (1:2560) and desfervesed after treatment with rifampicin. The age distribution is shown in Figure 1. The range is from 1.5 to 14 years and the mean age is 9.9 years. The male to female ratio is 2.6/1. The monthly distribution is shown in Figure 2. There was no case between January and April. Clinical findings The clinical findings of these 25 cases were analyzed (Tables 1, 2). An average of 9.4 days elapsed between the onset of fever and hospitalization. The average peak temperature during the first 24 hours of admission was 39.7 C. In most of the cases, the fever was unremitting. Headache, nausea and vomiting were present in 52-60% of the patients.

3 24 ::-'n" 6.1V v Vn" I " 11 H u.n.-u.n ~ r771 Table 1 Comparison of the data in this study and others* 3 '" ~ c3 2 '0 o z S.+P. B.+K. Sayen et a1. Year of study Number of patients Fever PTA (day) Age (mean) 9.9 adult adult Age (range) (1.5-14) adult adult M:F 18/7 all male all male *ref. 15, 16 o L..,_ r------,,-l-4Ll--J..4<~;LL.lL,L.LlL,L-!--J.~~' '_'::~ Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Month Fig. 2 Monthly distribution. About one third had history of upper respiratory tract infection symptoms and non-productive cough which had subsided by the time of admission. There were 5 patients with abdominal pain and tenderness, in two of which acute abdomen were strongly suspected. Four cases had history of convulsion before admission. Diarrhea, when present, was not severe and had subsided before admission in most of the cases. The most common physical findings besides fever were hepatomegaly, generalized lymphadenopathy and conjunctivitis (Table 3). The average liver enlargement is 2.5 em. below right costal margin (2 cases with underlying hemoglobinopathy were excluded from the calculation). The liver was not significantly tender. A maculopapular rash was found in 9 cases on physical examination. In another case, the rash disappeared before admission. The rash was not easily recognized without careful observation and appeared from the fourth to the fourteenth day of fever. An eschar was found in 7 cases at the following sites: scrotum, 2; finger, 1; arm, 1; flank, 1; thigh, 1; popliteal fossa, 1. The eschar was not painful. All three cases with subconjunctival hemorrhage were cases with severe conjunctivitis. Drowsy conciousness occurred on day of fever. Abnormal neurological examination were presented in 12 cases. Four cases had nuchal rigidity and papilledema (one case in this group also had abnormal cerebellar sign). Seven cases had only nuchal rigidity and one case had only papilledema. Laboratory data (Table 4) On admission leukocyte counts ranged from 6,050 to 25,200/mm 3 with an average of 11,462. Atypical lymphocytes were significantly increased in 4 cases (ranged 11-33%). In two patients who had severe myalgia in the hospital, the creatinine phosphokinase level (CPK) were elevated (268 and > 1,000 unit/l). Chest roentgenograms were done in 12 cases and were found abnormal in 4 cases (only one in this 4 cases had abnormal lung signs). The infiltration in

4 J Infect Dis Antimicrob Agents Vol. 6 No.1 Jan. - Mar Table 3 Comparison of the signs in this study and others* (%) Signs S.+P. B.+K. Sayen et ai. Temp 39.7 ( ) Pulse/min 114 (90-140) RR/min 31 (20-55) Hepatomegaly 88 Gen lymph adenopathy 76 Conjunctivitis 60 Nuchal rigidity 44 Rash 36 Splenomegaly 28 Eschar 28 Papilledema 20 Abdominal tenderness 20 Muscle tenderness 12 Drowsy conciousness 12 Subconj. hemorrhage 12 Abnormal chest examination 4 Jaundice *ref. 15, 16 o the lungs were perihilar in two cases and at right lower lobe in the other two cases. Lumbar puncture was perfonned in 14 cases (12 with abnonnal neurological findings, one with severe headache and vomiting and one with history of convulsion before admission). Cerebrospinal fluid (CSF) examination were abnormal in all 14 cases. The white blood cell (WBC) count ranged from 0 to 1,410 cells/mm,3 with an average of 299 cells/mm. 3 The CSF protein ranged from 50 to 364 mg%, with an average of 130 mg%. Seven cases (50%) had CSF glucose level less than half of the concurrent blood level. The Weil-Felix test with Proteus OX-K was positive (defined as a fourfold rise in titer and/or the titer of 1:160 or greater) in 15 cases (60%). Widal test, heterophile antibody, leptospirosis antibody and cold agglutinin were reported as negative in 22 out of 22, 12 out of 12, 11 out of 11, and 7 out of 7 tested cases respectively. Sixteen patients received chloramphenicol and nine received tetracycline for 7-10 days. There was no adverse reaction from antibiotic therapy. Fever subsided within an average of 38 hours after antibiotic therapy. There was no death. One case with meningoencephalitis had residual central nervous system damage. Two patients developed another episode of fever about one week after discontinuation of antibiotic. In both cases the fever subsided within 4 days: one with chloramphenicol, the other without any antibiotic. DISCUSSION The diagnosis of scrub typhus by method of inoculation into experimental animals is rather difficult to perform. The detection of immunofluorescent antibody, although is more sensitive than Weil-Felix test 13 is not available at Chiang Mai University Hospital. In this study, we used clinical features and response to antibiotic therapy9 as inclusion criteria. In Chiang Mai, chiggers of Leptotrombidium deliense were found from wild rats, especially in the raining season. 14 No case was found during the dry season (between January and April) in our study. The findings that most of the cases were older, predominantly male children could be explained by the chance of exposure to chiggers. Older children, especially boys, like to play outdoor. The time elapsed between the onset of fever and hospitalization is longer than that of the other study. IS Chiang Mai University Hospital is a tertiary care center. Patients with prolonged fever were usually diagnosed as having typhoid fever and were referred only after unsuccessful treatment with cotrimoxazole. The pathology of scrub typhus involves may organ systems. The predominant signs and symptoms depend on the organ systems involved. Tables 1 to 4

5 l.""\ci V c:4 26 U:!,In.i. 6 '''1J~1Jn''; 1.. H J./.fI.-J./.fl if71 I'jfIrJ'ill 'Fall f/::tj7rj TIJ v, f/7j'h Table 4 Laboratory findings in this study and in the others Hemoglobin (g%) Hematocrit (%) Leukocyte count mean range PMN (%) L(%) Lymphocytosis Platelet> 200, , ,000 < 100,000 Proteinuria Normal EKG Abnormal CXR Abnormal CSF WBC (cells/cumm.) PMN (%) Mono (%) RBC (cells/cumm.) Protein (mg%) Low CSF sugar «1/2 blood sugar) Weil-Felix test (with Proteus OX-K): positive S.+P. B.+K. Sayen et at 11.6( ) 36 (27-45) 11,462 (6,050-25,200) 64 (28-84) 30 (16-65) 16% (4/25) 17/24 6/24 1/24 14% (3/21) 4/4 4/12 14/14 Range Average 0-1, , cases 60% 8,000 (3,000-22,000) 70% 20% 47% 50% *ref, 15,16 compare the findings in this study to those of Berman et al 15 and Sayen et a1. 16 The former is the study in American forces in Vietnam between 1967 and The latter is the study in American soldiers in Assam and Burma in In this study, the common presenting symptoms are similar to those of Berman et al and Sayen et al (Table 2). Convulsion was found in 16% in this study, compared to 6% in the study of Sayen et al. Hepatomegaly was found significantly more frequently in this study (Table 3). The average liver size was 2.5 em. below right costal margin. Generalized lymphadenopathy, was common in all studies and was helpful in making diagnosis. Eschar was found in only 28% of the patients in this study, but, when present, it was helpful in making diagnosis. Rashes were found in 36% of the patients in our study. They were muculopapular and developed after day 6 of fever. The incidence of rash was similar to that reported by Berman et a1. 15 The patients in these two studies were treated with tetracycline or chloramphenicol. Without specific antibiotic treatment, the incidence of rash was 71%.16 The cause of the relatively low incidence of lymphadenopathy, rash, and eschar in our study may be the proportion of patients previously exposed to R. tsutsugamushi (Le. secondary infection) in our endemic population. This is in contrast with presumed primary infection in American soldiers studied by Berman et al 15 and Sayen et a1. 16 Eschar may have been overemphazised in the diagnosis of scrub typhus. It was found in only 28% of the patients in this study. In secondary infection, eschar may not be present. It can also be atypical and difficult to be recognized. Two patients had lesions of chigger bite on moist intriginous surfaces which appeared as shallow, yellow-based ulcers without surrounding hyperemia and without black crust. Subconjunctival hemorrhage were found in cases with severe conjunctivitis. Abnormal neurological signs and symptoms were more often found in this study and that of Sayen et

6 J Infect Dis Antimicrob Agents al. 16 This may be related to the severity of the disease at the time the patients were seen. As shown in Table 4, the peripheral white blood cell (WBC) count ranged from 6,050 to 25,200/mm 3 with polymorphonuclear cell (PMN) predominating. The average duration between the onset of fever and the determination of count was 9 days. Serial WBC count and differential count were not performed. Thus we cannot confirm or dispute Berman's finding that lymphocytosis developed in 70% of the patients by day 14. Low platelet count was found in 7 patients. In one patient, it was less than 100,000/ mm. 3 This finding was not mentioned in other studies. Although there were several reported cases of adult respiratory distress syndrome in scrub typhus in adultsio,ll and an older child/ 2 the symptoms of the patients and infiltrations were mild in all four cases with abnormal chest roentgenograms. Although the Weil-Felix test with Proteus OX K is generally available, it was positive (defined as a fourfold rise and/or the titer of 1 :160 or greater) in only 60% of cases in this study. This is similar to other reports. IS, 16 The low prevalence of OX-K antibody can be due to two possibilities: firstly it is often negative in the second and subsequent infections,2 and secondly it is related to the infecting strains of Rickettsia. Is The two patients with relapse had mild symptoms and probably did not need antirickettsial drugs. Because neither tetracycline nor chloramphenicol is rickettsidal under oridinary circumstances ultimate freedom from clinical relapse (Le., "cure") is probably dependent on an adequate immune response by the patient. The duration of chloramphenicol and tetracycline therapy depend on the stage of the disease at the time therapy is begun. It is suggested as a practical conservative guide that tetracycline or chloramphenicol be administered until the patient has been afebrile for 48 hours and for an additional period until the total time elapsed from onset of disease is 12 to 14 days. I? Relapses respond to retreatment with the same drug. In fact, in many instances, relapses or recrudescences of fever are self-limited and resolve spontaneously about as rapidly as they do with additional chemotherapy. The incidence of scrub typhus in Thailand is rising. 1 This is probably caused by the real increase in the number of cases as well as the increase in the diagnoses made by physicians. When chloramphenicol was usually administered to patients with prolonged fever and a provisional diagnosis of typhoid fever, patients with scrub typhus who responded to chloramphenicol were misdiagnosed as typhoid fever. When cotrimoxazole became available and replaced chloramphenicol as a less toxic treatment for typhoid Vol. 6 No.1 Jan. - Mar fever, physicians began to make the diagnosis of scrub typhus in patients who did n<;)t respond to cotrimoxazole. This, in turn, increased the physicians' awareness of scrub typhus. The age distribution of patients with scrub typhus in Thailand in 1983 has been reported. 1 Most patients were adult, 6% of the patienti (6/104) were between years of age and none of the patients was below 10 years of age. Our study suggests that the incidence of scrub typhus in children may be underestimated. Further study of scrub typhus in children should be carried out. REFERENCES 1. Ministry of Public Health, Division of Epidemiology, Annual summary. Bangkok: Ministry of Public Health, (in Thai). 2. Wisseman CL Jr. Scrub typhus. In: Strickland GT, ed. Hunter's tropical medicine. 5th ed. Philadelphia: WB Saunders, 1984: Thainua M. A case report of scrub typhus. J Med Assoc Thai 1952; 35:9-27. (in Thai). 4. Uttayopas J. Scrub typhus. Med J 1957; 6 : (in Thai). 5. Thainua M, Busapavanich S. Outbreak of scrub typhus and malaria during a war game at Ubonrajtanee. J Med Assoc Thai 1958; 41 : (in Thai). 6. Uttayopas J, Uttayopas P. Scrub typhus: a report of one case. Med J 1959; 8: (in Thai). 7. Trishnananda M, Harinasuta C, Kongrod S. The isolation of Rickettsia tjutsugamushi from scrub typhus patients in Thailand. J Med Assoc Thai 1965; 48: (in Thai). 8. Trishnananda M, Bhaibulaya M, Kongrod S, Harinasuta C. Study on scrub typhus in the jungle of Panasnikhom district, Chonburi province. J Med Assoc Thai 1965; 48: (in Thai). 9. Leelarasamee A. Aswapokee P. Scrub typhus: report of two cases who seek medication in Bangkok. Siriraj Hosp Gaz 1984; 36: (in Thai). 10. Punyagupta S. Interesting infectious disease cases presentation: cardiopuhnonary complication in an acute febrile patient. J Infect Dis Antimicrob Agents 1985; 2: (in Thai) 11. Pothiratana C. Scrub typhus pneumonia with adult respiratory distress syndrome. J Infect Dis Antimicrob Agents 1.987; 4: (in Thai) 12. Sirisanthana V, Chaisate D, Poneprasert B, Scrub typhus in children: a report of two cases. J Pediatr Soc Thai 1987; 26: (in Thai) 13. Brown GW, Shirai A, Rogers C, Groves MG. Diagnostic criteria for scrub typhus: probability values for immunofluorescent antibody and Proteus OX K agglutinin titers. Am J Trop Med Hyg 1983; 32: Takada N, Khamboonruang C, Yamaguchi T, Thitasut P, Vajrasthira S. Scrub typhus and chiggers in northern Thailand. Southeast Asian J Trop Med Public Health 1984; 15: Berman SJ, Kundin WD. Scrub typhus in South Vietnam: a study of 87 cases. Ann Intern Med 1973; 79: Sayen II, Pond HS, Forrester IS, Wood FC. Scrub typhus in Assum and Burma. Medicine 1946; 25: Weissernan CLJr. Rickettsial and bartonella infections. In: Strickland GT, ed. Hunter's tropical medicine. 6th ed. Philadelphia: WB Saunders, 1984:

J of Evolution of Med and Dent Sci/ eissn , pissn / Vol. 4/ Issue 34/ Apr 27, 2015 Page 5817

J of Evolution of Med and Dent Sci/ eissn , pissn / Vol. 4/ Issue 34/ Apr 27, 2015 Page 5817 A STUDY OF CLINICAL AND EPIDEMIOLOGICAL CHARACTERISTICS OF SCRUB TYPHUS IN TERTIARY CARE HOSPITAL IN ANDHRA PRADESH I. V. Ramachandra Rao 1, Kumbha Thulasiram 2, H. V. S. S. Laxman 3 HOW TO CITE THIS ARTICLE: