Scrub Typhus in Children at Chiang Mai University Hospital

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					                                                                                                                                          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 lym­
                          phadenopathy 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 phospho­
                          kinase 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 abnor­
                          mal neurological findings, one with severe headache and vomiting and one with history of convul­
                          sion 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 admi­

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Department of Pediatrics. Faculty of Medicine, Chiang Mai University, Chiang Mai.

J Infect Dis Antimicrob Agents                                               Vol. 6 No.1 Jan. - Mar. 1989   23

                   INTRODUCTION                          tem and who defervesced within 72 hours after tetra­
                                                         cycline or chloramphenicol therapy were included
      Reports from the Division of Epidemiology, the     in the study. The history was taken, and physical
Ministry of Public Health, Thailand, revealed that the   examination was performed on admission and during
number of cases of scrub typhus in Thailand in­          hospitalization. The following laboratory tests were
creased from 17 cases in 1980 to 26, 42,99,104, 274      performed: complete blood count (CBC), urine analy­
and 513 in 1981, 1982, 1983, 1984, 1985 and 1986         sis, Weil-Felix test on acute and convalescent sera.
respectively. 1                                          Lumbar puncture was performed in cases with abnor­
      The disease is caused by infection with Rickett­   mal neurological signs or symptoms. Chest roent­
sia tsutsugamushi. It is transmitted to human by the     genography, electrocardiography, Widal test, hetero­
bite of infected larval tro mbiculid mites (chiggers).   phil antibody determination, and cold agglutinin de­
The mites transmit the rickettsia from one generation    termination were performed when indicated.
to the next through the egg (transovarial passage) and
probably constitute the main reservoir of Rickettsia                           RESULTS
tsutsugamushi as well as serving as vectors. Chiggers
are the only stage to feed on man and rat. The spec­          Twenty-five patients were included in this study.
trum of clinical manifestations of untreated scrub       All except one fit the criteria for inclusion. The
typhus ranges from inapparent to severe, with morta­     other patient had a very high OX-K titer in the Weil­
lity rates varying from zero to more than 30%.2          Felix test (1:2560) and desfervesed after treatment
      In Thailand, the first case was reported in        with rifampicin. The age distribution is shown in
1952. 3 The patient lived in Nakornpatom province.       Figure 1. The range is from 1.5 to 14 years and the
After that there were very few case reports, all of      mean age is 9.9 years. The male to female ratio is
which were adults. 4 - 11 Although not many cases were   2.6/1. The monthly distribution is shown in Figure
reported from northern Thailand, our experience sug­     2. There was no case between January and April.
gested that the disease was not uncommon, even in
children. 12 This study was carried out to emphasize     Clinical findings
the importance of scrub typhus in pediatric patients.         The clinical findings of these 25 cases were
                                                         analyzed (Tables 1, 2). An average of 9.4 days
             MATERIAL AND METHOD                         elapsed between the onset of fever and hospitaliza­
                                                         tion. The average peak temperature during the first
      From 1 January 1987 to 31 December 1987,           24 hours of admission was 39.7°C. In most of the
patients who came in with 5 days or more of high         cases, the fever was unremitting. Headache, nausea
fever, no obvious site of infection in any organ sys­    and vomiting were present in 52-60% of the patients.
24       ::-'n" 6 .1VVn" I u.n.-u.n.
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                                                                                Table 1 Comparison of the data in this study and others*

                                                                                                        S.+P.        B.+K.     Sayen et a1.
     3                                                                        Year of study             1987         1968         1944
                                                                              Number of patients           25          87          200
~                                                                             Fever PTA (day)             9.4         5.1
c3   2
'0                                                                            Age (mean)                  9.9        adult        adult
z                                                                             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
                                                                              appeared from the fourth to the fourteenth day of
                                                                              fever. An eschar was found in 7 cases at the follow­
                    Fig. 2 Monthly distribution.                              ing 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
About one third had history of upper respiratory                              cases with severe conjunctivitis. Drowsy conciousness
tract infection symptoms and non-productive cough                             occurred on day 10-14 of fever. Abnormal neuro­
which had subsided by the time of admission. There                            logical examination were presented in 12 cases. Four
were 5 patients with abdominal pain and tenderness,                           cases had nuchal rigidity and papilledema (one case in
in two of which acute abdomen were strongly                                   this group also had abnormal cerebellar sign). Seven
suspected. Four cases had history of convulsion be­                           cases had only nuchal rigidity and one case had only
fore admission. Diarrhea, when present, was not                               papilledema.
severe and had subsided before admission in most of
the cases.                                                                    Laboratory data (Table 4)
      The most common physical findings besides                                    On admission leukocyte counts ranged from
fever were hepatomegaly, generalized lymphadeno­                              6,050 to 25,200/mm 3 with an average of 11,462.
pathy and conjunctivitis (Table 3). The average liver                         Atypical lymphocytes were significantly increased in
enlargement is 2.5 em. below right costal margin (2                           4 cases (ranged 11-33%). In two patients who had
cases with underlying hemoglobinopathy were ex­                               severe myalgia in the hospital, the creatinine phos­
cluded from the calculation). The liver was not signi­                        phokinase level (CPK) were elevated (268 and >
ficantly tender. A maculopapular rash was found in                            1,000 unit/L).
9 cases on physical examination. In another case, the                              Chest roentgenograms were done in 12 cases and
rash disappeared before admission. The rash was not                           were found abnormal in 4 cases (only one in this 4
easily recognized without careful observation and                             cases had abnormal lung signs). The infiltration in
  J Infect Dis Antimicrob Agents                                                          Vol. 6 No.1 Jan. - Mar. 1989      25

                                   Table 3 Comparison of the signs in this study and others* (%)

      Signs                                                                              S.+P.        B.+K.      Sayen et aI.

      Temp                                             39.7 (38.3-40.5)
      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                                                                                   o
 *ref. 15, 16

  the lungs were perihilar in two cases and at right               4 days: one with chloramphenicol, the other without
  lower lobe in the other two cases.                               any antibiotic.
         Lumbar puncture was perfonned in 14 cases (12
  with abnonnal neurological findings, one with severe                                    DISCUSSION
  headache and vomiting and one with history of con­
  vulsion before admission). Cerebrospinal fluid (CSF)                    The diagnosis of scrub typhus by method of ino­
• examination were abnormal in all 14 cases. The                   culation into experimental animals is rather difficult
  white blood cell (WBC) count ranged from 0 to 1,410              to perform. The detection of immunofluorescent an­
  cells/mm,3 with an average of 299 cells/mm. 3 The                tibody, although is more sensitive than Weil-Felix
  CSF protein ranged from 50 to 364 mg%, with an                   test 13 is not available at Chiang Mai University Hospi­
  average of 130 mg%. Seven cases (50%) had CSF                    tal. In this study, we used clinical features and re­
  glucose level less than half of the concurrent blood             sponse to antibiotic therapy9 as inclusion criteria.
  level.                                                                  In Chiang Mai, chiggers of Leptotrombidium
         The Weil-Felix test with Proteus OX-K was posi­           deliense were found from wild rats, especially in the
  tive (defined as a fourfold rise in titer and/or the titer       raining season. 14 No case was found during the dry
  of 1:160 or greater) in 15 cases (60%). Widal test,              season (between January and April) in our study.
  heterophile antibody, leptospirosis antibody and                 The findings that most of the cases were older, predo­
  cold agglutinin were reported as negative in 22 out of           minantly male children could be explained by the
  22, 12 out of 12, 11 out of 11, and 7 out of 7 tested            chance of exposure to chiggers. Older children,
  cases respectively.                                              especially boys, like to play outdoor. The time elaps­
         Sixteen patients received chloramphenicol and             ed between the onset of fever and hospitalization is
  nine received tetracycline for 7-10 days. There was              longer than that of the other study. IS Chiang Mai
  no adverse reaction from antibiotic therapy. Fever               University Hospital is a tertiary care center. Patients
  subsided within an average of 38 hours after antibio­            with prolonged fever were usually diagnosed as having
  tic therapy. There was no death. One case with                   typhoid fever and were referred only after unsuccess­
  meningoencephalitis had residual central nervous sys­            ful treatment with cotrimoxazole.
  tem damage.         Two patients developed another                      The pathology of scrub typhus involves may or­
  episode of fever about one week after discontinuation            gan systems. The predominant signs and symptoms
  of antibiotic. In both cases the fever subsided within           depend on the organ systems involved. Tables 1 to 4
26      :!,In.i.   6   '''1J~1Jn''; 1 J./.fI.-J./.fl. 2532
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                                                    Table 4 Laboratory findings in this study and in the others·

                                                                              S.+P.                        B.+K.                                  Sayen et at
Hemoglobin (g%)                                                           11.6(7.8 -14.5)
Hematocrit (%)                                                            36 (27 - 45)
Leukocyte count
       mean                                                               11,462                        8,000
                                                             (6,050 - 25,200)              (3,000 - 22,000)
   PMN (%)
                                                               64 (28 - 84)
                                                                  30 (16 - 65)
Lymphocytosis                                                             16% (4/25)                    70%
Platelet> 200,000                                                         17/24
100,000 - 200,000                                                          6/24
< 100,000                                                                  1/24
Proteinuria                                                               14% (3/21)                    20%
Normal EKG                                                                4/4
Abnormal CXR                                                              4/12
Abnormal CSF                                                              14/14
                                                                          Range        Average
     WBC (cells/cumm.)
                                                   0-1,410      299
         PMN (%)
                                                         17 ­ 97       54
         Mono (%)
                                                        3 ­ 83        46
     RBC (cells/cumm.)
                                                   0-2,845      369
     Protein (mg%)
                                                       50 ­ 364     130
     Low CSF sugar
                                                       7 cases
     « 1/2 blood sugar)

Weil-Felix test (with Proteus OX-K): positive                             60%
                          47%                                       50%
*ref, 15,16

compare the findings in this study to those of Berman                              chloramphenicol. Without specific antibiotic treat­
et al 15 and Sayen et a1. 16 The former is the study in                            ment, the incidence of rash was 71%.16 The cause of
American forces in Vietnam between 1967 and 1969.                                  the relatively low incidence of lymphadenopathy,
The latter is the study in American soldiers in Assam                              rash, and eschar in our study may be the proportion
and Burma in 1944.                                                                 of patients previously exposed to R. tsutsugamushi
       In this study, the common presenting symptoms                               (Le. secondary infection) in our endemic population.
are similar to those of Berman et al and Sayen et al                               This is in contrast with presumed primary infection
(Table 2). Convulsion was found in 16% in this                                     in American soldiers studied by Berman et al 15 and
study, compared to 6% in the study of Sayen et al.                                 Sayen et a1. 16
      Hepatomegaly was found significantly more                                          Eschar may have been overemphazised in the
frequently in this study (Table 3). The average liver                              diagnosis of scrub typhus. It was found in only
size was 2.5 em. below right costal margin. Genera­                                28% of the patients in this study. In secondary infec­
lized lymphadenopathy, was common in all studies                                   tion, eschar may not be present. It can also be atypi­
and was helpful in making diagnosis. Eschar was                                    cal and difficult to be recognized. Two patients had
found in only 28% of the patients in this study, but,                              lesions of chigger bite on moist intriginous surfaces
when present, it was helpful in making diagnosis.                                  which appeared as shallow, yellow-based ulcers with­
Rashes were found in 36% of the patients in our                                    out surrounding hyperemia and without black crust.
study. They were muculopapular and developed after                                 Subconjunctival hemorrhage were found in cases with
day 6 of fever. The incidence of rash was similar to                               severe conjunctivitis.
that reported by Berman et a1. 15 The patients in                                        Abnormal neurological signs and symptoms were
these two studies were treated with tetracycline or                                more often found in this study and that of Sayen et
J Infect Dis Antimicrob Agents                                                       Vol.	 6 No.1 Jan. - Mar. 1989            27

al. 16 This may be related to the severity of the disease   fever, physicians began to make the diagnosis of scrub
at the time the patients were seen.                         typhus in patients who did n<;)t respond to cotrimoxa­
       As shown in Table 4, the peripheral white blood      zole.    This, in turn, increased the physicians'
cell (WBC) count ranged from 6,050 to 25,200/mm 3           awareness of scrub typhus. The age distribution of
with polymorphonuclear cell (PMN) predominating.            patients with scrub typhus in Thailand in 1983 has
The average duration between the onset of fever and         been reported. 1 Most patients were adult, 6% of the
the determination of count was 9 days. Serial WBC           patienti (6/104) were between 10-14 years of age
count and differential count were not performed.            and none of the patients was below 10 years of age.
Thus we cannot confirm or dispute Berman's finding          Our study suggests that the incidence of scrub typhus
that lymphocytosis developed in 70% of the pa­              in children may be underestimated. Further study of
tients by day 14. Low platelet count was found in 7         scrub typhus in children should be carried out.
patients. In one patient, it was less than 100,000/
mm. 3 This finding was not mentioned in other stu­
dies.                                                                                  REFERENCES
       Although there were several reported cases of
adult respiratory distress syndrome in scrub typhus          1.	 Ministry of Public Health, Division of Epidemiology, Annual sum­
in adultsIO,ll and an older child/2 the symptoms of              mary. Bangkok: Ministry of Public Health, 1986. (in Thai).
                                                             2.	 Wisseman CL Jr. Scrub typhus. In: Strickland GT, ed. Hunter's
the patients and infiltrations were mild in all four
                                                                 tropical medicine. 5th ed. Philadelphia: WB Saunders, 1984:221­
cases with abnormal chest roentgenograms.                       3.
       Although the Weil-Felix test with Proteus OX­         3.	 Thainua M. A case report of scrub typhus. J Med Assoc Thai
K is generally available, it was positive (defined as a          1952; 35:9-27. (in Thai).
fourfold rise and/or the titer of 1 :160 or greater) in      4.	 Uttayopas J. Scrub typhus. Med J 1957; 6 :482-8. (in Thai).
only 60% of cases in this study. This is similar to          5.	 Thainua M, Busapavanich S. Outbreak of scrub typhus and mala­
other reports. IS, 16 The low prevalence of OX-K anti­           ria during a war game at Ubonrajtanee. J Med Assoc Thai 1958;
body can be due to two possibilities: firstly it is              41 :103·9. (in Thai).
often negative in the second and subsequent infec­           6.	 Uttayopas J, Uttayopas P. Scrub typhus: a report of one case.
                                                                 Med J 1959; 8:630-4. (in Thai).
tions,2 and secondly it is related to the infecting
strains of Rickettsia. Is
                                                             7.	 Trishnananda M, Harinasuta C, Kongrod S. The isolation of Ri­
                                                                 ckettsia tJUtsugamushi from scrub typhus patients in Thailand. J
       The two patients with relapse had mild symp­              Med Assoc Thai 1965; 48:482-92. (in Thai).
toms and probably did not need antirickettsial drugs.        8.	 Trishnananda M, Bhaibulaya M, Kongrod S, Harinasuta C. Study
Because neither tetracycline nor chloramphenicol is              on scrub typhus in the jungle of Panasnikhom district, Chonburi
rickettsidal under oridinary circumstances ultimate              province. J Med Assoc Thai 1965; 48:642-54 (in Thai).
freedom from clinical relapse (Le., "cure") is probab­       9.	 Leelarasamee A. Aswapokee P. Scrub typhus: report of two cases
ly dependent on an adequate immune response by the               who seek medication in Bangkok. Siriraj Hosp Gaz 1984; 36:537­
patient. The duration of chloramphenicol and tetra­              41. (in Thai).
cycline therapy depend on the stage of the disease at       10.	 Punyagupta S. Interesting infectious disease cases presentation:
the time therapy is begun. It is suggested as a practi­          cardiopuhnonary complication in an acute febrile patient. J Infect
cal conservative guide that tetracycline or chloram­             Dis Antimicrob Agents 1985; 2:194-7. (in Thai)
                                                            11.	 Pothiratana C. Scrub typhus pneumonia with adult respiratory
phenicol be administered until the patient has been
                                                                 distress syndrome. J Infect Dis Antimicrob Agents 1.987; 4:68-72.
afebrile for 48 hours and for an additional period
                                                                 (in Thai)
until the total time elapsed from onset of disease is       12.	 Sirisanthana V, Chaisate D, Poneprasert B, Scrub typhus in chil­
12 to 14 days. I? Relapses respond to retreatment                dren: a report of two cases. J Pediatr Soc Thai 1987; 26:111-4.
with the same drug. In fact, in many instances, re­              (in Thai)
lapses or recrudescences of fever are self-limited and      13.	 Brown GW, Shirai A, Rogers C, Groves MG. Diagnostic criteria for
resolve spontaneously about as rapidly as they do                scrub typhus: probability values for immunofluorescent antibody
with additional chemotherapy.                                    and Proteus OX K agglutinin titers. Am J Trop Med Hyg 1983;
       The incidence of scrub typhus in Thailand is              32:1101-7.
rising. 1 This is probably caused by the real increase in   14.	 Takada N, Khamboonruang C, Yamaguchi T, Thitasut P, Vajrasthi­
the number of cases as well as the increase in the diag­         ra S. Scrub typhus and chiggers in northern Thailand. Southeast
                                                                 Asian J Trop Med Public Health 1984; 15:402-6.
noses made by physicians. When chloramphenicol
                                                            15.	 Berman SJ, Kundin WD. Scrub typhus in South Vietnam: a study
was usually administered to patients with prolonged
                                                                 of 87 cases. Ann Intern Med 1973; 79: 26-30.
fever and a provisional diagnosis of typhoid fever, pa­     16.	 Sayen II, Pond HS, Forrester IS, Wood FC. Scrub typhus in
tients with scrub typhus who responded to chloram­               Assum and Burma. Medicine 1946; 25:155-214.
phenicol were misdiagnosed as typhoid fever. When           17.	 Weissernan CLJr. Rickettsial and bartonella infections. In: Strick­
cotrimoxazole became available and replaced                      land GT, ed. Hunter's tropical medicine. 6th ed. Philadelphia:
chloramphenicol as a less toxic treatment for typhoid            WB Saunders, 1984:198-210.

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