Typhoid Fever

Clinical Article

Clinical and Laboratory Presentation of Typhoid Fever

Ahmet Yaramis, MD; Idris Yildirim, MD; Selahattin Katar, MD; M. Nuri zbek, MD;
Isik Yalin, MD; M. Ali Tas, MD; Salih Hosoglu, MD

Abstract
A total of 314 children with clinical and/or laboratory diagnosis of
typhoid fever admitted to the Dicle University Hospital pediatric infectious diseases ward were reviewed for demographic data such
as age, sex, clinical features, and results of laboratory tests. There
were 187 male and 127 female patients, with a mean age of 9.6
years ranging from 6 months to 16 years. Eleven of all the children
were less than one year of age, while 23 were under the age of five
years. Predominant symptoms were fever, abdominal pain, vomiting, and headache. Hepatomegaly was almost twice as frequently
observed as splenomegaly. Common clinical signs of typhoid fever
in adults such as relative bradycardia and spots were seldom documented. A febrile convulsion was the presenting symptom in nine
of the patients, all of whom were under the age of five years. Intestinal perforation was present in five of the patients. Antibiotic susceptibility tests in 67 cases revealed resistance rates of 17% for
ampicillin, 5% for trimethoprim-sulfamethoxazole, 4% for
ceftriaxone, and 6% for sulbactam-ampicillin. No resistance was
detected against the quinolones and chloramphenicol. Elevated
serum alanine and aspartate aminotransferase (50 > /U/L) levels
were observed in 32% of our patients. At presentation, 38% of all
patients were anemic (Hb <12 g/dl), 10% were thrombocytopenic
(<105/mm3). Except the two bacteriologically confirmed typhoid
fever patients died during the period of observation, all patients
survived from their severe illness completely. Int Pediatr.
2001;16(4):227-231.

Key words: typhoid fever, S. typhi

Introduction
Salmonella typhi infection remains a serious problem
in developing countries. It has been estimated that approximately 12.5 million cases of typhoid fever occur annually in the developing world (excluding China) with
7.7 million cases in Asia alone.1 The disease is predominantly a disease of school age children and young adults
and is reported to be milder in infants and young children.2-4 Various organs have been involved in the course
of enteric fever, resulting in a wide array of presentation.5
From the Department of Pediatrics (Dr Yaramis, Dr Katar, Dr Tas)
and Infectious Diseases and Clinical Microbiology (Dr Hosoglu),
Dicle University Hospital, Diyarbakir, Turkey. Department of
Pediatrics Nizip State Hospital (Dr Yildirim), Gaziantep, Turkey.
Department of Pediatric Infectious Unit, University of Istanbul,
Medical School of Istanbul (Dr Yalin), Istanbul, Turkey.
Address reprint requests to Dicle Universitesi, Tip Fakltesi, ocuk
Sagligi ve Hastaliklari ABD, Diyarbakir, Turkey (Dr Yaramis).

The presenting symptoms and sign of typhoid fever in

children differ significantly from those in adults.6,7 Studies from endemic areas show that younger children are
more likely to present with a nonspecific febrile illness.8,9
The aim of our study was to determine the clinical and
laboratory presentation of typhoid fever in hospitalized
children in this endemic area between 1990 to 1999.
Material and Methods
We reviewed the medical records of all patients admitted to the Ward of Pediatric Infectious Diseases between January 1990 and May 1999. This is a pediatric
referral hospital at the southeastern region of Turkey,
where typhoid fever is endemic.10 In this study, the children were divided into two groups: those who had blood
and/or stool culture positive for S. typhi, and who had
clinical features strongly suggestive of enteric fever (n:
67); and those who had culture-negative and serology
positive and had clinical features strongly suggestive of
enteric fever (n: 247). There were 187 male and 127 female patients, with a mean age of 9.6 years ranging from 6
months to 16 years. Number of cases below 5 years of age
was 34 (15 of them females). All of the cases were living
in this endemic area, the southeastern region of Turkey,
and none of the cases were vaccinated for typhoid fever
that was not included in the routine immunization program.
Table 1 shows the clinical features of the children on
admission. The predominant symptoms were fever (95%),
abdominal pain (66%), vomiting (44%), and headache
(38%). Fever, vomiting, abdominal pain, loss of appetite,
diarrhea and cough were the predominant symptoms for
those under 5 years of age. None of the patients presenting with a cough had radiological evidence of pneumonia. However, typical symptoms in adults such as cough,
headache and constipation were uncommon, tending to
occur in older children. Common clinical signs of typhoid
fever in adults such as relative bradycardia and rose spots
were seldom documented.11
Hepatomegaly was detected in 132 (42%), splenomegaly in 63 (20%) patients. Intestinal perforation was
present in five of the patients. Their mean age was 13.7
years. The predominant symptoms in those patients with
intestinal perforation were fever and abdominal pain, with
a mean duration of 12.3 days. The diagnosis of perfora-

International Pediatrics/Vol. 16/No. 4/2001 227

Typhoid Fever

Table 1 - Clinical Symptoms & Signs of Patients at Admission

Feature

No (%) of Patients

Symptoms
Fever
Abdominal pain
Vomiting
Headache
Diarrhea
Constipation
Cough
Anorexia
Weakness
Nausea

298 (95)
207 (66)
138 (44)
119 (38)
72 (23)
24 (8)
48 (15)
122 (39)
116 (37)
72 (23)

Signs
Hepatomegaly
Splenomegaly
Abdominal tenderness
Rose spots
Relative bradycardia
Rales
Cervical lymphadenopathy
Encephalopathy

132
63
27
5
6
6
18
16

(42)
(20)
(8)
(1)
(2)
(2)
(6)
(5)

tion was usually based on the history and physical examination alone. Among the 5 children, 3 had a single perforation, and 2 had multiple perforations. None of these
children with perforated typhoid enteritis died during and
after operation in the pediatric surgery ward. The deaths
of the two patients with bacteriologically confirmed typhoid fever were attributed to overwhelming sepsis during the period of observation.
Laboratory Investigations
On admission blood was taken for hematocrit, platelet count, differential white cell count, liver function test,
examination for malaria parasites and Widal test. A blood
culture and fecal culture were performed before treatment.
The antibiotic susceptibility tests to eight antibiotics
(ampicillin, trimethoprim-sulfamethoxazole, ceftriaxone,
sulbactam-ampicillin, ofloxacin, ciprofloxacin, and
chloramphenicol) were determined by using the KirbyBauer disk diffusion technique or Scepter microdeletion
method according to the recommendations of the National Committee for Clinical Laboratory Standards.12 Of
the 314 patients with clinically suspected typhoid fever
included into the study, 67 (21%) had blood cultures positive for S. typhi. Twenty-one and twenty-three patients
with positive blood cultures also had positive stool cultures and positive Widal serology, respectively. Widals
agglutination titers of at least 160 were positive in all children. The H agglutinin titer of 1:320 was found in 42
patients (20%). In the 67 blood culture isolates, the antimicrobial resistance rates were as follows; ampicillin

228 International Pediatrics/Vol. 16/No. 4/2001

(17%); trimethoprim-sulfamethoxazole (5%); ceftriaxone

(4%); sulbactam-ampicillin (6%). There was no resistance
to quinolones and chloramphenicol. Table 2 shows the
hematological and biochemical profile of typhoid fever
patients.
The mean total white blood cell count was 7.3 (2.418) 103/mm3. The presence of a shift to left was found in a
significantly larger proportion of patients (78%). A white
blood cell count of < 4,5 x 109/L was found in 18% of all
patients. Elevated serum alanine and aspartate aminotransferase (>50) levels were observed in 100 (32%) of our
patients. At presentation, 38% of all patients were anemic (Hb <12 /dl), 10% were thrombocytopenic (< 105/
mm3)
Discussion
Salmonella typhi infection remains a serious problem
in developing countries. With an estimation of 12.5-16.6
million cases each year and 600 000 deaths, typhoid fever
continues to be a major cause of morbidity and mortality
in tropical countries, especially among children.1,13 However, in more affluent regions of the world, proper sanitation has successfully diminished the infections with S.
typhi. In Turkey, the number of cases with S. typhi infections has shown an increase in recent years from 10 001/
year in 1991 to 20 960/year in 1995.14
Typhoid fever in children in the first 2 years of life
exhibits certain differences from the clinical course in
adults.15 In our study, 17% of all patients with typhoid
fever were under 5 years, which is close to the figure in
some series.8,16 School-children were the most affected.
Children in this series commonly presented with fever,
headache, and gastrointestinal symptoms, and diarrhea was
more common than constipation in this study, which is in
accordance with the results from other studies.16-19
Typhoid fever may be particularly difficult to diagnose
in infants, as Mathieu et al. have reported, 10 patients in
their series having mild illness characterized by non-specific symptoms such as fever and cough.20 In our series, 6
infant cases had fever and only one infant had cough. Febrile convulsion was the presenting symptom in 13 (20%)
of the patients, all of whom were under the age of five
years.
Hepatomegaly (42%) and splenomegaly (20%) were
the major physical findings in our study. Semeer et al.
reported that, in a large series in children with enteric
fever, besides, 68.5% had elevated liver enzymes, while
only 44.4% had hepatomegaly with or without splenomegaly.21 In a study, 31 children with typhoid fever with
ages of 2 months to 12 years and blood culture positive
for multidrug resistant S. typhi were prospectively studied for their hepatic functions at the time of hospitalization.22 Hepatic manifestations included hepatomegaly

Typhoid Fever

Table 2 - Hematological and Biochemical Profile of Typhoid Fever Patients

Total WBC
3

WBC

Hb

Hb

Hb

(10 /mm ) (<4,500/mm ) (g/dl) ( 8g/dl) (8-12 g/dl)

7.3
(2,4-18)

18 %

9.8
(7-14)

7%

38 %

Platelets
5

(10 /mm )

216
(7-580)

Platelets
5

(<10 /mm )

10 %

ALT

ALT

AST

AST

Serum

Serum

(U/L)

(>50 U/L)

(U/L)

(>50 U/L)

Creatinine
(mg/dl)
1.8

74
(12-923)

(51.6%), jaundice (16.1%), raised levels of SGOT

(61.3%), SGPT (48.4%), and reduced levels of serum albumin (41.9%). Anemia was present in 44%, leukopenia
in 16% and leukocytosis in 11.1% of the cases.
Oh et al. and Laditan reported that, in their series,
hepatomegaly was almost twice as frequently observed as
splenomegaly.16,17 Elevated serum aminotransferase levels
were observed in 32% of our patients. Sixteen of our cases
presented with encephalopathy and 32% had reactive salmonella hepatitis.
In another study in Turkey, Kanra et al. found 17%
encephalopathy, 73% reactive salmonella hepatitis, 4%
pneumonia and 4% gastrointestinal bleeding.23 In our
study, 3 patients had gastrointestinal bleeding and perforation.
Oh et al. and Thisyakorn et al. have reported increases
in aminotransferase levels in 38% of the cases.24,25 The
hepatic reticuloendothelial system plays a major role in
engulfing the invading bacteria. The extent of liver involvement in typhoid fever varies from mild elevation of
transaminases, almost all patients being in the second and
third week of illness, to a more dramatic presentation with
a picture indistinguishable from viral hepatitis in 1 to 26%
of cases.26-28 Typhoid hepatitis is associated with a significant morbidity, and in one series, the mortality rate
reached to 20%.28 None of our patients had positive serology for acute viral hepatitis A.
The Widal test is a useful diagnostic test in children
in endemic area.29 In a study in Hong Kong, the usefulness of the Widal test in diagnosing childhood typhoid
fever in endemic areas was investigated.29 The test was
done on 150 children with other febrile illnesses and 98
bacteriologically proven cases of typhoid fever. Of the 150
children with non-typhoidal fever, only one had an H
agglutinin titer of 1:50. By using an H or O-agglutinin
titer of 1:50 or more as a criterion for diagnosis, a positive
Widal test was found in 88% of typhoid fever cases on the
first occasion when the test was done. Parry et al also reported that, in their large series, the O-agglutinin titer
was 100 in 83% of the blood culture-positive typhoid
fever cases, and the H-agglutinin titer was 100 in 67%.30
Of the 314 patients with clinically suspected typhoid fe-

30 %

108
(14-728)

34 %

Urine

Serum

Serum

urea nitrogen

proteinuria

protein

albumin

(md/dl)

(100ng/dl)

(g/dl)

(g/dl)

38

36 %

5.7

3.2

(4.7-8,4)

(2,3-4,9)

ver included into the present study, 67 (21%) had blood

cultures positive for S. typhi. Twenty-three patients with
positive blood cultures also had positive Widal serology.
Widals agglutination titers of at least 160 were positive
in all children. The H agglutinin titer of 1:320 was found
in 42 patients (20%).
Though multiple resistant S. typhi isolates have been
reported in many parts of the world, it is not as yet a problem for Turkish isolates.31-35 In a study, Phuong et al. reported that, 85% of isolates of S. typhi were resistant to
chloramphenicol,
ampicillin,
trimethoprimsulfamethoxazole and tetracycline.34 In another study in
Turkey, Akan et al. found no resistance to the antibiotics
studied except tetracycline in their isolates of S. typhi.35
Of the 67 blood culture isolates in the present study, the
percentage of antimicrobial resistance rate were as follows: ampicillin (17%), trimethoprim-sulfamethoxazole
(5%), ceftriaxone (4%), sulbactam-ampicillin (6%). There
was no resistance to quinolones and chloramphenicol.
One of the most lethal complications of typhoid fever
is ileal perforation, which affects especially young men.
Basten and Stockenbrugger reviewed the literature published after 1960 on typhoid perforation in different developing countries, with special attention to the incidence
and outcome of typhoid perforation.36 Information was
obtained on a total number of 1,990 cases of typhoid perforation in 66 157 patients with typhoid fever, published
in 52 reports all over the world. The overall frequency of
intestinal perforation in typhoid fever was 3% with an
overall mortality rate of 39.6%. Late presentation, delay
in operation, multiple perforations, and drainage of copious quantities of pus adversely affected the mortality rate.37
Aggressive resuscitation with a combined antibiotic regimen in the preoperative period, selected operative procedure and metabolic support decrease the morbidity and
mortality of typhoid enteric perforation.38
Meier and Tarpley reported that, among 75 children
with perforated typhoid enteritis, 53 had a single perforation, and 22 had multiple perforations.39 They reported
that, in their studies, the usual symptoms were fever and
abdominal pain, with a mean duration of 10.5 days and
the mean age was 11.4 years.

International Pediatrics/Vol. 16/No. 4/2001 229

Typhoid Fever

In another study of 65 patients with perforated typhoid

enteritis, 45 were males and 20 females with ages ranging
from 5 to 15 years, presenting symptoms were fever, abdominal pain, vomiting and either diarrhea or constipation.40 The overall mortality rate in this study was 20%
and was adversely influenced by the longer duration of
perforation, presence of shock and fecal peritonitis. In our
study, intestinal perforation was present in five of the patients. The mean age was 13.7 years. The usual symptoms
were fever and abdominal pain, with a mean duration of
12.3 days. The diagnosis of perforation was usually based
on the history and physical examination alone. Among 5
children, 3 had a single perforation, and 2 had multiple
perforations. None of these children with perforated typhoid enteritis died during and after operation in the pediatric surgery ward. In an endemic area of typhoid fever,
the diagnosis of typhoid perforation should be made on
physical examination. Surgery is preferable to medical
treatment.37
Leukopenia is thought to be a characteristic finding
in patients with typhoid fever. Hemophagocytosis is an
important mechanism in producing neutropenia, anemia
and thrombocytopenia in several infectious and noninfectious disorders.41 In a study, of 29 children with 8
months to 15 years of age, leukopenia was found in 6 (20%)
patients.38 In the present study, the mean total white blood
cell count was 7.3 (2.4-18) 103/mm3. A white blood cell
count of < 4,5 x 109/liter was found in 18% of patients
and the presence of a left shift was found in a significantly
larger proportion of patients (78%). Complications noted
in this series included thrombocytopenia (< 105/mm3) in
10%, urine proteinuria in 36% and gastrointestinal perforation in 1.5% of patients. A stormy course with
rhabdomyolysis, intestinal ulcers, intestinal perforation,
and pancreatitis occurred rarely, as have been described
by others.42-44
References
1.
2.

3.
4.
5.

6.

7.

Endelman R, Levine MM. Summary of an international workshop on typhoid fever. Rev Infect Dis. 1986;88:329-349.
Palacios MPG, Acosta JJV, Gutierrez AW. La fiebre tifoidea en
el mino menor de dos arios. Bol Med Hosp Infant Mex. 1981;8:473483.
Ashcroft MT. Typhoid and paratyphoid fevers in the tropics. J
Trop Med Hyg. 1964;67:185-189.
Baver FK, Bower AG. Typhoid fever of short duration. Am J
Med Sci. 1951;22:174-178.
Hoffman TA, Ruiz CJ, Counts GW, Sachs JM, Nitzkin JL.
Waterborne typhoid fever in Dade country, Florida. Clinical and
therapeutic evaluations of 105 bacteremic patients. Am J Med.
1975;59.481-487.
Mahle WT, Levine MD. Salmonella typhi infection in children
younger then five years of age. Pediatr Infect Dis J. 1993,12:627631.
Choo KE, Razif A, Arrifin WA, Sepiah M, Gururaj A. Typhoid
fever in hospitalized children in Kelantan, Malaysia. Ann Trop
Pediatr. 1988;8:207-212.

230 International Pediatrics/Vol. 16/No. 4/2001

8.
9.
10.
11.

12.

13.

14.

15.

16.
17.

18.

19.

20.

21.

22.

23.

24.
25.

26.

27.
28.
29.

30.

31.

Johnson AO, Aderele WI. Enteric fever in childhood. J Trop

Med Hyg. 1981;84:29-35.
Scragg J, Rubidge C, Wallace HL. Typhoid fever in African and
Indian children in Durban. Arch Dis Child. 1969;44:18-28.
Sirmatel F. GAP ve infeksiyon hastaliklari. ANKEM. 1998; 12:
191-194.
Hook EW. Salmonella species (including typhoid fever) In.
Mandell GL, Douglas RG, Bennett JE. (eds) Principles and Practice of Infectious Disease (3 rd ed.). New York ChurchilLivingstone. 1990.
National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Test. 5th. ed.
Approved Standard NCCLS Document M2-A5, Villanova PA:
NCCLS, 1993.
Pang T, Bhutta ZA, Finlay BB, Altwegg M. Typhoid fever and
other salmonellosis: a continuing challenge. Trends Microbiol.
1995;3:253-255.
Ministry of Health (Turkey), Hacettepe University Institute of
Population Studies, an Macro International Inc 1994. Turkish
Demographic and Health Survey, Ankara, Turkey. 1993: 87-106.
Hornick RB, Greisman SE, Woodward TE, DuPont HL, Dawkins
AT, Snyder MJ. Typhoid fever: pathogenesis and immunologic
control. N Engl J Med.1970; 283:739-746.
Oh HML, Masayu Z, Chew SK. Typhoid fever in hospitalized
children in Singapore. J Infect. 1997;34:237-242.
Laditan AA, Alausa KO. Problems in the clinical diagnosis of
typhoid fever in children in the tropics. Ann Trop Paediatr.
1981;1:191-195.
Yap YF, Puthucheary SD. Typhoid fever in childrena retrospective study of 54 cases from Malaysia. Singapore Med J.
1998;39:260-262.
Rasaily R, Dutta P, Saha MR, Mitra U, Lahiri M, Pal SC. Multidrug resistant typhoid fever in hospitalized children. Clinical,
bacteriological and epidemiological profiles. Eur J Epidemiol.
1994;10:41-46.
Mathieu J, Henning K, Bell E, Friede T. Typhoid fever in New
York City 1980 through 1990. Arch Intern Med. 1994;154:17131718.
Secmeer G, Kanra G, Cemeroglu AP, Ozen H, Ceyhan M, Ecevit
Z. Salmonella typhi infections. A 10-year retrospective study.
Turk J Pediatr. 1995;37:339-341.
Jagadish K, Patwari AK, Sarin SK, Prakash C, Srivastava DK,
Anand VK. Hepatic manifestations in typhoid fever. Indian
Pediatr. 1994;31:807-811.
Kanra G, Yurdakk M, Semeer G, et al. Clinical findings of
pediatric patients during an outbreak of typhoid fever in Ankara. Turk J Pediatr. 1985;27:11-15.
Oh HML, Chew SK, Manteiro EH. Multi-drug resistant typhoid
fever in Singapore. Sing Med J. 1994;35:559-601.
Thisyakorn U, Mansuwan P, Taylor DN. Typhoid and paratyphoid fever in 192 hospitalized children in Thailand. Am J Dis
Child. 1987;141:862-865.
Morgenstern R, Hayes PC. The liver in typhoid fever: always
affected, not just a complication. Am J Gastroenterol.
1991;86:1235-1239.
Pais P. A hepatitis like picture in typhoid fever. Br Med J.
1984,289:225-226.
Khosla SN. Typhoid hepatitis. Postgrad Med J. 1990; 66:923925.
Chow CB, Wang PS, Cheung MW, Yan WW, Leung NK. Diagnostic value of the Widal test in childhood typhoid fever. Pediatr
Infect Dis J. 1987; 6:914-817.
Parry CM, Hoa NT, Diep TS, et al. Value of a single tube Widal
test in diagnosis of typhoid fever in Vietnam. J Clin Microbiol.
1999;37:2882-2886.
Wilke A, Atalay G, Erdem B. The susceptibility of Salmonella
spp to various antibiotics. Mikrobiyol Bul. 1988; 22:17-24.

Typhoid Fever
32.

33.

34.

35.

36.

37.

Olarte J, Galindo E. Salmonella typhi resistant to chloramphenicol, ampicillin and other antimicrobial agents: strains isolated
during an extensive typhoid fever epidemic in Mexico.
Antimicrob Agents Chemother. 1973;4:597-601.
Rasaily R, Dutta P, Saha MR, Mitra U, Lahiri M, Pal SC. Multidrug resistant typhoid fever in hospitalised children. Clinical,
bacteriological and epidemiological profiles. Eur J Epidemiol.
1994;10:41-46.
Cao XT, Kneen R, Nguyen TA, Truong TL, White NJ, Parry
CM. A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. Pediatric Infect Dis J.
1999;18:245- 248.
Akan , Kanra G, Semeer G, Ceyhan M, Ecevit Z, Berkman
E. Antibiotic susceptibility of Salmonella serogroups isolated
from Turkish children. Turk J Ped. 1997;39:7-11.
van Basten JP, Stockenbrugger R. Typhoid perforation. A review of the literature since 1960. Trop Geogr Med. 1994;46
(6):336-339.
Adesunkanmi AR, Ajao OG. The prognostic factors in typhoid
ileal perforation: a prospective study of 50 patients. J R Coll Surg
Edinb. 1997; 42:395-399.

38.
39.
40.
41.
42.
43.

44.

Akgun Y, Bac B, Boylu S, Aban N, Tacyildiz I. Typhoid enteric

perforation. Br J Surg. 1995;82:1512-1515.
Meier DE, Tarpley JL. Typhoid intestinal perforations in Nigerian children. World J Surg. 1998;22:319-323.
Gupta V, Gupta SK, Shukla VK, Gupta S. Perforated typhoid
enteritis in children. Postgrad Med J. 1994;70:19-22.
Mallouh AA, Sadi AR. White blood cells and bone marrow in
typhoid fever. Pediatr Infect Dis J. 1987 ;6:527-529.
Quale JM, Lanono F. Case Report. Salmonella myonecrosis in a
patient with diabetes mellitus. Am J Med Sci. 1991;301:335-336.
Faierman D, Ross FA, Seckler SG. Typhoid fever complicated
by hepatitis, nephritis and thrombocytopenia. JAMA. 1972;
221:60-61.
Renner F, Nimeth C, Demmelbaver N. High frequency of concomitant pancreatitis in salmonella enteritis (letter). Lancet.1991;337:1611.

Miami Childrens Hospital 2001

International Pediatrics/Vol. 16/No. 4/2001 231