TYPHOID FEVER

Y O G YA K A R TA , M A R C H 9 th 2 0 2 3
 Case
Buzğan et al., 2007. A case of typhoid fever presenting with multiple complications. Eur J Gen Med. 4(2):83-86

An 18-year-old female patient referred to emergency

department with complaints of fever and fatigue beginning 15
days ago accompanied by headache, weakness, palpitation,
abdominal pain, and diarrhea a week later.

On her physical examination, temperature was 39C, pulse rate:

92/min, rhythmic, breath rate: 24/min, blood pressure: 100/60
mmHg. She had apathic confusion, her sclerae were subicteric,
her skin and conjunctivae pale, her lips and tongue dry and
tongue rusty. She had a painful hepatomegaly which exceeds
the costal ridge 1 cm and she had no lymphadenopathy.
 Case
Buzğan et al., 2007. A case of typhoid fever presenting with multiple complications. Eur J Gen Med. 4(2):83-86

Laboratory Examinations
leukocytes 2.500/mm3, Hb: 9.9 gr/dl, platelets: 31.000/mm3,
ESR: 30 mm/h, CRP: 75 mg/dl.
AST: 161 U/ L, ALT: 67 U/L, total bilirubin: 2.05 mg/dl, direct
bilirubin: 1.65 mg/dl, LDH: 1250 U/L, CK: 898 U/L
BUN: 19 mg/dl, creatinine: 0.8
Occult blood in stool was ++ positive
Typhus?

Typhoid?
DEFINITION

● A potentially fatal multisystemic infection,

characterized by fever and abdominal pain,
produced primarily by Salmonella enterica typhi
and paratyphi A, B, and C.
● Untreated typhoid fever is a life-threatening
illness (CFR 10 – 30%) with long-term morbidity
often involving the CNS.
● Treated properly  Typically a short-term
febrile illness with few long-term sequelae and a
1 – 4% risk of mortality.
EPIDEMIOLOGY

• Occurs worldwide, primarily in developing

nations whose sanitary conditions are
poor.
• 80% of cases come from Bangladesh,
China, India, Indonesia, Laos, Nepal,
Pakistan, or Vietnam.
• It infects ± 21.6 million people (incidence
of 3.6 per 1,000 population) and kills an
estimated 200,000 people/year.
• Mostly affects school-aged children and
young adults.
 • Data from 2008  incidence rate of TF at 148.7 per 100,000
persons (age 2–4 y.o), 180.3 (5–15 y.o), and 51.2 (>16 y.o)

INDONESIA
ETIOLOGY

• Salmonella enterica serotype typhi

• Salmonella enterica serotypes paratyphi A, B, and C
TRANSMISSIONS

• Faecal-oral route
• Close contact with patient / carriers
• Contaminated water & food
• Flies and cockroaches
PATHOGENESIS

Bacteremia 1
(asymptomatic)

Bacteremia 2
(Systemic signs/symptoms)

After the acute illness, about 3 –

5% of the people become carriers
 Inadequate response of mucosal
humoral immunity (IgA)
High acid tolerance

replication of Salmonella

Ingestion of contaminated
food/water
Small intestine lumen

Duct.thoracicus Peyeri patch

Mesenteric lnn
Distal ileum

Blood circulation Blood circulation

(Bacteremia 1) (Bacteremia 2)
asymptomatic Systemic sign & symptoms

Cytokine release (systemic Signs & symptoms

Reticuloendothelial organ (liver, Liver inflammatory reaction)
spleen)

Gallbladder Hyperplasia of Peyeri Erosion of blood

(Replication) Hyperactive
patch vessels

(Modified from PAPDI, 2014)

Leaving
phagocytes Intestinal lumen Macrophage already
Penetrates intestine again activated

Necrosis hyperplation
Delayed type GI bleeding
Replication in extracellular Feces
organ/sinuosoid hypersensitivity reaction Perforation
Accumulation of mononuclear cell
 CLINICAL MANIFESTATIONS

● Incubation period : 7 – 14 days (3 –

60 days) after ingestion of
contaminated food or water
● Ranging from asymptomatic 
typical signs & symptoms with
complication until death
● Majority of patients present with
abdominal pain, fever, and chills
CLINICAL MANIFESTATIONS

● 1st week  sign & symptoms of non-specific acute infection

(fever, headache, myalgia, anorexia, nausea, vomiting, obstipation, diarrhea, cough,
epistaxis) – fever increase gradually, mostly on evening – night (step-ladder).

● 2nd week  fever, relative bradycardia (an increase in pulse rate of <8 bpm for each
1°C rise in body temperature), coated tongue, hepatomegaly, splenomegaly,
meteorism, altered mental status (somnolence, sopor, coma, delirium, psychosis);
rose spot (seldom in Indonesian)

Figure 2. Rose spot

COMPLICATIONS

Serious complications occur if illness prolong > 2 weeks (10%)

● Intestinal : bleeding, perforation, ileus paralytic, pancreatitis

● Extra-intestinal :
• Cardiovascular : shock, myocarditis, thrombophlebitis
• Hematology : hemolytic anemia, thrombocytopenia, DIC, thrombosis
• Pulmo : pneumonia, emphysema, pleuritis
• Hepatobiliary : hepatitis, cholecystitis
• Bone : osteomyelitis, periostitis, spondylitis, arthritis
• Neuropsychiatric : toxic typhoid

3rd Week of illness

DIAGNOSIS
Routine examination
● Leukopenia/normal leukocyte count/leukocytosis, eosinopenia, lymphopenia, mild anemia,
thrombocytopenia, increase in ESR, ALT/AST (mild), mild hypokalemia & hyponatremia
● A combination of absolute eosinopenia, elevated AST, and CRP levels (>40 mg/L) have been shown
to be a positive predictor of S typhi and S paratyphi bacteremia.
● ALT to LDH ratio ≥ 9:1 supports a diagnosis of acute viral hepatitis, while ratio ≤ 9:1 supports
typhoid hepatitis.
● Dengue & malaria should also be ruled out.

Standard diagnosis  culture

●Serology test is not recommended (difficult to interpret in endemic populations)

DIAGNOSIS
Widal Test
● Detection antibody to S.typhi  agglutination between antigen with antibody (agglutinin O, H)

Factors related to result:

 Use of early antibiotics
 Disorders of antibody
formation
 Use of corticosteroids
 Timing of blood sample
 Endemic / non-endemic area
 History of vaccination
 Amnestic reaction
Agglutinin O is still detected after 4 – 6 months  Technical difference
Agglutinin H persists longer (9 – 12 months)

Vi antigen is indicator to carrier stage

 Typhidot
• Detect IgM and IgG antibodies present in the outer membrane protein of S.thypi
• Positive results are obtained 2-3 days after infection
• Sensitivity 98%, specificity 76.6%
• IgG can be present until 2 years after infection  difficult to differentiate between acute
infection/reinfection/convalescent in primary infection  Typhidot-M (inactivation of total IgG 
allow binding of specific IgM & antigen)  more sensitive (100%), faster result (3 hours)

IgM dipstick
• Detect specific IgM antibody to S.typhi in serum/whole blood
• Use of strip containing antibody anti IgM  semi-quantitative assessment with reference strip

Tubex Test
• Rapid semi-quantitative colometry with sensitivity of 100%, specificity 90%
Culture  gold standard
Specimens: blood, bone marrow, urine, stool, rose spot biopsy, duodenal aspirates

Negative blood culture

(does not rule out typhoid)
• Use of antibiotics
• Not enough blood volume (<5 ml
 at least 20 ml in adults)
• Vaccination  agglutinin will
suppress bacteremia
• Timing of blood sampling  after
first week, formation of agglutinin
will increase
DIFFERENTIAL DIAGNOSIS

• Abdominal Abscess • Malaria

• Amoebic Liver/Hepatic Abscesses • Rickettsia diseases
• Appendicitis • Toxoplasmosis
• Brucellosis • Tuberculosis (TB)
• Dengue • Tularaemia
• Influenza • Typhus
• Leishmaniasis
MANAGEMENT
● Bedrest
● Hygiene
● Diet (soft, easily digestible unless abdominal distension/ileus)
● Antibiotic treatment
 Usually treated with single antibiotic
 Combination of ≥ 2 antibiotics is indicated only in toxic typhoid,
peritonitis/perforation, septic shock with other causative microorganisms
confirmed with blood culture.
● Symptomatic & supportive treatment (antipyretic, fluids, etc.)
● Steroid can be given in patients with shock septic or toxic typhoid
(dexamethasone 3x5mg iv).
ANTIBIOTIC TREATMENT
• Chloramphenicol 4x500mg PO/IV, given until 7 days after fever has subsided.
• Thiamphenicol 4x500mg  effectivity is the same as chloramphenicol but has
lower risk of hematological complication (e.g. aplastic anemia)
• Cotrimoxazole 2x960mg (14 days)
• Ampicillin & amoxicillin 50 – 150 mg/kg (14 days)
• 3rd gen cephalosporin (ceftriaxone) 3-4 g/d (3 – 5 days)
• Fluoroquinolone
 Norfloxacin 2x400mg (14 days)
 Ciprofloxacin 2x500mg (6 days)
 Ofloxacin 2x400mg (7 days)
 Pefloxacin 400mg/d (7 days)
 Fleroxacin 400mg/d (7 days)
 Levofloxacin 1x500mg (5 days)
• Azithromycin loading dose 1 gram followed with 1x500mg – 1 g (depending
on BW) for 7 - 10 days  avoid prescribing as empirical treatment (reserved
for stable XDR Typhoid)

Multidrug resistant Salmonella typhi

(MDRST)
(PAPDI, 2014) (Harrison 20th Ed, 2018)
Non-Resistant Typhoid First Line Drugs:
Typhoid fever caused by S.typhi/S.paratyphi strains which are Chloramphenicol, Ampicillin, Trimethoprim-
sensitive to first line drugs and third generation cephalosporins Sulfamethoxazole
(with/without resistant to second line drugs)

Multidrug Resistant Typhoid (MDR) Second Line Drugs:

Resistant to first line drugs but sensitive to third generation Fluoroquinolones
cephalosporins (with/without resistant to second line drugs)

Extensively Drug Resistant Typhoid Third Gen Cephalosporins:

(XDR) Cefixime (uncomplicated)
Ceftriaxone (complicated)
Resistant to all recommended antibiotics for typhoid fever, but is
sensitive to carbapenems and azithromycin.
 Pregnant patients
• Chloramphenicol  contraindicated in 3rd trimester (premature
delivery, IUFD, grey syndrome)
• Thiamphenicol  contraindicated in 1st trimester (teratogenic effect)
• Fluoroquinolone, cotrimoxazole  also contraindicated
• Drug of choice in pregnancy  ampicillin, amoxicillin, ceftriaxone
 TYPHOID CARRIER

DEFINITION
• Someone whose feces/urine contains S.typhi after one year
after typhoid fever without clinical symptoms
• Typhoid cases with S.typhi still found in feces/urine for 2-3
months are called post-convalescent carriers
• 25% denied any history of acute typhoid fever

DIAGNOSIS
● Positive S.typhi in stool/urine cultures in asymptomatic
patients or 1 year post-typhoid fever
● Vi serological examination (positive if antibody titers > 160,
sensitivity 75%, specificity 92%)
 TREATMENT
Co-infection with
Without Cholelithiasis
Schistosoma haematobium in urinary tract
Treatment regimen for 3 months:
1. Ampicillin 100mg/kg/day + probenecid 30mg/kg/day S. haematobium eradication must be carried out in
2. Amoxicillin 100mg/kg/day + probenecid 30mg/kg/day this case
3. Cotrimoxazole 2x960mg 1. Praziquantel 40mg/kg single dose, or
2. Metrifonate 7.5-10mg/kg 3-doses with 2-weeks
With Cholelithiasis interval
Cholecystectomy + regimen as the above for 28 days
After that, treatment regimen for carrier typhoid
Or
can be given to patients
Cholecystectomy + one of the following:
1. Ciprofloxacin 2x750mg
2. Norfloxacin 2x400mg

(PAPDI, 2014)
Typhoid Fever in Children
• Typhoid fever in older children (> 10 y.o) generally
has a clinical picture resembling adults.
• The degree of severity will be more severe than
younger pediatric patients.
• General symptoms: fever (>1 week) and complaints
of the GI tract (nausea, vomiting, diarrhea, or
constipation in older children).
• These symptoms can also appear in other
gastrointestinal infections  often referred by
parents as "typhoid symptoms".
 Treatment
Oral IV
Chloramphenicol (50 – 75 mg/kg/day, 14 – 21 Chloramphenicol (75 mg/kg/day, 14 – 21 days)
days)
Without complication
Amoxicillin (75 – 100 mg/kg/day, 14 days) Ampicillin (75 – 100 mg/kg/day, 14 days)
TMP-SMX (8/40 mg/kg/day, 14 days)
Cefixime (15 – 20 mg/kg/days, 7 – 14 days)
Alternative Azithromycin (quinolone resistant, 80 – 100
mg/kg, 7 days)
Chloramphenicol (100 mg/kg/day, 14 – 21 days)
Ampicillin (100 mg/kg/day, 14 days)
Complicated typhoid
Ceftriaxone (75 mg/kg/day) or
Cefotaxime (80 mg/kg/day) 10 – 14 days
 PREVENTION

Ensure proper Eat clean fruits &

sanitation & regularly Drink boiled water vegetables and other Get typhoid vaccination
wash hands fully cooked meal
TYPHOID VACCINE IN INDONESIA
THANK YOU
Cont. After samples were taken for microbiological analyses, oral
treatment of ciprofloxacin 2x500 mg was initiated by means of
nasogastric tube and electrolyte replacement was maintained.
Case After 8 hours of her admission, discordance between pulse and
fever disappeared and pulse rate increased to 116/min while
fever was 38oC.

Tachycardia was attributed to hypopotassemia.

In Gruber-Widal test, TO antibody was 1:200 and TH antibody

1:100.

After 2 days of admission, S. typhi was grown in blood culture.

Salmonella did not grow on urine and stool cultures.

In antibiotic susceptibility testing of the isolated strain, there

was only moderate resistance to ceftriaxone, but sensitive to
ciprofloxacin, chloramphenicol and co-trimoxazole.
Cont. Fever disappeared at the third day of her admission and
electrolytes came to normal at the fifth day.
Case Repeated Gruber-Widal test revealed that TO antibodies
increased to 1:800 and TH antibodies to 1:200 one week later.

Her platelets came to 199.000 and also her leukopenia

improved. Hb level gradually reduced to 7.6 gr/dl after
admission and remained at that level. She was given 2 units of
whole blood, occult blood positivity in stool disappeared after
10 days of admission.

After 2 weeks of antibiotic treatment, the patient was

discharged with full recovery