4/16/2013

Pathophysiology and Diagnosis of

Thyphoid Fever

Iskandar Zulkarnain

Division of Tropical Medicine and Infectious Diseases

Departement of Internal Medicine
Faculty of Medicine, University of Indonesia
Dr. Cipto Mangunkusumo General Hospital
Jakarta

Typhoid Fever
l Typhoid fever is an acute systemic
infection caused by Salmonella enterica
serotype typhi or paratyphi,
characterized by constitutional and
gastrointestinal symptoms

Epidemiologic Distribution of Typhoid Fever

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Organism
l Salmonella typhi, a Gram-negative bacteria.

l Similar but often less severe disease is caused by

Salmonella serotype paratyphi A & B.

l Contains 3 important antigens:

1. O antigen: a lipopolysaccharide part of the cell wall. It is an
important pathogenic factor and is common for typhi and
paratyphi species (group-specific)
2. H or flagellar antigen: strain specific; important in
diagnosis
3. Polysaccharide capsule Vi: present in about 90% of all
freshly isolated S. typhi and has a protective effect against
the bactericidal action of the serum of infected patients.

S. typhi

Transmission

l Reservoir is chronic carriers: Organisms may live

for months or years in the Gall Bladders of
carriers and are passed intermittently in stool and
less frequently in urine.

l Infection occurs by fecal-oral route. Common

sources are infected water supply and polluted
vegetables and food. Direct contact and insects
as flies play a minor role.

l Occurrence of clinical disease depends on the

amount of infecting organism.

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Some example of commonly

Occuring Salmonella serotypes and groups
Group Serotype
A S. paratyphi A
B S. paratyphi B
S. stanley
S. saintpaul
S. agona
S. typhimurium
C S. paratyphi C
S. choleraesuis
S. virchow
S. thompson
D S. typhi
S. enteritidis
S. dublin
S. gallinarium

Pathogenesis
Contaminated food of drinks Gastric acid

Bowel lumen

Mucosal defence

Adhesion to mucose Colonization

Invasion to Peyer Patch

Regional Lymphadenitis Thoracic duct

1st systemic bacteriemia

Pathogenesis
Infection of RE system 2nd Bacteriemia
Liver, Spleen

Lung, Myocard
Gall bladder Kidney, etc

Feces

Reinfection in bowel mucose Systemic manifestation

Hyperplasia Peyer Patch Inflammation, erosion

Bleeding, perforation

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Pathology of typhoid fever

Clinical features: symptoms

Classic disease passes into 3 stages each lasting
one week:

First week
- Fever : Temp rises gradually in a stepladder
manner.
- Headache, malaise, myalgia, drowsiness
- Abdominal pain and distension, constipation
(pea-soup diarrhea and vomiting in children)
- Cough, sore throat

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Clinical features: symptoms

l Second week
Patient is more ill, prostrated with continuous high
fever. Abdominal symptoms are more severe with
jaundice in some cases. Others may have delerium or
stupor.

l Third week Cure or Complications ?

Untreated, patients may improve gradually or
toxaemia increases and pass into coma (typhoid
state). This is rare now and the course is modified by
the early use of antibiotics.

Fever pattern in Typhoid Fever

Leucopenia
High fever Mild thrombocytopenia
Headache Relative neutrofilia
Abdominal discomfort Aneosinofilia
Diarrhea or constipation
Relative bradicardia

0 5 7 14

Fever pattern : typhoid fever

Typhus Inversus Pattern
Lowest early in the morning
Highest about 5.30 to 6.30 pm
Can be found in typhoid fever, TB

Pulse Temperature dissosiation

In normal temperature 37oC (99oF) pulse 80 beats/min
Increased 8 beats/min every 1o C
Relative bradicardia can be found in
enteric/typhoid fever,
mycoplasma, malaria falciparum

Devervescence à 3-7 days after treatment

usually on 2nd or 3rd weeks

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Female 31 yo, fever since 2 weeks ago

Hb 9.3 L 1600 Ht 28 Tr 107.000
Diff -/1/4/62/31/2 ESR 60 CRP 68
Widal ty O 1/160 H >1/640 ty B H 1/160
Treatment : Ceftriaxone 3g/day
Gall culture - PCR S typhi +

Clinical features: signs

l Relative bradycardia (pulse-temp dissociation)

l Fine rose-spot rash on the trunk appearing on the 4th – 5th day
of fever, more in whites. Rash fades on pressure and
disappears in 3-4 days.

l Coated tongue

l Diffuse abdominal distension and tenderness. Rigidity and

rebound tenderness suggest intestinal perforation.

l Mild splenomegaly is detectable by the end of first week.

Hepatmegaly and jaudice are uncommon.

l Delerium, stupor. Sign of meningism are occasional.

l Leucopenia is typical. Leucocytosis (and tachycardia) suggest

a complication as intestinal bleeding or perforation.

Typhoid rash

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Clinical Presentation of Typhoid Fever

Clinical sign and symptom (n=119) %

Headache 94.9
Epigastric pain 94.7
Nausea 90.7
Anorexia 90.2
Fever (>37.2) 89.8
Muscular pain 78.6
Rigor 78.4
Coated tongue 41.8
Vomiting 57.7
Cough 46.2
Relative bradicardia 34.2
Diarrhea 32.1
Constipation 33.9
Hepatomegaly 12.3
Splenomegaly 0.8

Pohan HT, Indones J Int Med 2004;36(2)

Clinical scoring scale for typhoid fever

Fever < 1 wk 1 Insomnia 1

Headache 1 Hepatomegaly 1
Weakness 1 Spelenomegaly 1
Nausea 1 Fever > 1 wk 2
Anorexia 1 Relative bradicardia 2
Abdominal pain 1 Typhoid tongue 2
Vomiting 1 Melena stools 2
Disturb GI motility 1 Impaired consciousness 2
Clinical typhoid fever if score > 13 of maximal 20

Adapted from : Nelwan RHH. Conns Current Traatment 2003

Laboratory Examination : Diagnosis

Peripheral blood count Leucopenia, leucocytosis
normal WBC count
mild anemia
thrombocytopenia
increased ESR

Serum transaminase increased ALT and AST

Albumin Hypoalbuminemia

Serology Increased titer of

aglutinin O, H and Vi

Blood culture Salmonela typhi

PCR Positive

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Laboratory diagnosis : Culture

l Culture: is essential for diagnosis.

– Blood culture is positive in >70% in the first week and rate
of positivity declines thereafter.
– Bone marrow aspirate culture gives the highest yield all
through the disease and should be performed in presence
of a negative blood culture.
– Urine culture is positive in 10% temporarily in the first week.
– Stool culture is positive in 30% in the 2nd and 3rd weeks but
is difficult and unreliable due to presence of other
Salmonellae in stool.

Laboratory Diagnosis: Widal test

Agglutination test that detects antibodies against S. typhi and paratyphi
in the patient’s serum.
Involves reaction against 5 antigens : O antigen and H antigens of typhi
and paratyphi A, B & C; O antibodies appear on days 6-8 and H
antibodies on days 10-12.

The role of Widal test in diagnosis of typhoid vever is complicated by:

1. False negative results in up to 30% of culture-proven cases of typhoid
fever
2. False positive results: S. typhi shares O and H antigens with other
Salmonella serotypes and has cross-reacting epitopes with other
Enterobacteriacae
3. Results should be interpreted with care in accordance with
appropriate local cut-off values for the determination of positivity
which depends on endemicity of infection and application of
vaccination.
Cut off titres à depends on local data

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Diagnostic criteria
l Definite
- Positive gall culture or PCR Salmonella typhi
- Widal serology agglutinin O titer > 1/640 or H
titer >1/1280
- Increased of O titer twice or more

l Probable
Widal serology agglutinin O titer 1/320 or H titer 1/640.

Treatment
l Non Pharmacologic : Bed Rest, Nutrition

l Pharmacologic :
1. Symptomatic & Supportive Treatment

2. Antibiotic
Ampicillin/Amoxicillin 2x750 or 3x500 mg
Cotrimoxasazole 2 x 960 mg
Chloramphenicol 4 x 500mg / Tiamphenicol 4 x 500 mg
Cephalosporin : Ceftriaxone 3-4 g/days
Fluoroquinolones : Ciprofloxaxin 2 x 500 mg
Levofloxacin 1 x 500mg
Ofloxacin 2 x 400 mg
Azithromycin 1 x 500 mg

Complications
Intestinal Complication
Intestinal perforation
Gastrointestinal hemorrhage
Hepatiitis, pancreatitis, paralytic ileus

Extraintestinal Complication
Cardiovascular : shock, myocarditis
Neuropsychiatric : encephalopaty, delirium
psychosis
TOXIC TYPHOID

Respiratory : bronchitis, pneumonia, pleuritis

Hematology : anemia, DIC
Kidney : glemerulonephritis, pyelonephritis
Others : osteomyelitis, focal abscess

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Intestinal Complications
Basic pathogenesis :
Plaque peyeri lesions
Mild Bleeding
Perforations --> Severe bleeding

Clinical Diagnosis :
Physical signs of acute peritonitis
Leucocytosis; neutrophils shift to the left
Abdominal x-ray

Treatment :
Maintain adequate blood pressure
Blood tranfusion (if indicated)
Broad spectrum Antibiotics
Surgical procedure

Extraintestinal Complications
Hematologic complications
DIC

Hepatitis typhosa
Enlargement of livers in 50% of cases

Pancreatitis typhosa
Very rare complication

Myocarditis typhosa
Occur in 1-5% of all cases
ECG abnormality occur in 10-15% of cases
May cause sudden death due to acute cardiac failure

The Role of Steroids :

Indicated only on severe typhoid complications :

1. Toxic Typhoid
2. Typhoid with Shock

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Carrier State
• Exist. of S. typhi in feces or urine without
clinical manifestation 1 year after recovery from
typhoid fever
S. typhi still be found in feces of urine 2 or 3 months
after recovery in 16% patients

• Impairment of host defence mechanism,

gall and kidney stone, chronic gall and
kidney infection contribute in pathogenesis of
carrier state

Carrier State
• Diagnosis of carrier state :
Feces and urine culture

• Treatment :
Without gall stone :
Ampicillin, Amoxicillin, Cotrimoxazole

With gall stone :

Cholecystectomi and treatment with
Ciprofloxacin or Norfloxacin

With Schistosomiasis :
Eradication of schistosomiasis before treatment
of carier state

Prevention

• Avoid risky food or drinks

• Hand washing
• Vaccination
• Detection of carrier state in food handler

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Clinical Trials of Typhoid Fever

Amoxicillin in Typhoid fever study with twice

daily dosage
Hendarwanto, Nelwan RHH, Zulkarnain I, et al

Drugs : Amoxicillin loading dose 2250mg then 2x750

vs 3x 1000 oral for 14 days
Design : Open randomized controlled
Subject : 25 vs 23 uncomplicated typhoid fever
Results : Clinical efficacy 100%
Microbiological efficacy 88 vs 91% on day 3rd
100% in day 10th
Devervescens 6.8 vs 7.2 days

CLASSIFICATION OF FLUOROQUINOLONE
GEN. NAME ANTIBACT. ACTIVITY

Gen I Nalidixic acid predominantly for

enterobacteriaceae

Gen II Ciprofloxacin predominantly for gram

Pefloxacin negative bacteria & limited
Ofloxacin gram positive bacteria

Gen III Levofloxacin ‘Broad spectrum’ active

Sparfloxacin gram neg & pos,atypical

Gen IV Gatifloxacin 3rd generation plus

Moxifloxacin anaerobes
Gemifloxacin
Clin Inf. Dis, 2000; 31:47- 82

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Clinical Trials of Fluoroquinolones

in Typhoid fever
Invest Year Medication Treatment number Clinical Bacterial
Igator duration cases efficacy efficacy

Arnold 1993 FLX 14 35 100 96

Nelwan 1993 PEF 7 20 100 100
Hien 1994 FLX 7 16 100 100
Nelwan 1994 OFL 7 12 100 100
Nelwan 1995 CIP 6 31 100 100
Duong 1995 FLX 5 41 97.5 94
Duong 1995 FLX 3 22 100 100
Nelwan 1997 FLX 3 4 100 100

COMPARISON OF DEFERVESCENCE IN TYPHOID FEVER

Name of Drug Dosage Duration Fever

Clearance

Ciprofloxacine(5) 500 BID 6 days 3,60 days

Ofloxacine(6) 600 mg OD 7 days 3,40 days

Pefloxacine(7) 400 mg OD 7 days 3,10 days

Fleroxacine(8) 400 mg OD 5 days 3,4 days

Fluoroquinolones for treating typhoid and

paratyphoid fever (Cochrane Review)
Thaver D, Zaidi AK, Critchley J, Madni SA, Bhutta ZA

Main results:
Compared with chloramphenicol, fluoroquinolones were not statistically
significantly different
Compared with co-trimoxazole, we detected no statistically significant
difference
Among adults, fluoroquinolones reduced clinical failure compared with
ceftriaxone but showed no difference for microbiological failure or
relapse.
We detected no statistically significant difference between
fluoroquinolones and cefixime orazithromycin
In trials of hospitalized children, fluoroquinolones were not statistically
significantly different from ceftriaxone or cefixime

Authors' conclusions: Many trials were small, and methodological quality

varied widely. Although enteric fever most commonly affects children,
trials in this group were particularly sparse. Insufficient data in all
comparisons preclude any firm conclusions to be made regarding
superiority of fluoroquinolones over first-line antibiotics in children and
adults.

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Open Study of Efficacy and Safety 500 mg Once Daily

Levofloxacin in Treatment of Uncomplicated Typhoid
Fever

R H H. Nelwan, Khie Chen, Nafrialdi

Division of Tropical Medicine and Infectious Diseases,

Department of Internal Medicine, Medical Faculty
University of Indonesia/Dr. Cipto Mangunkusumo National
General Hospital, Jakarta, Indonesia.

Aims
Primary endpoint:
efficacy and day of defervesecence
Secondary endopoint :
Safety

Methods
Design : Open Study
Location : Dr. Cipto Mangunkusumo and Affiliated
Hospital in Jakarta
Period : October 2003 – April 2004
Subject : Uncomplicated Typhoid fever
Levofloxacin (Daichi) 500 mg od (oral or iv) for 7 days.

Diagnostic criteria
l Definite :
Positive gall culture or PCR Salmonella typhi Widal
serology agglutinin O titer > 1/640
or H titer >1/1280
Increased of O titer twice or more
l Probable :
Widal serology agglutinin O titer 1/320
or H titer 1/640.

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Results
Enrolled : 52 subjects

47 pt received therapy severe, pregnant, fever decr 5 pt exc

44 pt continue 3 pt withdrawal

Definite 20 4 excl other diagnosis

Probable 9 Analyzed
Clinical 11

DISTRIBUTION OF SUBJECTS ACCORDING

TO DIAGNOSTIC CRITERIA

Diagnostic criteria n %

Definite (n= 21 ) 70
Positive Microbiological Blood Culture 4
Positive Salmonella typhi PCR 8
Positive S.typhi PCR & Blood Culture 1
Widal agglutinin O titer 1/640 1
Widal agglutinin H titer 1/1280 1
Increasing Widal agglutinin O titer > 2 times 6
Probable (n=9) 30
Widal agglutinin O titer 1 /320 7
Widal agglutinin H titer 1/640 2

CLINICAL RESULTS OF TREATMENT

Treatment results Definite cases Probable cases

n % n %

Clinical efficacy
Response 21 100 9 100
Failure 0 0

Defervescence on:
1st day after treatment 4 19.0 1 11.1
2nd day after treatment 6 28.6 6 66.7
3rd day after treatment 10 47.6 1 11.1
4th day after treatment 0 1 11.1
5th day after treatment 1 4.8 0
Mean (days) 2.43 2.22

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ADVERSE EVENTS EXPERIENCED (N=48)

Adverse events n %

Mild
Nausea * 4 8.3
Vomit * 1 2.1
Insomia * 1 2.1
Rash /Pururitis ** 2 4.2
Moderate
Meteorism *** 1 2.1
Severe
None

* probably related **definitely related *** unlikely related

Results of Preliminary study of Levofloxacin

for uncomplicated typhoid fever

A preliminary open study of levofloxacin in treatment

of uncomplicated typhoid fever showed that this drug
was effective and relatively safe.
The day of defervescence also quite short (mean 2.4
days).

Conclusions
l Typhoid fever is an acute systemic infection caused by
Salmonella enterica serotype typhi or paratyphi
l Clinical manifestation include local symptoms in GI tract,
systemic manifestation and/or complications
l Treatment include supportive and antimicrobials
l Antibiotics include :
Amoxicillin, Cotrimoxazole, Chloramphenicol, Ceftriaxone
and fluoroquinolones (Cipro, Oflo, Flero,Peflo) are effective.
l Some complications possible include severe toxic, intestinal
bleeding and perforation should be anticipated.

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Conclusions
l Typhoid fever is an acute systemic infection caused
by Salmonella enterica serotype typhi or paratyphi

l Clinical manifestation include local symptoms in GI

tract, systemic manifestation and/or complications

l Diagnosis of Typhoid fever is essentially be made

through clinical judgement and wise implementation
of laboratory results.

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