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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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