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Clinical,

Clinical, Laboratory
Laboratory
Diagnosis
Diagnosis and
and Management
Management
of
of Typhoid
Typhoid Fever
Fever
Sudirman Katu
Division of Tropical Medicine and Infectious Diseases
Departement of Internal Medicine
Faculty of Medicine
Hasanuddin University/General Hospital of Wahidin
Sudirohusodo

Alexander The Great died when he was 34 years old due to acute fever
illness possibly due to typhoid fever or malaria

DEFINITION
Typhoid Fever

Typhoid fever is an acute systemic


infection caused by Salmonella enterica
serotype typhi or paratyphi which is also
known as Salmonella typhi

Salmonella
Enteric Fever and Paratyphoid Salmonellae:

Salmonella typhi

Salmonella paratyphi A

Salmonella schottmuelleri (S. paratyphi B)

Epidemiologic Distribution of Typhoid Fever

Strongly endemic
Endemic
Sporadic cases

Clin.Infect.Diseases 1997; J of Antimicrobial Chemoth 2009 ; J Infect Dev Ctries 2011

Patterns of disease in Community

Developed Countries:
Good sewage and water supply system
Most cases are sporadic or imported or can

be traced to contact with chronic carriers

Developing World:
Endemic
Peak in hot dry months or rainy season
The incidence of typhoid fever is 2- 3

times that of paratyphoid fever

Typhoid fever

Global health problem and highly


endemic in Indonesia

Incidence in Indonesia estimated 350810 cases/100.000 population per year

Case fatality rate 2.8-16%

3 % of all mortality (50.000 death/year)


Seowandojo E, 1998

ETIOLOGY
Salmonella:
Structure, Classification, & Antigenic Types
1. Gram-negative, flagellated and facultative anaerobic
bacteria
2. The cell envelope contains a complex
lipopolysaccharide (LPS) structure. (an outer Opolysaccharide coat, a middle portion, the R core, and
an inner lipid A coat)
3. This LPS structure is thought as an endotoxin, and
important in determining virulence of the organisms.

Toxin production
S. typhi contains ;

Gluco-lipo-protein complexes. The endotoxin is obtained


by extracting the bacterial emulsion with trichloracetic
acid.

This endotoxin is ; Thermostable, Surviving a temperature


of 120 C for 30 minutes, and is characterized by a highly
specific precipitin reaction and pronounced toxic and
antigenic properties.

Investigations have shown the presence of exotoxic


substances in S. typhi which are inactivated by light, air,
and heat (80 C), as well as enterotropic toxin
phosphatase, and pyrogenic substances.

Some example of commonly


Occuring Salmonella serotypes and groups
Group
A
B

Serotype
S. paratyphi A
S. paratyphi B
S. stanley
S. saintpaul
S. agona
S. typhimurium
S. paratyphi C
S. choleraesuis
S. virchow
S. thompson
S. typhi
S. enteritidis
S. dublin
S. gallinarium

Method of Transmission

Ingestion of contaminated food or water

The stools and urine of chronic carriers usually


contains from 106 to 109 organisms/g

Raw shell fish from polluted water presents with


an enormous dose of S. typhi

Contact with an acute case of typhoid fever.

Contact with a chronic asymptomatic carrier.

Transmission

S typhi has no nonhuman vectors.


Via food handled by an individual who
chronically sheds the bacteria through stool or,
less commonly, urine
Hand-to-mouth transmission after using a
contaminated toilet and neglecting hand
hygiene
Oral transmission via sewage contaminated
water or shellfish

Pathogenesis and diseases in man


S.Typhi.
2nd bacteremia

liver spleen gall


BM ,ect
early stage&acme stage
(1-3W

stomach

(mono
nuclea
r
phago
cytes )

Bac. In gall

Bac. In
feces

Lower
ileum

peyer's patches &


mesenteric lymph nodes
LN Proliferate,swell
necrosis
defervescence stage
Enterorrhagia,i
ntestinal
perforation

3-4w

thoracic
duct

1st bacteremia
(Incubation stage)
10-14d

S.Typhi eliminated
convalvescence stage
(4-5w)

How does the bacteria cause disease ?

Clinical Presentation of Typhoid Fever


Clinical sign and symptom
Headache
Epigastric pain
Nausea
Anorexia
Fever (>37.2)
Muscular pain
Rigor
Coated tongue
Vomiting
Cough
Relative bradicardia
Diarrhea
Constipation
Hepatomegaly
Splenomegaly

sum (n=119)
59
57
108
41
118
14
37
84
104
91
117
109
109
117
117

%
94.9
94.7
90.7
90.2
89.8
78.6
78.4
41.8
57.7
46.2
34.2
32.1
33.9
12.3
0.8

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

Symptoms
Symptoms usually develop 13 weeks after exposure,
and may be mild or severe
FIRST WEEK:
High fever 103 or 104 F (39.4 or 40 C)
Malaise
Headache
Constipation (adults) or diarrhea (children)
Rose-colored spots on the chest
Enlarged spleen and liver
Healthy carrier state may follow acute illness

17

Symptoms
SECOND WEEK:

Continuing high fever

Either diarrhea that has the color and consistency of pea


soup, or severe constipation

Considerable weight loss

Extremely distended abdomen


THIRD WEEK:

Become delirious

Lie motionless and exhausted with your eyes half-closed


in what's known as the typhoid state

Life-threatening complications often develop at this time


18

Symptoms
FOURTH WEEK:
Improvement may come slowly during the fourth
week
Fever is likely to decrease gradually until your
temperature returns to normal in another week to
10 days
Signs and symptoms can return up to two weeks
after fever has subsided

19

Typhoid Specialties
Fever pattern in Typhoid Fever

High fever
Headache
Abdominal discomfort
Diarrhea or constipation
Relative bradicardia

Leucopenia
Mild thrombocytopenia
Relative neutrofilia
Aneosinofilia

14

Diagnosis
Diagnosis of typhoid fever is made by

Clinical examination
Blood, bone marrow, or stool cultures for
S. typhi
Serological Tests

Laboratory Examination
Peripheral blood count
leucopenia,
thrombocytopenia
aneosinophilia
Inflammatory

increased CRP

Serum transaminase

increased ALT and AST

Serology

Widal,Typhidot
Tubex (Salmonella IgM)

Blood culture

Gall (Salmonela Shigella)

PCR

Salmonella typhi

Serodiagnosis of Typhoid :
1.Detection of Antibodies in serum:
1.Widal test (Tube or Slide),
3.Tubex system,

2.Typhidot assay
4. Dipstick assay.

2. Detection of Antigens in serum:


1. Tubex system
2. Countercurrent Immunoelectrophoresis
(CIE)
3. Co-agglutination test. 4. ELISA

3. Detection of Antigens in urine:


1.Tubex system
3. Latex agglutination

2. CIE,
4. Co-agglutination

Widal test

O (somatic) antigens
LPS in the cell wall;
Heat stable
Less immunogenic

Agglutination with antisera:


Fine, compact, granular
chalky clumps

H (flagella) antigens
Present in flagella;
Heat labile;
Strongly immunogenic;
Induce rapid & High Ab titres;
Agglutination with antisera:
Large, loose, cotton wool
clumps

Vi (virulence) antigen
Capsular polysaccharide expressed on certain serotypes
Heat labile;
Poorly immunogenic, BUT antibodies are protective:

1.
2.
3.

Detection of Vi antibody not helpful in diagnosis


Absence in a case of typhoid poor prognosis;
Persistence of Vi antibody : carrier state

WIDAL Test

Tube agglutination test.


Detects anti O and H antibodies in serum
Diagnosis of Typhoid and Paratyphoid cases
Carriers of typhoid bacilli possess antibody against the
Vi antigen of S. typhi. (Vi tires seem to correlate better
with the carrier state than do O or H titres).
For this reason, the use of Vi agglutination for detection
of carriers was suggested .
Significance

I st week negative.
Titers raise in 2nd week
Raise of titers is diagnostic

26

How do you read Widal test results for


typhoid fever?

The highest dilution of the patients serum in which


agglutinations occurs is noted, ex. if the dilution is 1 in 160
then the titer is 160.
Agglutination in dilution up to <1:60 is seen in normal
individuals . Agglutination in dilution 1:160 is suggestive of
Salmonella infection.
Agglutination in dilution of >1:320 is confirmatory of
Enteric fever .

Prozone phenomenon in Agglutination tests


Prozone effect - Occasionally, it is observed that when
the concentration of antibody is high (i.e. lower
dilutions), there is no agglutination and then, as the
sample is diluted, agglutination occurs.
Lack of agglutination in the prozone is due to antibody
excess resulting in very small complexes that do not
clump to form visible agglutination

Limitation of Widal Test

The Widal test is time consuming and often times when


diagnosis is reached it is too late to start an antibiotic
regimen.
In spite of several limitation many Physicians depend on
Widal Test

Interpretation of Widal test


Test results need to be interpreted carefully in the
light of :
1.
2.
3.

Past history of enteric fever,


Typhoid vaccination,
general level of antibodies in the healthy populations in
endemic areas of the world.

False Positive Reactions with WIDAL Test


1.

2.
3.
4.

patients who have had previous vaccination or infection


with S typhi.
Cross-reaction with non typhoidal Salmonella.
in association with some autoimmune diseases.
Infection with malaria

False Negative Reactions with WIDAL Test


1.
2.
3.

Early treatment,
Relapses of typhoid fever.
Occasionally the infecting strains are poorly
immunogenic.

Duration of
diseaseS

Specimen
examination

%positivity

1st week

Blood culture

90%

2nd week

Blood culture,

75%

Faeces culture

50%

Widal test

Low titre

Widal test

80-100%

Blood culture

60%

Faeces culture

80%

3rd week

PRODUCT
PRODUCT PERFORMANCE
PERFORMANCE

Karen H Keddy, Arvinda Sooka, Maupi E Letsoalo, Greta Hoyland, Claire Lise Chaignat, Anne B Morrissey & John A Crump (2011). Sensitivity and
specificity of typhoid fever rapid antibody tests for laboratory diagnosis at two sub-Saharan African sites. Bulletin of WHO, vol 89 (9);p.640-647
(Pak-Leong Lim,et al,, 1998. One-Step 2-Minute Test to Detect Typhoid-Specific Ab Based on Particle Separation in Tubes. Journal of Clinical
Microbiology, August 1998, p. 2271-2278, Vol. 36, No. 8)

tc

PRODUCT
PRODUCT PERFORMANCE
PERFORMANCE
Comparative performance analysis of 4 serological tests for S. typhi.
Test kit

Sensitivity
95% CI

Specificity
95% CI

PPV

NPV

TUBEX
IgM (n=177)

94.7%
(86.2-98.3)

80.4%
(71.1-87.3)

78.0%

95.3%

SD Bioline (n=150)
IgM
IgG

69.0% (55.3-80.1)
70.7%(57.1-81.5)

79.3%(69.4-86.8)
76.1%(65.9-84.1)

67.8%
65.1%

80.2%
80.5%

TYPHIDOT (n=177)
IgM
IgG

54.7%(42.8-66.1)
73.3%(61.7-82.6)

64.7%(54.6-73.7)
46.1%(36.3-56.2)

53.2%
50.0%

66.0%
70.1%

MEGA (n= 177)


IgM
IgG

90.7%(81.1-95.8)
96.0%(88.0-99.0)

49.0%(39.1-59.1)
39.2%(29.0-49.4)

56.7%
53.7%

87.7%
93.0%

Razel L. Kawano, et al 2007. Comparison of Serological Test Kits for Diagnosis of Typhoid Fever
in the Philipines. J Clin Microb, 246-247.

tc

PRODUCT
PRODUCT PERFORMANCE
PERFORMANCE
Score
< 2

Interpretation Guide
NEGATIVE - Does NOT indicate current typhoid fever
infection
Borderline, inconclusive score.
Repeat analysis. If still inconclusive, repeat sampling at a
later date.

4-5

POSITIVE - Indication of current typhoid fever infection

> 6

POSITIVE - Strong indication of current typhoid infection

INDETERMINATE

No clear score obtained due to :


1) Poor adherence to assay protocol. Repeat
analysis.
2) Poor specimen quality. Repeat sampling and analysis

tc

Cultures in Typhoid fever


Blood

In Adults 5-10 ml of Blood is inoculated into 50 100 ml of


Bile broth ( 0.5 % ).

Larger volumes 10-30 ml and clot cultures increase


sensitivity

Blood culture is positive as follows:


1st week in 90%
2nd week in 75%
3rd week in 60%
4th week and later in 25%

Bone marrow culture


Urine and stool cultures
Duodenal string test to culture bile

Treatment

Indication for hospitalization :


Severe

Manifestations
Poor intake
Toxic typhoid
Perforation symptoms

TREATMENT
General :

Isolation and rest

Suitable diet include easy digested


food or half-liquid food and drinking
more water

IV fluid to maintain water and acidbase and electrolyte balance

Symptomatic : antipyretic

Treatment

Non Pharmacologic : Bed rest, Nutrition

Pharmacologic
Symptomatic
Antibiotic :
Cephalosporin
: Ceftriaxone
3-4 g/days

Ampicillin/Amoxicillin : Ampicilin/Amoxicilin
4x500mg

Chloramphenicol
: Cholramphenicol 4x500mg
Fluoroquinolones
:
Ciprofloxaxin
2x500 mg
Ofloxacin
2x400 mg
Pefloxacin
1x400 mg
Levofloxacin
1x500mg
Macrolide
: Azithromycin
1x500mg

Treatment of uncomplicated typhoid

Treatment of severe typhoid

South East Asia J Trop Med Pub Health


2006; 37 (1):126

Acta Med Indones


2007;39 (1):22

KONAS PETRI 2010

Antibiotics during pregnancy and lactation period


Embryioni
c period*

Post
Embryonic
period**

Peripart
al
period**
*

Lactatio
n

Penicillin

None known

Cephalospori
ns

None known

Aminoglycosid
es

Inner ear damage

Erythromycin

(+)

None known, dont use erythromycin


estolate

Clindamycin

(+)

(+)

(+)

(+)

Tetracyclines

Disturbance of bone and tooth growth

Chloramphenic
ol

Gray syndrome, myelosuppresion

Co-trimoxazole

(+)

(+)

Teratogenic in animal experiments,


kernicterus

Fusicid Acid

(+)

None known

Rifampicin

Coagulation disorder, liver dam. in


mother & fetus

Vancomycin

(+)

(+)

(+)

(+)

Quinolones

(+)

Agent

Nitrofurantoin
Metronidazol
e

Contraindicated or
Anot recommended

* Embryonic period (1st to 12th wk. of pregnancy)


Amphotericin
B)
pregnancy
till delivery

(+)
+ safe for use
A
when indicated

Possible foetal impairment

None known, pseudomembranous


enterocolitis in mother

None known
Disturbance of chodral growth

Teratogenic in animal experiments


(+) only if clearly
A to be prescribed
Teratogenic
in
animal
experiments
A
indicated
only
in exceptional cases

** Postembryonic period (13th to 39th wk. of pregnancy) *** Peripartal period (40th wk. of

A(+)

A(+)

Abortion and foetal retardation reported

Complications
Intestinal complication
intestinal perforation
gastrointestinal hemorrhage
hepatiitis, pancreatitis, paralytic ileus

Rujuk

Extraintestinal
Cardiovascular : shock, myocarditis
Neuropsychiatric : encephalopaty, delirium
psychosis
Respiratory : bronchitis, pneumonia, pleuritis
Hematology : anemia, DIC
Kidney : glemerulonephritis, pyelonephritis
Others : osteomyelitis, focal abscess

Relapse after treatment:

10- 25% in patients receiving chloramphenicol


1- 6% patients receiving newer antibiotics
(cephalosporins and FQ)
Mostly relapses occur during 2-4 weeks after
end of antibiotic therapy.
Retreatment should be performed

Chronic Carrier:

A person who excretes the organism in


stools 12 months after the initial illness.
20% at 2 months
10% at 3 months
3% go on to become carriers
(range 1-6%)

Chronic carriage more frequent with


typhoid than non-typhoid strains

Higher prevalence in females and with gall


stones

Treatment of Chronic Carriers of S. typhi:

No Gall-Stones:

Presence of Gall-stones:

Oral Ampicillin/amoxicillin/TMP-SMX for 3 months


Asymptomatic and have positive stool or rectal swab cultures
for S. typhi a year following recovery from acute
illness.Treatment: co-trimoxazole 2 tab twice/d for 6 wk, OR
ciprofloxacin 750 mg twice/d for 4 wk
Try above regimen prior to surgery (if required)
In some cases antibiotic plus cholecystectomy required
Ciprofloxacin 750mg PO BID or Norfloxacin 400mg BID for 28
days

Chronic urinary carriers:

Treat schistosomiasis first, if present, before antibiotics

Dexamethasone

Prompt administration of high-dose dexamethasone


reduces mortality in patients with severe typhoid fever
without increasing incidence of complications, carrier
states, or relapse among survivors.

Initial dose of 3 mg/kg by slow i.v. infusion over 30


minutes.

1 mg/kg 6 hourly for 2 days.

Prevention - General

General sanitation especially for water supply, waste


disposal and insect control.

Health education and sanitary life style

The organism is susceptible to boiling and common


disinfectants.

Identification and treatment of carriers especially in


foodhandlers (specific stool cultures). Antibiotics are
effective in eradication of carrier state. The best is
ciprofloxacin 750mg BID for 4 weeks. Ampicillin, cotrmoxazole and chlramphenicol are less effective.

Cholecystectomy may be required.

Prevention - specific

Vaccination is indicated for travelers to endemic areas


and are sometimes used on a limited scale in presence of
outbreaks. Two parentral and oral vaccines are available.

Vi polysaccharide, is given in a single IM dose.

Protection begins seven days after injection

Maximum protection being reached 28 days after injection when the


highest antibody concentration is obtained.

Protective efficacy was 72% one and half years after


vaccination and was still 55% three years after a single
dose.

Vi-negative strains have been reported in some Asian


countries in up to 3% of isolates. Vi vaccine is not
effective for these strains.

Vaccines for Typhoid Prevention


Two types :
1. Oral A live vaccine ( typhoral )
One capsule given orally taken before food, with
a glass of water or milk, on day 1, 3, 5 ( three
doses )
No antibiotics should be taken during the period
of administration of vaccine
2. The injectable vaccine, ( typhim vi)
Given as single sc or im injection

Prognosis:

Case fatality 0.5-1%.

but high in old ages, infant, and


serious complications

immunity long lasting


About 3% of patients become fecal
carriers .

Prophylaxis
Wash your hands.
Avoid drinking
untreated water.
Avoid raw fruits and
vegetables
Choose hot foods.

Conclusions

Typhoid fever : acute systemic illness due


to Salmonella typhi and paratyphi
Transmission : fecal oral : food water
Clinical manifestation :
Fever, GI symptoms, systemic symptoms
Treatment : Supportive and symptomatic
Causative : Ampicillin, Chloramphenicol
FQ : Ciprofloxacin,
Levofloxacin etc
3rd Gen Cephalosporine
Azithromycin
Prevention : hand washing, avoiding non
hygiene food, vaccination and detectection
carrier

Terima Kasih

Analisis Sensitifitas Uji Diagnostik


Suatu alat uji diagnostik harus ada
informasi tentang nilai sensitifitas,
spesifisitas, dan Rasio Likelihood agar
bisa dilakukan evaluasi pembuktian
probabilitas dari penyakit yang diduga.
Adapun proses diagnose suatu penyakit
itu terdiri dari anamnesa, pemeriksaan
fisik dan pemeriksaan penunjang seperti
laboratorium dan radiologi

Setiap kriteria dari anamnesis dan


pemeriksaan fisis adalah sebuah uji
diagnosis yang dapat meningkatkan atau
menurunkan probabilitas suatu penyakit
sehingga menghasilkan diagnose
sementara yang relative.
Setiap kriteria dari anamnesis dan
pemeriksaan fisis itu kita katakan pretes probabilitas

Pada kasus demam tifoid, kita sudah


dapat menentukan pretes probabilitas
berdasarkan manifestasi klinis , namun
hasilnya adalah berupa diagnosa demam
tifoid yang sementara atau dugaan.
Untuk itu kita bisa memilih alat uji
diagnostik dari Widal, Tubex TF,
Typhoid dot, kultur darah atau bahkan
PCR salmonella dalam menetapkan
kepastiannya

Dari kedua penelitian di atas, tampak kekuatan


nilai sensitifitas dan spesifisitas yang tidak
jauh berbeda nilainya, sehingga kita bisa
memilih berdasarkan harga pemeriksaan yang
murah namun spesifisitasnya yang tinggi.
Seperti kondisi di pelayanan dasar PUSKESMAS,
maka uji widal masih ada tempatnya untuk
menentukan diagnosa demam tifoid, disamping
harganya lebih murah dibandingkan dengan uji
cepat diagnostik dari Tubex TF dan typhoid dot.

Bagaimana keputusan klinik kasus


DEMAM ini ?
Diagnosis of Thypoid Fever
(Ochiaii RL,et al, Bulletin of WHO,2008)
Prevalensi demam tifoid dg usia di atas 16 tahun
menurut WHO adalah 47% berdasarkan hasil
kultur darah yang positif typhoid.
Seorang wanita, 22 tahun, demam 5 hari, pola
demam khas timbul sore hari, memuncak pada
malam hari dan menurun menjelang subuh.
Keluhan disertai mual, muntah, rasa tidak
nyaman di perut dan tidak BAB selama 2 hari.

Data dari Evidence based

Bila kita curiga dengan Demam tifoid, maka kita lakukan pemeriksaan
penunjang seperti
Widal. Hasil nya positif, lalu kemungkinan diagnose demam tifoidnya
adalah
Kita lihat prevalensi nya adalah 47% (0,47)., selanjutnya kita konversi
ke nilai odds,
Odds = P / (1-P) = 0,47 / (1-0,47) = 0,89. Sehingga nilai odds demam
tifoid dari hasil widal :
Pre-test Odss X LR+ = 0,89 X 6,5 = 5,76 (kita sebut post test odds).
Maka probabilitas terjadinya demam tifoid = odd / (odds+1) = 5,76 /
6,76 = 0,85 atau 85%
Tubex TF. Hasil nya positif, seperti halnya widal;
Odds = 0,89. post test odds = 0,89 x 5,8 = 5 dan Probabilitasnya
adalah = 5/6 = 83%
Typhoid Dot. Hasilnya positif;
Odds = 0,89 Post test odds = 0,89 x 7,9 = 7 sehingga
probabilitasnya = 7/8 = 0,88 = 88%
Blood Culture. Hasilnya positif.
Odds = 0,89 Post test odds = 0,89 x 5 = 4,45 sehingga
probabilitasnya=4,45/5,45 = 0,82% atau 82%

Kelemahan uji cepat diagnostik


Adapun ketiga uji cepat diagnostik demam tifoid adalah
pendekatan diagnosa suatu penyakit infeksi yang
diduga demam tifoid, jadi bukan merupakan uji
konfirmasi.
Untuk konfirmasi kepastian diagnosa demam tifoid atau
bukan bisa kita lakukan tambahan dengan melakukan
pemeriksaan kultur darah atau bahkan PCR
salmonella.
Kelemahan lain dari uji cepat diagnostik demam tifoid
ini adalah bukan untuk evaluasi suatu pengobatan.
Standar baku untuk evaluasi hasil pengobatan tetap
dari kultur darah dan PCR salmonella.