Typhoid Fever

By Dr. Bambang SN, Sp.PD

Department of Internal Medicine,
General Hospital of Dr. Soedarso, Pontianak

INTRODUCTION
Typhoid fever is a systemic disease characterized
by fever and abdominal pain caused by
dissemination of S. typhi or S. paratyphi. (Butler,
Scheld 2004)

Its unique to human.

Characterized by malaise, fever, abdominal
discomfort, transient rash, and leukopenia.

The most prominent major complication are

intestinal hemorrhage and perforation.

INTRODUCTION

According to the best global estimates, there are at least 16

million new cases of typhoid fever each year, with 600,000
deaths.

The introduction of chloramphenicol for the treatment of

typhoid fever in 1948 which transformed a severe,
debilitating, and often fatal disease into a readily treatable
condition. The emergence of resistance to chloramphenicol
and other antimicrobial agents have been a major setback.
In 1989, MDR S. typhi emerged. These bacterial are resistant
to chloramphenicol, ampicillin, trimethoprim. In 1994, 12%
of S. typhi isolates in the United States were MDR.

Thus either quinolones or third-generation cephalosporins

(ceftriaxone) are currently recommended for emperical
antibiotic treatment (Lesser and Miller, 2005)

The Virulence key

factor S. typhi

Somatic (O), LPS

antigen

Flagellar (H) antigen

Virulent (VI) antigen

in the cell capsul

OMPs antigen

Lipid A

Porins

PATHOGENESIS (1)
Typhoid bacilli reach the small intestine shortly

after ingestion and may multiply there. May than

penetrate the mucosa with minimal epithelial
destruction and enter intestinal lymphatic
perhaps via Peyers patches to be carried to the
blood stream.
This initial early bacteremia apparently occurs
within 24-72 hours after ingestion of organism
and as rarely detective in natural infection
because patients are usually asymptomatic at this
early stage.

PATHOGENESIS (2)

The bacteremia is transient and rapidly

terminated as bacilli are phagocytized by

cells of RES. Nevertheless viable bacilli are
disseminated throughout the body and
apparently persist within RE cells. After
intracellular multiplication take place
organism re-enter the blood stream,
producing a continuous bacteremia for
days or weeks. The re-appearance of
bacteremia corresponds with the onset of
manifestation of the disease.

PATHOGENESIS (3)
During the phase of persistent bacteremia all

organs are repeatedly exposed to typhoid bacilli.

Abscess formation may occur but is unusual.
However localization does occur in the GB in
almost all cases. Organisms multiply in the bile to
high titer, usually without manifestation of
cholecystitis and are excreted with bile into the
intestinal tract. Stool cultures which are usually
negative for S.typhi during the incubation period
and early phases of the disease, become positive
in a large proportion of cases during the third of
forth week of the disease, when excretion of
organism in the bile reaches a peak.

DIAGNOSIS
Clinical presentation of
Typhoid fever

The diagnostic gold standard

is blood culture positive for S.
typhi or S. paratyphi

The classic widal test for febrile

agglutinins; however, given high
rates of false-positivity and
false-negativity
Harrisons Principles of Internal Medicine
(Lesser and Miller, 2005)

A diagnosis can also be based

on positive culture of stool,
urine, bone marrow, and gastric
secretions

Other serological tests, detection

antibodies to various antigen like Vi,
LPS, flagellin, OMP

Molecular techniques: Hibridization

using DNA probes, PCR-based
method and DNA probe assays

Clinical Manifestations

Enteric fever

Diarrhea or

Gastrointestinal

Hepatosplenomegaly

symptoms

Harrisons Principles of Internal Medicine

(Lesser and Miller, 2005)

constipation

EVOLUTION OF TYPICAL SYMPTOMS AND

SIGNS OF TYPHOID FEVER
DISEASE
PERIOD
First week

Second
week

Third week

Fourth
week and
later

SYMPTOMS

SIGNS

PATHOLOGY

Fever, chills gradually

increasing and
persisting;
headache
Rash, abdominal pain,
diarrhea or
constipation,
delirium,
prostration

Abdominal
tenderness

Bacteremia

Rose spots,
splenomegaly,
hepatomegaly

Complications of
intestinal bleeding
and perforation,
shock
Resolution of
symptoms, relapse,
weight loss

Hematosechia,
ileus, rigid
abdomen, coma

Mononuclear cell
vasculitis of skin,
hyperplasia of ileal
Peyers patches,
typhoid nodules in
spleen and liver
Ulcerations over Peyers
patches, perforation
with peritonitis

Cecil Textbook of Medicine

(Butler and Scheld, 2004)

Reappearance of
acute disease,
cachexia

Cholecystitis, chronic
fecal carriage of
bacteria

Untreated TF can be divided into 3 stages :

Average incubation 10 days (3 - 60)

1. Prodromal Stage

Period of invasion
Increasing malaise, headache, cough,
general body iching, sore throat, epistaxis
Frequently there is abdominal pain,
constipation or diarrhea, vomiting
Fever ascends in a step ladder fashion
generally higher in the evening than in the
morning.

2. Fastigium Stage
After 7-10 days, the fever stabilizes,
varying less than 1.1 C during the day.
Patient becomes quite sick.

Pea soup diarrhea of severe

constipation or marked abdominal
distention is common.
Severe cases, patient lies motionless
and unresponsive, with eyes half shut,
appearing wasted and exhausted
(typhoid state).

3. Defervescence Stage
If the patient survives the severe toxemia of the
second stage and develops no complication,
improvement occurs gradually.
Fever declines in a step ladder fashion
to normal 7-10 days.
Patient becomes more alert & abdominal
symptoms disappear.
Relapse may occur as late as 1-2 weeks after
the temperature has returned to normal.
The relapse is usually milder than
the original infection.

During the early prodrome, physical finding

are slight. Later, splenomegaly, abnominal
distention and tenderness, relative
bradycardia, dicrotic pulse, and
occasionally meningismus, systolic murmur
and gallop rythm appears.

The rash (rose spots) commonly appears

during the second week of the disease.
The individual spots, found principally on
the trunk, is a pink papule 2-3 mm in
diameter that fades on pressure. It
disappears over a period of 3-4 days.

Laboratory Findings
Blood culture may be positive in the first week and
remain positive for a variable period thereafter.

Stools are positive for the organism after the first

weeks.

Urine may be positive at anytime.

Laboratory Findings
During the second week, antibodies appear in
the blood and continue to rise in titer until the
end of the third week. (Widal test)
If an anamnestic response to other infectious
diseases or recent vaccination is ruled out, an
O (somatic) antibody titer of 1:160 is
presumptively diagnostic.

A rising titer (as demonstrated by 2

specimens taken approximately a week apart)
is diagnostic.
Moderate anemia and leukopenia are the rule.

Differential Diagnosis
Enteric form of infection can be produced by

other salmonella species (eg. Salmonella

paratyphi A, B, C)
Typhoid fever must be distinguished from other
prolonged fevers associated with normal or
depressed white count.
Examples : - tuberculosis
- viral pneumonia
(primary atypical pneumonia)
- richetsiosis
- leptospirosis
- infectious hepatitis
- malaria

COMPLICATIONS
About 30% of untreated cases.
Intestinal hemorrhage is most likely to occur

during the third week and is manifested by a

sudden drop in temperature, rise in pulse, sign
of shock followed by dark or fresh blood in the
stool.
Intestinal perforation is most likely to occur
during the third week, sudden rigor, drop in
temperature, increases in pulse rate,
accompanied by abdominal pain ant tenderness
may be not.

 Less frequent complications are :

-

urinary retention
pneumonia
thrombophlebitis
myocarditis
psychosis
cholecystitis
nephritis
spondylitis (typhoid spine)
meningitis

Prevention (1)

Active immunisation should be provided for:

- household contacts of a typhoid carrier

- travelers to endemic areas.
- during epidemic outbreaks.
There is now an oral typhoid vaccine and a
single-dose injectable vaccine that produces
fewer side effects than the older two-dose
injectable vaccine. Both vaccines are equally
effective and offer 65% to 75% protection
against the disease.

Prevention (2)
The oral vaccine (Vivotif) contains a live
but weakened strain of the Salmonella
bacteria that causes typhoid fever. The
vaccine consists of four capsules that are
taken every other day over a one-week
period. The capsule protects the vaccine
against stomach acid so it remains active
when it reaches the intestine where the
immunity develops.

Prevention (3)
The oral vaccine can be given either as a
first-time dose or as a booster dose. The
protection should last about 5 years, at
which time another booster dose would be
needed if traveling. The single-dose
injectable vaccine (Typhim Vi) containing
capsular polysaccharide antigen became
available in February, 1995.

Prevention (4)
The protection offered by this vaccine is
effective starting 2 weeks after injection
and should last for 2 years. Subsequent
booster doses are recommended at 2-year
intervals. This vaccine can be used in
children as young as 2 years old. Side
effects, while greater than those of the
oral vaccine, are much less than those
experienced with the old 2-dose injectable
vaccine.

Prevention (5)

Environmental hygine control requires

protection of food & water and adequate

waste disposal.
Carriers must not be permitted to work as
food handlers.

MANAGEMENT
Bed rest
Nutrition therapy based on macronutrients and micronutrients
Antimicrobial therapy
In the preantibiotic era, the mortality rate from typhoid fever was as high
as 15%.
Drugs of choice are: chloramphenicol, thiamphenicol, cotrimoxazol,
ampicillin, depend on the condition of patient
In 1989, MDR S. typhi emerged. These bacterias are resistant to
chloramphenicol, ampicillin, trimethoprim, streptomycin, sulfonamides, and
tetracycline.
Treatment with fluoroquinolones is associated with fewer treatment failures
and more rapid resolution of symptoms than treatment with -lactam
agents.
In cases of severe typhoid fever (fever; an abnormal state of cosciousness
or septic shock), dexamethasone treatment should be considered (a single
dose of 3 mg/kg followed by 1 mg/kg, given every 6 h) decrease the
mortality rate from 56% to 10%) (Lesser and Miller, 2005)
The management of complication
Harrisons Principles of Internal Medicine
(Lesser and Miller, 2005)

MANAGEMENT (1)
A. Specific Measures
Chloramphenicol is the choice of treatment

Nevertheless the response is not dramatic or

rapid, subjective improvement usually occurs
within about 48 hour after beginning therapy.
Bacteremia usually clear within hours.
The dose of Chloramphenicol should be
50 mg/kg BW/day divided into 3-4 dose given
usually at intervals of 6-8 hour.
After the patient afebrile the dose may be
reduced to 30 mg/kg BW/day.
Therapy should be continued for 2 weeks.

MANAGEMENT (2)

Ampicillin in doses of 50 mg/kg BW/day or 6 g

per day for adults divided into 4-6 dose given
parenterally or a combination of Trimethoprim
& Sulfamethoxazole.
Quinolone (IV or PO),
- Ciprofloxacine 400 mg (IV) / 500 mg (PO)
q 12 h
- Gathifloxacine 400 mg (IV or PO) q 24 h
- Levofloxacine 500 mg (IV or PO) q 24 h
- Moxifloxacine 400 mg (IV or PO) q 24 h

MANAGEMENT (3)
B. General Measures
- Give a high calorie, low residue diet.
- Hydrocortisone 100 mg i.v.ly every 8 hours
may tide over severely toxic patients
(or dexametason as mentioned).
- Parenteral fluids may be necessary to
supplement oral intake and maintain urine
output.
- Abdominal distention may be relieved by
abdominal stupes.
Vasopressin & neostigmin must be used with
great caution because of the danger of
perforation. Strict stool and urine isolation
must be observed.

MANAGEMENT (4)
C. Treatment of Complications
- Secondary pneumonia maybe treated with
antibiotic, depending on the etiologic agent.
- Transfusion should be given as required for
hemorrage
- If perforation occurs, immediate surgery is
required
Anticipate and treat shock before it becomes
manifest.

MANAGEMENT (5)

D. Treatment of Carriers
- Chemotherapy is usually ineffective in
abolishing the carrier state.
However a trial of ampicilin first and
than chlorampenicol is worth while.
Cholecystectomy may be effective.

Prognosis
The mortality rate of TF is about 2 % in

treated cases.
Elderly or debilitated persons are likely to
do poorly.
The course is milder in children.
With complication, the prognosis is poor.
Relapse occur in up to 15% of cases.
A residual carrier state frequently persists
in spite of chemotherapy.