TYPHOID FEVER

JI Gian Carlo Bermoy

Enteric fever, or typhoid fever, is
a distinctive acute systemic
febrile infection of the
mononuclear phagocytes
caused by S. Typhi, S. Paratyphi
A, S. Paratyphi B (Schottmuelleri),
and S. Paratyphi C (Hirschfeldii)
Etiology
Salmonellae
a genus that belongs to the family
Enterobacteriacae & contains 3
species:
S. typhi
S. choleraesuis
S. Enteritidis

has more than 2300 serotypes

gram-negative, flagellate,
nonsporulating, facultative anaerobic
bacilli
ferment glucose, reduce nitrate to
nitrite, and synthesize peritrichous
flagella when motile
All but S typhi produce gas upon sugar
fermentation
resistant to many physical agents but
can be killed by heating to 130°F
(54.4°C) for 1 hr or 140°F (60°C) for 15
min
salmonellae are grouped based on the
somatic O antigen and further
divided into serotypes based on
flagellar H and surface virulence
(Vi) antigens
O antigens are the heat-stable
lipopolysaccharide components of the
outer membrane
H antigens are heat-labile proteins
that can be present in phase 1 or 2
S typhi, S paratyphi C, and Salmonella
Dublin are the only Salmonella
serotypes that carry Vi antigen
Epidemiology
In the U.S., about 400 cases of
typhoid fever are reported each year,
giving an annual incidence of less
than 0.2 cases/100,000 population,
which is similar to that in Western
Europe and Japan
In developing countries, S. Typhi is
often the most common Salmonella
isolate, with an incidence that can
reach 500 cases/ 100,000 population
Ranked 10th in the leading causes
of morbidity in the Philippines w/ a
rate of 19.5/100,000 population &
an almost equal prevalence
between male & female
affects all ages including infants
The WHO has estimated that at
least 12.5 million cases occur
annually worldwide
humans are the only natural
reservoir
direct or indirect contact with
an infected person (sick or
chronic carrier) is necessary for
infection
Ingestion of foods or water
contaminated with human feces
is the most common mode of
transmission
Water-borne outbreaks due to
poor sanitation and direct fecal-
oral spread due to poor personal
hygiene are encountered, mainly
in developing countries
Oysters and other shellfish
cultivated in water contaminated
by sewage are also a source of
widespread infection
Pathogenesis
inoculum size: 105 –109 S. ser. Typhi
organisms (in volunteers)
ingestion of contaminated food

bacteria invade through the Peyer

patches

multiplies within the mononuclear

phagocytic cells in the liver, spleen,
lymph nodes, and Peyer patches of
monocytes, unable to destroy the bacilli
early in the disease process, carry
these organisms into the mesenteric
lymph nodes

organisms then reach the bloodstream

through the thoracic duct, causing a
transient bacteremia

circulating organisms reach the

reticuloendothelial cells in the liver,
spleen, and bone marrow and may
seed other organs
after proliferation in the
reticuloendothelial system,
bacteremia recurs
from blood or from the liver via bile
ducts, it infects the gallbladder and
reenters the gastrointestinal tract in
the bile, spreading to other hosts via
stool
further seeding of the Peyer patches
occurs through infected bile
hyperplasia of Peyer patches with
necrosis and sloughing of overlying
epithelium produces ulcers that may
bleed
ulcers heal without scarring
strictures and intestinal obstruction
virtually never occur after typhoid
fever
inflammatory lesion may occasionally
penetrate the muscularis and serosa of
the intestine and produce perforation,
causing peritonitis
Several virulence factors seem to
be important:
invasion of Peyer patches is encoded
by genes closely related to the
invasion genes of Shigella and
enteroinvasive E. coli
surface Vi capsular antigen found
in S. Typhi interferes with
phagocytosis by preventing the
binding of C3 to the surface of the
bacterium
the ability of organisms to survive
within macrophages after
phagocytosis is an important
virulence trait encoded by the
phoP regulon
leading to modification of protein
and lipopolysaccharide elements
of the bacterial inner and outer
membranes
Salmonella resists lysis and
decreases host proinflammatory
signaling
macrophage provides Salmonella a
vehicle safe from other elements of
the immune system and in which it
can multiply and travel
passes through the mesenteric
lymph nodes into the thoracic duct
and the lymphatics beyond to seed
the reticuloendothelial tissues—
liver, spleen, bone marrow, and
lymph nodes
Salmonella multiply until some critical
density is reached
causing the apoptosis in the
macrophages and enters the
bloodstream to attack the rest of the
body
finally, the Vi antigen (polysaccharide
capsule) forms a capsule to protect
the bacterium from complement and
from phagocytic immune cells
Clinical Manifestations
incubation period: 7–14 days
may range from 3–30 days,
depending mainly on the size of
the ingested inoculum
the clinical manifestations of
enteric fever depend on age
SCHOOL-AGED CHILDREN AND
ADOLESCENTS
Insidious onset
Incubation period: 8-14 days
Initial symptoms: 2–3 days
May resemble an URTI
Fever
- low grade which increases in a stepwise
fashion, becomes an unremitting and
high fever within 1 wk, often reaching
40°C
often pxs present w/ undiagnosed
fever several days to a week or more
w/c has not responded to treatment
malaise, anorexia, myalgia, headache,
and abdominal pain
diarrhea having a pea soup
consistency -early course of the
disease
constipation later becomes a more
prominent symptom
cough and epistaxis may ensue

2nd week:
high fever is sustained, and fatigue,
anorexia, cough, and abdominal
symptoms increase in severity
Physical Examination:
relative bradycardia - disproportionate to
the high fever
patients appear acutely ill, disoriented,
and lethargic
hepatomegaly, splenomegaly, and
distended abdomen with diffuse
tenderness - very common
a macular or maculopapular rash (rose
spots) appears on about the 7th–10th day
– in 50% of patients
usually discrete, erythematous, and 1–
5 mm in diameter; the lesions are
slightly raised and blanch on pressure
appear in crops of 10–15 lesions on
the lower chest and abdomen last
2–3 days
leave a slight brownish discoloration of
the skin on healing
cultures of the lesions have a 60%
yield for Salmonella organisms
INFANTS AND YOUNG CHILDREN
(<5YR)
relatively rare in this age group in endemic
areas
disease is surprisingly mild at presentation,
making the diagnosis difficult
mild fever and malaise, misinterpreted as a
viral syndrome, occur in infants with
culture-proven typhoid fever
temperature may be of the septic spiking or
“saw-tooth” type of fever last 2-3days
diarrhea is more common in young
children than in adults, leading to a
diagnosis of acute gastroenteritis
abdominal distention is an
accompanying manifestation
rose spots & splenomegaly are
infrequent
convulsions or meningeal signs are
occasionally encountered
NEONATES
cause abortion and premature
delivery
enteric fever during late
pregnancy may be transmitted
vertically
neonatal disease usually begins
within 3 days of delivery
vomiting, diarrhea, and
abdominal distention are common
temperature is variable but may
be as high as 40.5°C
seizures may occur;
hepatomegaly, jaundice, anorexia,
and weight loss can be marked
Complications
usually occur after the 1st week of the
disease
severe intestinal hemorrhage - 1–10%
intestinal perforation - 0.5–3%
hemorrhage
usually precedes perforation
manifested by a decrease in temperature
and blood pressure and an increase in
the pulse rate
perforations
typically occur in the distal ileum and
are accompanied by a marked increase
in abdominal pain, tenderness, vomiting,
and signs of peritonitis
hepatitis w/ jaundice and
cholecystitis may occur
pneumonia caused by superinfection
with organisms other than Salmonella
is more common in children than in
adults - approximately 10%
Neurologic complications:
increased intracranial pressure, cerebral
thrombosis, acute cerebellar ataxia,
chorea, aphasia, deafness, psychosis
Others:
fatal bone marrow necrosis
Pyelonephritis
nephrotic syndrome
endocarditis
parotitis
orchitis
suppurative lymphadenitis
Criteria and Indications for
Admission
A. All patients suspected of having
typhoid fever with one or more of the
ff:
 Persistent vomiting or unable to
take oral fluids
 Severe dehydration
 Spontaneous bleeding
 Persistent abdominal pain
 Listlessness
 Restlessness
  Changes in mental status
 Weak, rapid pulse
 Cold, clammy skin
 Circumoral cyanosis
 DOB
 Seizures
 Hypotension or narrowing pulse
pressure (<20 mmHg)
B. All patients suspected of having
complicated typhoid fever
Diagnosis
A. Lab Studies
1. CBC with platelet count
 Leukopenia- 4,000-6,000 cells/mm
 Leukocytosis- may be as high as
20,000-25,000 in the presence of
pyogenic complications or
intestinal perforation
 Thrombocytopenia
 normochromic, normocytic anemia
- related to intestinal blood loss or
bone marrow suppression
B. Culture
1. Blood cultures:
 Gold standard test for typhoid fever
 Should be taken anytime during the
illness but yield is highest during the
1st 2 weeks
 positive in 40-60% of patients during
the 1st week
 Should be taken at least from 2
different sites. The 2nd & 3rd blood
spcimen will increase the yield (73-
97%)
2. Stool and urine cultures
positive on 2nd-4th week of illness

3. Duodenal string test

used to culture bile, in suspected cases
with negative results of stool cultures
a culture of aspirated duodenal fluid
cannot be performed on those too
young or too ill to cooperate
4. Bone marrow aspirate (BMA) culture
most sensitive method of isolating S
typhi
sensitivity is 90% at any point in the
disease course
less influenced by prior antimicrobial
therapy
positive in 85–90% of patients
not done routinely but indicated in
highly suspicious cases with negative
blood or stool culture
extremely painful
Serology
1. Typhidot-M test:
diagnostic tests for immunoglobulin
M (IgM) and immunoglobulin G (IgG)
antibodies
with rapid results (2 minutes to 3
hours)
has a specificity of 75% and a
sensitivity of 95%
the Tubex test is rapid and detects
the O9 antigen
2. Widal test:
measures antibodies against O
and H antigens of S. ser. Typhi
rarely used because of its low
sensitivity and specificity
not recommended
DNA testing: Polymerase
chain reaction assays
used to amplify specific genes of S.
Typhi in the blood of patients
enabling diagnosis within a few
hours
specific and more sensitive than
blood cultures, given the low level of
bacteremia in enteric fever
used mostly for research since the
test is generally too expensive
TREATMENT
1. Chloramphenicol
gold standard
initial drug of choice
not commonly used because of
widespread resistance, high relapse rates,
and risk of bone marrow toxicity
50mg/kg/dayPOor 75mg/kg/day IV in four
equal doses for 14 days (Nelson 17th)
100 mg/kg/day for 2-3 weeks (Del Mundo)
Adult: 3-4g/day in QID x 14 days
2. Ampicillin
200 mg/kg/day IV in four to six doses

3. Amoxicillin
100 mg/kg/day in three divided doses
for 14 days
Adult: 4-6 g/day TID x 14 days
4. Trimethoprim-sulfamethoxazole
10 mg of TMP/kg/day and 50 mg of
SMZ/kg/day PO in two doses for 14
days
Adult: 1-1 ½ tabs BID x 14 days
Short Courses:
1. Ceftriaxone
current drug of choice for children and
pregnant women
Children: 50-80 mg/kg IM QID for 5-7 days
Pregnant: 3-4 g IV as single dose for 5-7
days
2. Cefixime
20 mg/kg/day BID for 7 days

3. Ofloxacin
15 mg/kg/day for 2 days
Dexamethasone
3 mg/kg for the initial dose, followed
by 1 mg/kg q 6hr for 48hr
improves the survival rate of patients
with shock, obtundation, stupor, or
coma
shortens the febrile course
Typhoid Carrier
a patient is considered a long-term carrier if
he continues to excrete the organism in the
stool or urine for periods longer than 1 year
after appropriate treatment
Occurs in 1-4% of patients
Higher in women & in persons w/ biliary
abnormalities or concurrent gallbladder
infection w/ Schistosoma japonicum
Associated w/ increased incidence of CA of
the gallbladder & other gastrointestinal
malignancies
Recommended Therapy:
2. Amoxicillin 6 g/day plus Probenecid
for 6 weeks
3. TMP-SMX (160/800mg) 1 tablet BID
plus Rifampicin 600 mg OD for 6
weeks
4. Ciprofloxacin 500 mg BID for 4 weeks
5. Norfloxacin 400 mg BID for 4 weeks
Supportive treatment
maintenance of appropriate fluid and
electrolyte balance are essential
antipyretics
nutritional support
when intestinal hemorrhage is severe,
blood transfusion is needed
Surgical
recommended for intestinal
perforation
Surgical resection of 10 cm on each
side of the perforation has been
reported to improve survival
A course of 4–6 wk of high-dose
ampicillin (or amoxicillin) plus
probenecid or TMP-SMZ results in an
approximately 80% cure rate of
carriers if no biliary tract disease is
In the presence of cholelithiasis or
cholecystitis, antibiotics alone are
unlikely to be successful
cholecystectomy within 14 days of
antibiotic treatment is recommended
Prognosis
in developing countries, the mortality rate is
higher than 10%, usually because of delays in
diagnosis, hospitalization and treatment
infants and children with underlying
debilitating disorders are at higher risk
appearance of complications, such as
gastrointestinal perforation or severe
hemorrhage, meningitis, endocarditis, and
pneumonia, is associated with high morbidity
and mortality rates
Relapse after the initial clinical response
occurs in 4–8% of the patients who are not
treated with antibiotics – milder
individuals who excrete S. ser. Typhi for 3
months after infection usually become
chronic carriers
risk of becoming a carrier is low in children
and increases with age
of all patients with typhoid fever, 1–5%
become chronic carriers
incidence of biliary tract diseases is higher in
chronic carriers than in the general populatio
Prevention
improved sanitation and clean running water
personal hygiene measures
handwashing
attention to food preparation practices
carriers should be prevented from working in
food- or water-processing activities, in kitchens,
and in occupations related to patient care
Detection & treatment of carrier
Immunization
Recommended for:
 Food handlers such as dietary personnel,
cooks, waiters, servers, dieticians,
nutritionists
 Micobio lab technicians
 Persons w/ intimate exposure to a
documented S. Typhi carrier
 Travel to endemic area other than the
Philippines
 Travelers should be vaccinated at least 1
week prior to departing for an endemic
area
1. Live-attenuated preparation of the
Ty21a/ Enteric coated capsule
 VIVOTIF BERNA (Swiss Serum and
Vaccine Institute), ZEROTYPH
 oral
 oral vaccine that contains live
attenuated S typhi Ty21a strains in an
enteric-coated capsule.
 elicits both serum and intestinal
antibodies and cell-mediated immune
responses
 shown to have good efficacy (67–
82%)
 oral vaccine is recommended for
persons 6 yr of age
2. Vi capsular polysaccharide
antigen vaccine (ViCPS)/ prefilled
syringe
 TYPHERIX
 intamuscular
 composed of purified Vi antigen,
the capsular polysaccharide
elaborated by S typhi isolated from
blood cultures
 can be used in persons 2 yr of age
THANK YOU