INTERNAL MEDICINE—INFECTIOUS DISEASES: ENTERIC (TYPHOID) FEVER

o Lack of handwashing and toilet access

These notes are directly lifted from Harrison’s 18th and 19th ed. 
ENTERIC (TYPHOID) FEVER
 Systemic disease characterized by fever and
abdominal pain
 Caused by S. typhi and S. paratyphi
 Initially called typhoid fever because of its clinical
similarity to typhus
 Pathologically defined as a unique illness
characterized by enlarged Peyer’s patches and
mesenteric lymph nodes
o Prior H. pylori infection (related to
chronically reduced gastric acidity)
 S. typhi infection more common than S. paratyphi
(4:1), but numbers of S. paratyphi cases are rising
(esp. in India) due to S. typhi vaccine
 Multi-drug resistant (MDR) S.typhi
o (+) plasmids encoding resistance to
chloramphenicol, ampicillin, and TMP
 Increased FQ use S. typhi and S. paratyphi with
decreased ciprofloxacin susceptibility (DCS)
and ciprofloxacin resistance treatment failure
 Strains producing extended spectrum B-
lactamases have emerged recently

EPIDEMIOLOGY PATHOGENESIS
 27 million cases with 200, 000-600,000 deaths
Penetrate &
annually Ingestion of
invade the S.I. Formation of
organism from
 Highest incidence in South-Central and Southeast contaminated mucosal layer membrane
water & food via the ruffles of non-
Asia Phagocytic phagocytic
(Inf. Dose: 103-
 79% of CDC-reported cases (1999-2006) were 106 CFU)
Microfold (M) epithelial cells
cells
associated with recent international travel: India
(47%), Pakistan (10%), Bangladesh (10%), Mexico
(7%), and the Philippines (4%) Alteration of Bacteria-
Uptake of
 High incidence correlates with poor sanitation Salmonella
Actin Mediated
Cytoskeleton Endocytosis
and lack of access to clean drinking water
 More common in young children and adolescents
 Urban > Rural areas
Remodel the Promote
Salmonella is
 Etiologic agents S. typhi and S. paratyphi phagocytized by
Salmonella- bacterial
containing survival &
serotypes A, B, and C have no known hosts other macrophages
vacuole replication
than humans
 Food-borne or waterborne transmission results
from fecal contamination by ill or asymptomatic Dissemination
throughout the
chronic carriers Colonize the RES
body via the
 Sexual transmission—between male partners lymphatics

 Health care workers—after exposure to infected

patients or during processing of clinical specimens CLINICAL COURSE
and cultures
 “Enteric” is actually a misnomer because fever and
 Risk factors:
abdominal pain are variable (i.e only 30-40%
o Contaminated water or ice
present with abdominal pain and >75% present
o Flooding
with fever)
o Food and drinks purchased from street
vendors  Fever + history of recent travel to a developing
o Raw fruits and vegetables fertilized with country= HIGH INDEX OF SUSPICION!
sewage  Incubation period ranges from 5-21 days (ave. 10-
o Ill household contacts 14 days); depends on inoculum size and host’s
health and immune status

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 INTERNAL MEDICINE—INFECTIOUS DISEASES: ENTERIC (TYPHOID) FEVER

 Most prominent symptom: prolonged fever (38.8- myocarditis, orchitis, hepatitis,

40.5 C) up to 4 weeks if untreated
 S. paratyphi— milder disease, predominantly
gastrointestinal symptoms
 Early physical findings:
o Rash (Rose spots) (30%)
 Faint, salmon-colored, blanching,
maculopapular lesions located
primarily on the trunk and chest
 Evident in ~30% at the end of the
1st week and disappears w/o a
trace after 2-5 days
 Punch biopsy: (+) Salmonella
o Hepatosplenomegaly (3-6%)
o Epistaxis
o Relative bradycardia at the peak of high
fever (<50%)
 Severe disease (~10-15%)
o depends on host factors
(immunosuppression, antacid therapy,
previous exposure, and vaccination),
strain virulence and inoculum, and
antibiotic choice
o Gastrointestinal bleeding (10-20%) and
ileal perforation (1-3%)
 most commonly occur in the 3rd
and 4th weeks of illness
 secondary to hyperplasia,
perforation, and necrosis of the
ileocecal Peyer’s patches
 life-threatening, requires
immediate fluid resuscitation and
surgical intervention
 polymicrobial peritonitis: give
broad antibiotic coverage
o Neurologic Manifestations
(2-40%)
 Meningitis, GBS, neuritis, and
neuro-psychiatric symptoms
(“muttering delirium” or “ coma
vigil”) with picking at bed clothes
and imaginary objects
o Rare complications include DIC,
hematophagocytic syndrome, pancreatitis,
hepatic and splenic abscesses,
granulomas, endocarditis, pericarditis,
glomerulonephritis, pyelonephritis, and
HUS, severe pneumonia, arthritis,
osteomyelitis, endophthalmitis, and
parotitis
 Mild relapse within 2-3 weeks of fever resolution
in 10% of patients, associated with same strain
type and susceptibility profile
 10% of untreated patients—excrete S. typhi in
feces for 3 months
 Chronic, asymptomatic carriage (1-4%)
o shedding of S. typhi in urine and stool for
> 1 year
o more common in women, infants, and
persons with
biliary
abnormalities and
concurrent S.
haematobium
bladder infection
o these factors allow
prolonged
colonization
DIAGNOSIS
 Relatively nonspecific s/sx Dx must be
considered in any febrile traveller returning from a
developing country (India, Philippines, Latin
America)
 Differentials:
o Malaria, hepatitis, dengue fever, rickettsial
infection, leptospirosis, amebic liver
abscess, and acute HIV infection
 No specific laboratory test is diagnostic other
than a (+) culture
 Leukopenia and neutropenia in 15-25% of cases
 Leukopenia  more common in children, during
the 1st 10 days of illness, and cases complicated by
intestinal perforation or secondary infection
 Other nonspecific labs: moderately elevated LFT
and muscle enzymes
 Definitive diagnosis: isolation of organism in
blood, bone marrow, stool, or intestinal secretions

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 INTERNAL MEDICINE—INFECTIOUS DISEASES: ENTERIC (TYPHOID) FEVER

 Sensitivity of cultures o Relapse and fecal carriage rate <3%

o Blood: 40-80% (d/t high rates of
antibiotic use and small number of S. typhi
present in blood)
o Bone marrow: 55-90% (not reduced by
even up to 5 days prior antibiotic use)
o Blood + BM + GIT: >90%
o Stool: (-) in 60-70% of cases during 1st
week; (+) during the 3rd week
 Serologic tests: lower predictive values than
blood culture
o Widal test: febrile agglutinins
o Rapid test: Ab to outer membrane
proteins or O:9 Ag
TREATMENT
 1st and 2nd gen cephalosporins and
aminoglycosides: NOT EFFECTIVE!
 Uncomplicated enteric fever  oral antibiotics
and antipyretics
 Persistent vomiting, diarrhea, +/- abdominal
distention  hospitalization and supportive
therapy + parenteral 3rd gen cephalosporin or FQ
o Continue therapy for at least 10 days or for
5 days after fever resolution
 Chronic carriage  oral amoxicillin, TMP-SX,
ciprofloxacin or norfloxacin
o 80% effective in eradicating chronic
carriage of susceptible organisms
o If with anatomical abnormalities (biliary
or kidney stones)
 antibiotic + surgical correction

 Prompt, appropriate antibiotic use prevents

severe complications leading to a case-fatality rate
of <1%
 Initial antibiotic choice depends on the
susceptibility of strains in the area
 Fluoroquinolones  most effective agents for
drug-susceptible typhoid fever (cure rates of
~98% and relapse and fecal carriage rates of <2%
o Ciprofloxacin
o Ofloxacin – short-course tx successful
against infections by quinolone-
susceptible strains
 DCS typhoid fever  treated with ceftriaxone,
azithromycin, or high-dose ciprofloxacin
 7-day FQ therapy for DCS typhoid fever associated
with delayed resolution of fever and higher rates of
fecal carriage
o Thus, a 10-14 day course of high-dose
ciprofloxacin is preferred
 Ceftriaxone, cefotaxime, and Cefixime 
effective for treatment of MDR enteric fever,
including those caused by DCS and FQ-resistant
strains
o Clear fever in ~1 week PREVENTION AND CONTROL
o Failure rates of ~5-10%
o Fecal carriage <3%  Travelers should monitor their food and water
o Relapse rates 3-6% intake carefully and strongly consider vaccination
 Azithromycin  lower rates of treatment failure against S. typhi
and shorter hospitalization  Ty21a—oral live attenuated S. typhi vaccine
o Defervescence in ~4-6 days o Given on days 1, 3, 5, 7

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 INTERNAL MEDICINE—INFECTIOUS DISEASES: ENTERIC (TYPHOID) FEVER

o Booster every 5 years ADDITIONAL FIG URE (PATHOPHYSIOLOGY)

o Can be given as early as 6 yrs of age
o Cumulative efficacy of 48% at 2.5-3.5
years
 Vi CPS—parenteral vaccine, purified Vi
polysaccharide from bacterial capsule
o Single dose
o Booster every 2 years
o Can be given as early as 2 yrs of age
o Cumulative efficacy of 55% at 3 years
o Poorly immunogenic in children <5 y/o
because of T-cell independent properties
o Vi rEPA—Vi bound to nontoxic
recombinant identical to P. aeruginosa
exotoxin
 Higher T-cell responses and
serum IgG antibody to Vi
 91% efficacy at 27 mos and 87%
at 46 mos; very well tolerated
 Immunization is an adjunct and not a substitute
to avoidance of high-risk food and drinks
protective efficacy of vaccine is overcome by high
inocula in food-borne exposure
 Not recommended for adults residing in endemic
areas or those exposed to common-source
outbreaks