TYPHOID FEVER

Definition:

 Typhoid fever is an acute systemic illness unique to humans caused by

Salmonella typhi characterized by fever, prostration, abdominal pain, and
a rose-colored rash.
 It is a severe systemic illnesses characterized by sustained fever and
abdominal symptoms
 It is a classic example of enteric fever [a clinical syndrome characterized
by constitutional and gastrointestinal symptoms and by headache caused]
by the Salmonella family of bacteria.

Epidemiology

 Mode of transmission is fecal-oral through ingestion of contaminated

food (commonly poultry), water and milk.
 Incubation period varies from 7 to 21 days.

Etiology

 The clinical picture of typhoid fever is most commonly caused by

Salmonella typhi, or less frequent causes are S. paratyphi A, S. typhi B
(also known as S. schottmuelleri) and S. paratyphi C (also known as
Salmonella hirschfeldii)
 Even "nontyphoidal" Salmonellae (most commonly S. enteritidis and S.
typhimurium) may cause severe illness consistent with enteric fever
 Salmonella is an intracellular pathogen.

Pathogenesis:

 Typhoid bacilli are shed in the feces of asymptomatic carriers or in the

stool or urine of those with active disease.
 Inadequate hygiene after defecation may spread S. typhi to communal
food or water supplies.
 The development of enteric fever is influenced by the specific organism
involved and the number of organisms ingested (the infectious dose).
 This is followed by gastrointestinal infection, systemic spread and
persistence, and, in a minority of cases, a chronic carrier state
 Salmonella typhi has no known animal reservoir in nature and causes
disease only in humans.
 Infection therefore implies either direct contact with an infected
individual, or indirect contact via contaminated food or water.
 S. paratyphi species are generally thought to cause milder illnesses than
S. typhi
 Salmonella paratyphi B (S. schottmuelleri) has been related to milk or
cheese-borne outbreaks of gastroenteritis
 S. paratyphi B is more frequently cultured than S. paratyphi A; S.
paratyphi C is rarely isolated.
 The greater the dose, the higher the attack rate and the shorter the
incubation period
 Even smaller numbers of organisms are likely to induce disease in high-
risk individuals such as those with achlorhydria or immunosuppressive
illnesses such as AIDS
 After ingestion, S. typhi organisms that survive the gastric acid barrier
enter the small intestine
 S. typhi access the submucosal region of the bowel by two mechanisms:
via the M-cell, a specialized epithelial cell which serves as a sampling
and antigen presenting cell in the mucosa (or gut)-associated lymphoid
system; and via direct penetration into or around the epithelial cell itself
 The entry of S. typhi into the epithelial cell appears to be mediated by the
cystic fibrosis transmembrane conductance regulator (CFTR), the protein
that is abnormal in cystic fibrosis
 Once in the submucosal region, S. typhi proliferate, leading to
hypertrophy of the Peyer's patches via recruitment of mononuclear cells
and lymphocytes.
 Later in the disease, hypertrophy and resultant necrosis of the
submucosal tissues is probably responsible for abdominal pain and
subsequent ileal perforation, a potentially fatal complication.
 Dissemination of S. typhi from the Peyer's patches to the
reticuloendothelial system subsequently occurs via the lymphatic system
and bloodstream.
 Replication within the reticuloendothelial system is a hallmark of enteric
fever, and is responsible for the clinical findings of prostration,
generalized sepsis, and hepatosplenomegaly.
 There are, however, some individuals who contain the organism within
the gastrointestinal system and do not become systemically ill
 Eventually, organisms reside within monocyte-derived or tissue
macrophages in the liver, spleen and bone marrow, the latter being a
clinical "sanctuary" for S. typhi and an important source of diagnostic
culture material even after the onset of antimicrobial therapy
 These intracellular organisms are probably the source of both relapsing
infection and late pyogenic complications such as pericarditis, visceral
abscesses, or osteomyelitis.
 Persistence of intracellular S. typhi organisms within visceral and bone
marrow macrophages has long been believed central to the virulence and
persistence of the microorganism in vivo.
 S. typhi flagella and LPS are potent stimulators of pro-inflammatory
cytokine release.
 It has been proposed that these immunological mediators may cause
intestinal necrosis within the Peyer's patches as a result of repeated local
stimulation which occurs during the enterohepatic circulation of S. typhi
through the hepatobiliary system
 Approximately 1 to 4 percent of individuals in endemic settings become
chronic, asymptomatic carriers of S. typhi after acute infection.
 Chronic carriage is defined as persistence of Salmonellae in stool or
urine for more than one year.

Clinical features:

 Typhoid fever presents as a febrile illness 5 to 21 days after ingestion of

the causative microorganism in contaminated food or water.
 Typhoid fever usually presents nonspecifically with abdominal pain,
fever, chills, and constitutional symptoms; as a result, many other
diagnoses may be entertained.
 Classic presentation: Classic reports described characteristic stages of
typhoid fever in untreated individuals:
 First week of illness: Rising ("stepwise") fever and bacteremia i.e. [Slow
(stepladder) rise of fever to maximum and then slow return to normal]
 Second week: Abdominal pain and rash (rose spots, which are faint
salmon colored macules on the trunk and abdomen)
 Third week: Hepatosplenomegaly, intestinal bleeding and perforation,
related to ileocecal lymphatic hyperplasia of the Peyer's patches, may
occur with secondary bacteremia and peritonitis.
 Other "classic" findings of typhoid fever include septic shock or altered
level of consciousness
 Relative bradycardia or pulse-temperature dissociation has long been
associated with typhoid fever and may suggest the diagnosis.
 Others features are: Headache, Malaise, Arthralgias, pharyngitis,
Diarrhea (less common), Dry cough

Diagnosis

 Diagnosis is ultimately based on isolation of typhoid bacilli in cultures,

although the clinical setting and hematologic abnormalities may suggest
typhoid fever.
 Typhoid bacilli are usually isolated from cultures of blood or bone
marrow (most sensitive) only during the first 2 wk of illness, while stool
cultures are usually positive during the 3rd to 5th wk.
 Blood cultures are positive in 40 to 80 percent of patients, depending
upon the series and culture techniques used.
 Urine cultures are often positive.
 Cultures of liver biopsies or rose spots may also yield the organism.
 Serology is nonspecific and usually not useful
 Single serologic tests, such as the Widal test, are of limited clinical utility
in acutely ill patients because positive results may represent previous
infection in endemic areas.
 Typhoid bacilli contain antigens (O and H) that stimulate the host to form
corresponding antibodies.
 A fourfold rise in O and H antibody titers in paired specimens acquired 2
wk apart suggests S. typhi infection.
 However, this test (Widal's agglutination reaction) is only moderately
sensitive and lacks specificity
 An ELISA for antibodies to the capsular polysaccharide Vi antigen is
useful for detection of carriers but not for the diagnosis of acute illness
 Laboratory evaluation of patients with typhoid fever frequently reveals
anemia and either leukopenia or leukocytosis; the latter is more common
in children

Differential Diagnosis:

 Malaria
 "Enteric fever-like" syndrome caused by Yersinia enterocolitica,
Yersinia pseudotuberculosis, and Campylobacter sp.
 Enteric fever caused by non-typhi Salmonella
 Infectious hepatitis
 Atypical pneumonia
 Infectious mononucleosis
 Subacute bacterial endocarditis
 Tuberculosis
 Brucellosis
 Q fever
 rickettsioses,
 leptospirosis,
 disseminated TB
 tularemia,
 psittacosis,
 Lymphoma.

Treatment:

Definitive/Medications:

 Treatment of typhoid fever has been complicated by the development

and rapid dissemination of typhoidal organisms resistant to ampicillin,
trimethoprim-sulfamethoxazole, and chloramphenicol, which were
previously considered the drugs of choice

Antimicrobial regimens

 Typhoid fever is usually treated with a single antibacterial drug

 Choice will depend upon local resistance patterns, patient age, whether
oral medications are feasible, the clinical setting, and available resources.
 There may be locations where older agents such as chloramphenicol,
ampicillin, or trimethoprim-sulfamethoxazole are appropriate, but these
drugs are generally not used widely because of high levels of resistance.
 Successful treatment usually results in clinical improvement within three
to five days in uncomplicated cases.
 It is reasonable to begin with a parenteral agent and then complete
therapy with an oral drug once symptoms improve.
 Current drugs of choice for the treatment of typhoid fever in adults
include:
  A fluoroquinolone such as ciprofloxacin (500 mg twice daily) or
ofloxacin (400 mg twice daily), either orally or parenterally for 7 to
10 days.
 A beta-lactam such as ceftriaxone (2 to 3 g once daily) parenterally
for 7 to 14 days.
 Alternative agents for adult patients who cannot be treated with the
above antimicrobials, and for fluoroquinolone resistant isolates include
one of the following:
 Cefixime (20 to 30 mg/kg per day orally in two divided doses for 7 to
14 days)
 Azithromycin (1 g orally once followed by 500 mg once daily for 7 to
14 days, or 1 g orally once daily for five days)
 Chloramphenicol 2 to 3 g per day orally in four divided doses for 14
days.
 Fluoroquinolones appear to have therapeutic advantages over beta-
lactams for the treatment of uncomplicated typhoid fever and are now
considered by many experts to be the drug of choice for fully susceptible
organisms in patients who can take these drugs.
 Quinolones are bactericidal and concentrated intracellularly and in the
bile.
 Ciprofloxacin, ofloxacin, and pefloxacin are widely available and
efficacious: norfloxacin is very poorly absorbed and should not be used.
 When treating fully susceptible organisms the quinolones may result in
more rapid defervescence than beta-lactam agents or chloramphenicol
because of more rapid elimination of intracellular bacteria

Corticosteroids

 Early studies with chloramphenicol suggested that concomitant

corticosteroid therapy might be beneficial in patients with typhoid fever.
 The administration of 3 mg/kg of dexamethasone as an initial dose with
chloramphenicol was associated with a substantially lower mortality in
critically ill patients (shock, obtundation) with typhoid fever compared
with those who received chloramphenicol alone
 Severe typhoid fever remains one of the few indications for
corticosteroid therapy among acute bacterial infections
 The recommended dose in adults and children with severe disease
(delirium, obtundation, stupor, coma or shock) is an initial dose of 3
mg/kg followed by 1 mg/kg every 6 hours for a total of 48 hours.
Typhoid perforation:

 Ileal perforation usually occurs in the third week of febrile illness and is
due to necrosis of the Peyer's patches in the antimesenteric bowel wall
 Affected patients present with increasing abdominal pain, distension,
peritonitis, and sometimes secondary bacteremia with enteric aerobic and
anaerobic microorganisms
 Although individuals occasionally survive with medical therapy alone,
prompt surgical intervention is usually indicated, as is wider
antimicrobial coverage to cover fecal peritonitis.

Relapse:

 Relapse of typhoid fever after clinical cure is not uncommon in

immunologically normal individuals, and typically occurs two to three
weeks after resolution of fever.
 The fluoroquinolones may reduce relapse rates when the bacteria are
fully sensitive.
 An additional course of therapy with a drug to which the organism is
clearly sensitive is indicated for relapsing illness.
 Longer treatment courses with third generation cephalosporins would
also be an option

Chronic carriage of typhoidal Salmonellae:

 Chronic carriage of Salmonellae is defined as excretion of the organism

in stool for more than 12 months after the acute infection.
 Chronic carriers do not develop recurrent symptomatic disease.
 They appear to have reached an immunologic equilibrium in which they
are chronically colonized, and may excrete large numbers of organisms,
but have high levels of systemic immunity and do not develop clinical
disease.
 However, chronic carriers represent an infectious risk to others,
particularly if involved in food preparation.
 The fluoroquinolones appear to be much more effective for eradication
of chronic carriage and better tolerated.
 The cure rate with norfloxacin (400 mg orally twice daily for 28 days)
was 86 percent in those with normal gallbladders and 75 percent in those
with gallstones
 Several smaller studies, evaluating 10 to 12 patients each, have found
that ciprofloxacin (500 or 750 mg orally twice daily) for 14 to 28 days
eliminated carriage in 90 to 93 percent of cases
 Thus, attempted eradication with four weeks of fluoroquinolone therapy
(e.g. ciprofloxacin 500 to 750 mg orally twice daily or ofloxacin 400 mg
orally twice daily) is a reasonable approach, with consideration of
cholecystectomy and additional therapy, if needed and appropriate, at a
later date

Supportive

 Strict isolation of patient's linen, stool and urine

 Monitor clinically and consider serial plain abdominal films for evidence
of perforation, usually in the third to fourth week of illness
 Indication for treatment must be determined on an individual basis.
 Factors to be considered are age, public health (food handler, chronic
care facilities, medical personnel), intolerance to antibiotics, and
evidence of biliary tract disease.
 For hemorrhage - need blood transfusion and shock management

Complications:

 Intestinal hemorrhage and perforation in distal ileum

 Osteomyelitis especially in sickle cell anemia, systemic lupus
erythematosus, hematologic neoplasms and immunosuppressed hosts
 Endovascular infection in the elderly and in patients with history of
bypass operation or aneurysm
 Rarely, endocarditis or meningitis

Prevention

 A simple rule of thumb is "boil it, cook it, peel it, or forget it."
 Typhoid vaccine: For travelers to high-risk areas, such as the Indian
subcontinent, typhoid vaccination may provide protection at very little
risk.
 Neither of the two available vaccines (one oral and one intramuscular)
provides protection against paratyphoid fever and neither is completely
effective against S. typhi.