Typhoid fever

Typhoid fever is a systemic disease characterized by fever and abdominal pain caused by
dissemination of Salmonella typhi or S. paratyphi. The disease was initially called typhoid fever
because of its clinical similarity to typhus. However, in the early 1800s, typhoid fever was clearly
defined pathologically as a unique illness on the basis of its association with enlarged Peyer's
patches and mesenteric lymph nodes.
Humans are the only host of S. typhi, which is shed in the feces, urine, vomitus, and oral
secretions by acutely ill persons and in the feces by chronic carriers without overt disease.
Therefore, typhoid fever from S. typhi is a disease largely of developing countries, where sanitary
conditions are insufficient to stop its spread. Typhoid fever is a protracted disease that is
associated with bacteremia, fever, and chills during the first week; widespread mononuclear
phagocyte involvement with rash, abdominal pain, and prostration in the second week; and
ulceration of Peyer patches with intestinal bleeding and shock during the third week.

ETIOLOGY
Salmonellae constitute a genus of more than 2300 serotypes that are highly adapted for
growth in both humans and animals and that cause a wide spectrum of disease. The growth of S.
typhi and S. Paratyphi is restricted to human hosts, in whom these organisms cause enteric
(typhoid) fever. The remainder of Salmonella serotypes, referred to as nontyphoidal Salmonella, can
colonize the gastrointestinal tracts of a broad range of animals, including mammals, reptiles,
birds, and insects. More than 200 of these serotypes are pathogenic to humans, in whom they
often cause gastroenteritis and can also be associated with localized infections and/or bacteremia.
The initial identification of Salmonella in the clinical microbiology laboratory is based on growth
characteristics. Salmonellae, like other Enterobacteriaceae, produce acid on glucose fermentation,
reduce nitrates, and do not produce cytochrome oxidase. They are facultatively anaerobic and do
not form spores. In addition, all salmonellae except S. gallinarum-pullorum are motile by means of
peritrichous flagella, and all but S. typhi produce gas (H2S) on sugar fermentation. Notably, only
1% of clinical isolates ferment lactose; a high level of suspicion must be maintained to detect
these rare clinical lactose-fermenting isolates.

PATHOGENESIS
All Salmonella infections begin with ingestion of organisms in contaminated food or water. The
infectious dose of Salmonella varies from 103 to 106 colony-forming units. This variability probably
reflects the ability of salmonellae to resist the low pH of the stomach—a powerful component of
host defense. Conditions that decrease stomach acidity (an age of <1 year,antacid ingestion, or
achlorhydric disease) or intestinal integrity (inflammatory bowel disease, history of gastrointestinal
surgery, or alteration of the intestinal flora by antibiotic administration) increase susceptibility to
Salmonella infection.
Salmonella invades intestinal epithelial cells as well as tissue macrophages. Invasion of
intestinal epithelial cells is controlled by invasion genes that are induced by the low oxygen
tension found in the gut. These genes encode proteins involved in adhesion and in recruitment of
host cytoskeletal proteins that internalize the bacterium. Similarly, intramacrophage growth is
important in pathogenicity, and this seems to be mediated by bacterial genes that are induced by
the acid pH within the macrophage phagolysosome. The enteric nervous system also is a critical
regulator of fluid secretion in the normal gut. Neural reflex pathways increase epithelial fluid
secretion in response to enteric pathogens such as Salmonella and Clostridium difficile.
Once salmonellae reach the small intestines, the bacteria again encounter numerous host
defenses, including bile salts, lysozyme, complement, and cationic antimicrobial peptides — all
components of the host’s innate immune response. The salmonellae next penetrate the mucous
layer of the gut and subsequently traverse the intestinal layer through phagocytic microfold (M)
cells that reside within Peyer’s patches. Salmonellae can also trigger the formation of membrane
ruffles in normally nonphagocytic epithelial cells. These ruffles reach out and enclose adherent
bacteria within large vesicles by a process referred to as bacteria-mediated endocytosis (BME). BME
is dependent on the direct delivery of Salmonella proteins into the cytoplasm of epithelial cells by a
specialized bacterial secretion system (type III secretion). These bacterial proteins mediate
alterations in the actin cytoskeleton that are required for Salmonella uptake.
After crossing the epithelial layer of the small intestine, S. typhi and S. paratyphi, which cause
enteric (typhoid) fever, are phagocytosed by macrophages. Once internalized, the salmonellae are
protected from polymorphonuclear leukocytes (PMNs), the complement system, and the acquired
immune response (antibodies). However, these bacteria must survive the antimicrobial
environment of the macrophage, which includes the production of reactive oxygen and nitrogen
species, antimicrobial peptides, and hydrolytic enzymes. Environmental signals within the
macrophage trigger alterations in regulatory systems of the phagocytosed bacteria. The best-
characterized regulatory system is PhoP/PhoQ, a two-component regulon that senses changes in
bacterial location and alters bacterial protein expression. For example, PhoP/PhoQ triggers the
expression of outer-membrane proteins and mediates modifications in LPS so that the bacteria's
outer surface can resist microbicidal activities and potentially alter host cell signaling. In addition,
salmonellae encode a second type III secretion system that directly delivers bacterial proteins
from the phagosome into the macrophage cytoplasm. This secretion system is essential for
survival within macrophages.
Once phagocytosed, salmonellae disseminate throughout the body in macrophages via the
lymphatics and colonize reticuloendothelial tissues (liver, spleen, lymph nodes, and bone marrow).
Patients have relatively few or no signs and symptoms during this initial incubation stage. Signs
and symptoms, including fever and abdominal pain, probably result from secretion of cytokines by
macrophages when a critical number of organisms have replicated. For example, the development
of hepatosplenomegaly is likely to be related to the recruitment of mononuclear cells and the
development of a cell-mediated immune response to S. typhi colonization. The recruitment of
additional mononuclear cells and lymphocytes to Peyer’s patches during the several weeks after
initial colonization/infection can result in marked enlargement and necrosis of the Peyer’s patches.
It is not yet known why S. typhi and S. paratyphi cause systemic disease and are host
restricted, whereas the vast majority of pathogenic Salmonella strains cause gastroenteritis in a
broad range of hosts. Recently generated genome sequences show that S. typhi contains more
than 200 pseudogenes, which appear to be functional genes in S. typhimurium. These pseudogenes
may have been dispensable for S. typhi growth in humans.

CLINICAL COURSE
Enteric fever is a misnomer, in that the hallmark features of this disease—fever and abdominal
pain — are variable. While fever is documented at presentation in more than 75% of cases,
abdominal pain is reported in only 20 to 40%. Thus, a high index of suspicion for this potentially
lethal systemic illness is necessary when a person presents with fever and a history of recent
travel to a developing country.
Classically, the course of untreated typhoid fever is divided into four distinct stages, each
lasting about a week. Over the course of these stages, the patient becomes exhausted and
emaciated.
 In the first week, the body temperature rises slowly, and fever fluctuations are seen with
relative bradycardia (Faget sign), malaise, headache, and cough. A bloody nose (epistaxis) is
seen in a quarter of cases, and abdominal pain is also possible. A decrease in the number of
circulating white blood cells (leukopenia) occurs with eosinopenia and relative lymphocytosis;
blood cultures are positive for Salmonella typhi or S. paratyphi.
 In the second week, the person is often too tired to get up, with high fever in plateau around
40 °C (104 °F) and bradycardia (sphygmothermic dissociation or Faget sign), classically with a
dicrotic pulse wave.
Rose spots appear on the lower chest and abdomen in around a third of patients at the end
of the first week and resolves after 2 to 5 days without leaving a trace. Rose spots make up a
faint, salmon-colored, blanching, maculopapular rash located primarily on the trunk and chest.
Patients can have two or three crops of lesions, and Salmonella can be cultured from punch
 biopsies of these lesions. On occasion, patients who remain toxic manifest neuropsychiatric
symptoms described as a “muttering delirium” or “coma vigil,” with picking at bedclothes or
imaginary objects.
The abdomen is distended and painful in the right lower quadrant, where borborygmi can be
heard. Diarrhea can occur in this stage: six to eight stools in a day, green, comparable to pea
soup, with a characteristic smell. However, constipation is also frequent. The spleen and liver
are enlarged (hepatosplenomegaly) and tender, and liver transaminases are elevated. The
Widal test is strongly positive, with antiO and antiH antibodies. Blood cultures are sometimes
still positive at this stage. (The major symptom of this fever is that the fever usually rises in
the afternoon up to the first and second week.)
 In the third week of typhoid fever, a number of complications can occur:
 Intestinal haemorrhage due to bleeding in congested Peyer's patches; this can be very serious,
but is usually not fatal.
 Intestinal perforation in the distal ileum: this is a very serious complication and is frequently
fatal. These complications can develop despite clinical improvement and presumably result
from necrosis at the initial site of Salmonella infiltration at the Peyer’s patches of the small
intestine. Both complications are life-threatening and require immediate medical and surgical
interventions, with broadened antibiotic coverage for polymicrobial peritonitis and treatment of
gastrointestinal hemorrhages, including bowel resection.
 Rare complications whose incidences are reduced by prompt antibiotic treatment include
pancreatitis, hepatic and splenic abscesses, endocarditis, pericarditis, orchitis, hepatitis,
meningitis, nephritis, myocarditis, pneumonia, arthritis, osteomyelitis, and parotitis. Despite
prompt antibiotic treatment, relapse rates remain at _10% in immunocompetent hosts.
 The fever is still very high and oscillates very little over 24 hours. Dehydration ensues, and the
patient is delirious (typhoid state). One-third of affected individuals develop a macular rash on
the trunk.
 Platelet count goes down slowly and risk of bleeding rises.
 By the end of third week, the fever starts subsiding (defervescence). This carries on into the
fourth and final week.
Approximately 1 to 5% of patients with enteric fever become longterm, asymptomatic, chronic
carriers who shed S. typhi in either urine or stool for >1 year. The incidence of chronic carriage is
higher among women and among persons with biliary abnormalities (e.g., gallstones, carcinoma of
the gallbladder) and gastrointestinal malignancies. The anatomical abnormalities associated with
these conditions presumably allow prolonged colonization.

DIAGNOSIS
Since the clinical presentation of typhoid fever is relatively nondescript, the diagnosis needs to
be considered in any febrile traveler returning from an endemic areas. Other diagnoses that
should be considered in this patient population include malaria, hepatitis, bacterial enteritis,
dengue fever, rickettsial infections, leptospirosis, amebic liver abscesses, and acute HIV infection
(Chap. 108).
Other than a positive culture, no specific laboratory test is diagnostic for enteric fever. In 15 to
25% of cases, leukopenia and neutropenia are detectable. In the majority of cases, the white
blood cell count is normal despite high fever. However, leukocytosis can develop in typhoid fever
(especially in children) during the first 10 days of the illness, or later if the disease course is
complicated by intestinal perforation or secondary infection. Other nonspecific laboratory results
include moderately elevated values in liver function tests (aminotransferases, alkaline
phosphatase, and lactate dehydrogenase). In addition, nonspecific ST and T wave abnormalities
can be seen on electrocardiograms.
The diagnostic “gold standard” is a culture positive for S. typhi or S. paratyphi. The yield of
blood cultures is quite variable: it can be as high as 90% during the first week of infection and
decrease to 50% by the third week. A low yield is related to low numbers of Salmonella (<15
organisms per milliliter) in infected patients and/or to recent antibiotic treatment. Centrifugation
to isolate and culture the buffy coat, which contains abundant blood mononuclear cells associated
with the bacteria, decreases time to isolation but does not affect culture sensitivity.
A diagnosis can also be based on positive cultures of stool, urine, rose spots, bone marrow,
and gastric or intestinal secretions. Unlike blood cultures, bone marrow cultures remain highly
(90%) sensitive despite ≤5 days of antibiotic therapy. Culture of intestinal secretions (best
obtained by a noninvasive duodenal string test) can be positive despite a negative bone marrow
culture. If blood, bone marrow, and intestinal secretions are all cultured, the yield of a positive
culture is >90%. Stool cultures, while negative in 60 to 70% of cases during the first week, can
become positive during the third week of infection in untreated patients. Although the majority of
patients (90%) clear bacteria from the stool by the eighth week, a small percentage become
chronic carriers and continue to have positive stool cultures for at least 1 year.
Several serologic tests, including the classic Widal test for "febrile agglutinins," are available;
however, given high rates of false-positivity and false-negativity, these tests are not clinically
useful. Polymerase chain reaction and DNA probe assays are being developed.

TREATMENT
In the preantibiotic era, the mortality rate from typhoid fever was as high as 15%. The
introduction of treatment with chloramphenicol in 1948 greatly altered the disease course,
decreasing mortality to <1% and the duration of fever from 14 – 28 days to 3 – 5 days.
Chloramphenicol remained the standard treatment for enteric fever until the emergence of
plasmid-mediated resistance to this drug in the 1970s. Given the increased mortality associated
with resistance to chloramphenicol and the rare chloramphenicol-induced bone marrow toxicity,
ampicillin (1 g orally every 6 h) and trimethoprim-sulfamethoxazole (TMP-SMX; one double-
strength tablet twice daily) became the mainstays of treatment.
In 1989, MDR S. typhi emerged. These bacteria are resistant to chloramphenicol, ampicillin,
trimethoprim, streptomycin, sulfonamides, and tetracycline. Like chloramphenicol resistance,
resistance to ampicillin and trimethoprim is plasmid-encoded. In 1994, 12% of S. typhi isolates in
the United States were MDR. Thus either quinolones or third-generation cephalosporins are
currently recommended for empirical antibiotic treatment (Table 137-1). Despite efficient in vitro
killing of Salmonella, first- and second-generation cephalosporins as well as aminoglycosides are
ineffective in treating clinical infections.
Quinolones are the only available oral antibiotics for the treatment of MDR S. typhi infections.
The greatest experience has been gained for ciprofloxacin (500 mg orally twice a day for 10 days).
Shorter courses of ofloxacin (10 to 15 mg/kg in divided doses twice daily for 2 to 3 days) have
also been successful. Limited data suggest that treatment with fluoroquinolones is associated with
fewer treatment failures and more rapid resolution of symptoms than treatment with β-lactam
agents. However, quinolone resistance is emerging. In 1993, an outbreak of nalidixic acid–
resistant S. typhi (NARST) infections in Vietnam was linked to chromosomal mutations in the gene
encoding DNA gyrase (the target of the quinolones). NARST strains have also been isolated in
India. Thus, all strains of S. typhi must be screened for resistance to nalidixic acid and tested for
sensitivity to a clinically appropriate quinolone. Patients infected with NARST strains need to be
treated with higher doses of ciprofloxacin (10 mg/kg twice a day for 10 days) or longer courses of
ofloxacin (10 to 15 mg/kg in divided doses twice daily for 7 to 10 days) or with other antibiotics to
which the strains are sensitive.
Ceftriaxone (1 to 2 g intravenously or intramuscularly) for 10 to 14 days is equivalent to oral
or intravenous chloramphenicol in the treatment of susceptible strains. An alternative agent shown
to be effective in an open-label study for the treatment of NARST strains is azithromycin (1 g
orally once a day for 5 days or 1 g orally on day 1 followed by 500 mg orally for 6 days). In cases
of severe typhoid fever (fever; an abnormal state of consciousness—i.e., delirium, obtundation,
stupor, or coma—or septic shock; and a positive culture for S. typhi or S. paratyphi A),
dexamethasone treatment should be considered. In a single trial in Jakarta in the early 1980s in
chloramphenicol-treated patients, treatment with dexamethasone (a single dose of 3 mg/kg
followed by eight doses of 1 mg/kg, given every 6 h) decreased the mortality rate from 56% to
10%.
 The 1 to 4% of patients who develop chronic carriage of Salmonella can be treated for 6 weeks
with an appropriate antibiotic. Treatment with oral amoxicillin, TMP-SMX, ciprofloxacin, or
norfloxacin has been shown to be ~80% effective in eradicating chronic carriage of susceptible
organisms. However, in cases of anatomical abnormality (e.g., biliary or kidney stones),
eradication of the infection often cannot be achieved by antibiotic therapy alone and requires
surgical correction of the abnormalities.