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Epidemiology, microbiology, clinical manifestations, and diagnosis of typhoid fever
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Epidemiology, microbiology, clinical manifestations, and diagnosis of typhoid fever
Literature review current through: Jan
2013. | This topic last updated: jul 30, 2012.
INTRODUCTION — Typhoid fever is characterized by severe systemic illness
with fever and abdominal pain [1]. The organism classically responsible for the enteric fever syndrome
is S. enterica serotype Typhi (formerly S. typhi). Other Salmonella serotypes,
particularly S. enterica serotype paratyphi A, B, or C, can cause a similar
syndrome; however, it is usually not clinically useful or possible to reliably
predict the causative organism based on clinical findings [2]. The term “enteric fever” is a collective term that refers to both
typhoid and paratyphoid fever.
The
epidemiology, microbiology, clinical manifestations, and diagnosis of typhoid
fever will be reviewed here. The pathogenesis, treatment and prevention of
typhoid fever are discussed separately.
EPIDEMIOLOGY — Typhoid fever is more common in children and young adults
than in older patients [3]. Worldwide, typhoid fever is most prevalent in impoverished areas that
are overcrowded with poor access to sanitation. Non-epidemic incidence
estimates suggest that south-central Asia, Southeast Asia, and southern Africa
are regions with high incidence of S. typhi infection (more than 100 cases per
100,000 person years) [4]. Other regions of Asia and Africa, Latin America, the Caribbean, and
Oceania have a medium incidence of 10 to 100 cases per 100,000 person years.
These estimates, though, are limited by lack of consistent reporting from all
areas of the world and are based on extrapolation of data across regions and
age groups. As an example, the incidence estimates within Africa are based upon
reports from Egypt and South Africa only and thus may not be accurately
defined.
Because humans
are the only reservoir for S. enterica serotype Typhi, a history of travel to
settings in which sanitation is poor or contact with a known typhoid case or
carrier is useful for identifying people at risk of infection outside of
endemic areas, although a specific source or contact is identified in a
minority of cases.
Approximately
200 to 300 cases of S. typhi are reported in the United States each year [5]. About 80 percent of these cases occur among travelers to countries
where typhoid fever is endemic; in many circumstances, such travelers have not
received appropriate vaccination despite guideline recommendations. Among 580
cases of vaccine-preventable diseases among returned international travelers
reported to the multinational GeoSentinel Surveillance Network between 1997 and
2007, confirmed or probable enteric fever (due mainly to S. typhi but also S.
paratyphi) was the most common, particularly in travelers to south-central Asia
[6]. Only 38 percent of those with enteric fever had a pre-travel clinical
encounter. However, the possibility of S. typhi infection in returning
travelers with a history of vaccine receipt should not be discounted, since the
vaccine is not completely effective.
Patients who
acquire infection abroad are usually older than those who acquire disease in US
outbreaks and are more likely to have drug-resistant infection. S. typhi
outbreaks in the United States are most often foodborne; they are generally
limited in size but can cause substantial morbidity [7,8].
The risk
factors for the development of enteric fever due to typhoid or paratyphoid may
differ. In an Indonesian study, transmission of paratyphoid fever was more
frequently observed outside the home (eg, via consumption of food purchased
from street vendors); transmission of typhoid fever was more frequently
observed within the household (eg, via sharing utensils, presence of a patient
with typhoid, lack of soap or adequate toilet facilities) [9]. S. paratyphi also appears to be an increasing cause of enteric fever
among vaccinated travelers, as the typhoid
vaccine is
ineffective against most S. paratyphi infections [10,11].
Issues related
to the epidemiology of drug resistance are discussed separately.
Chronic carriage — Chronic Salmonella carriage is defined as excretion of the
organism in stool or urine >12 months after acute infection. Rates of
chronic carriage after S. typhi infection range from 1 to 6 percent [1,12,13]. Chronic carriage occurs more frequently in women and in patients with
cholelithiasis or other biliary tract abnormalities [14,15]. Chronic carriage in the urine is almost always associated with a
defect in the urinary tract (eg, urolithiasis, prostatic hyperplasia) or
concurrent bladder infection with Schistosoma [16].
Chronic
carriers represent an infectious risk to others, particularly in the setting of
food preparation. The story of "Typhoid Mary," a cook in early 20th
century New York who infected approximately 50 people (three fatally),
highlights the role of asymptomatic carriers in maintaining the cycle of
person-to-person spread [17]. For this reason, eradication of carriage when identified should be
attempted. This is discussed further separately. The S. typhi carrier state may
be an independent risk factor for carcinoma of the gallbladder as well as other
cancers [18,19].
MICROBIOLOGY — The organism classically responsible for the enteric fever
syndrome is S. enterica serotype Typhi (formerly S. typhi). Other Salmonellae
that can cause a similar clinical syndrome include but are not limited to [20]:
- Salmonella paratyphi A
- Salmonella paratyphi B
- Salmonella paratyphi C
- Salmonella choleraesuis
These organisms
are ingested and survive exposure to gastric acid before gaining access to the
small bowel, where they penetrate the epithelium, enter the lymphoid tissue,
and disseminate via the lymphatic or hematogenous route.
S. enterica
serotype Typhi causes disease only in humans; it has no known animal reservoir.
Infection therefore implies direct contact with an infected individual or
indirect contact via contaminated food or water.
Infection due
to Salmonella paratyphi species (also called S. enteritidis serotype paratyphi
in older reports) is less common than infection due to S. enterica serotype
Typhi. Regional variation in prevalence of S. paratyphi species has been
described: S. paratyphi B is more frequently cultured than S. paratyphi A; S.
paratyphi C is rarely isolated [21,22]. S. paratyphi species are generally thought to cause milder illnesses
than S. typhi, although it is not possible to predict the causative organism
based upon clinical findings [2]. Among 609 cases of bacteremic enteric fever in Nepal (409 with S.
typhi and 200 with S. paratyphi A), the clinical syndromes caused by these two
organisms were indistinguishable and of equal severity [23].
"Nontyphoidal"
Salmonellae may also cause severe illness consistent with enteric fever. In a
study of 809 patients suspected of having enteric fever in Nigeria, for
example, nontyphoidal Salmonellae (most commonly S. enteritidis and S.
typhimurium) were isolated in 7 percent of cases [21]. In Africa, bacteremia with nontyphoidal Salmonellae is often
associated with underlying HIV infection, which should be considered in such
patients.
CLINICAL FEATURES — Typhoid is a febrile illness with onset of symptoms 5 to 21
days after ingestion of the causative microorganism in contaminated food or
water. In general, lower inocula are associated with longer incubation times.
However, both the incubation period and inoculum needed to cause disease vary
depending upon host factors such as age, gastric acidity, and immunologic
status.
The majority of
patients with typhoid fever present with abdominal pain, fever, and chills.
Classic presentation — Classic reports described the characteristic stages of
typhoid fever in untreated individuals [24]. In the first week of illness, rising ("stepwise") fever and
bacteremia develop [25]. While chills are typical, frank rigors are rare [10]. Relative bradycardia or pulse-temperature dissociation may be
observed. In the second week of illness, abdominal pain develops and “rose
spots” (faint salmon-colored macules on the trunk and abdomen) may be seen.
During the third week of illness, hepatosplenomegaly, intestinal bleeding, and
perforation due to ileocecal lymphatic hyperplasia of the Peyer's patches may
occur, together with secondary bacteremia and peritonitis. Septic shock or an
altered level of consciousness may develop; among 300 cases of typhoid fever in
Indonesia, these findings were observed in approximately 15 percent of patients
[26]. In the absence of acute complications or death from overwhelming
sepsis, symptoms gradually resolve over weeks to months.
Effect of antimicrobial therapy — The clinical features of typhoid fever
in the United States have changed dramatically in the antibiotic era. When case
series from the 1930s were compared with series from the 1970s and 1980s, the
prevalence of splenomegaly fell from 63 to 10 percent, and the prevalence of
rose spots fell from 30 to 1.5 percent [27]. Intestinal bleeding was also less frequent.
In the
pre-antibiotic era, mortality rates were 15 percent or greater [24,28] and survivors experienced a prolonged illness lasting weeks, with
months of subsequent debilitation. Approximately 10 percent of untreated
patients relapsed, and up to 4 percent become chronic carriers of the organism.
In the
post-antibiotic era, the average mortality rate from typhoid fever is estimated
to be less than 1 percent [1], but this varies widely based upon site and resources, and may be 10-
to 20-fold higher in the most resource-limited settings. An epidemiological
survey of about 1100 cases in Spain (1997-2005) demonstrated a fatality rate of
0.9 percent [29]. A Centers for Disease Control and Prevention (CDC) compilation of 10
hospital-based typhoid fever series reported a mean case-fatality rate of 2
percent (range 0 to 14.8 percent), but noted that these series capture only the
most severe and hospitalized cases in those with access to care [30].
Other clinical manifestations — The symptoms, signs, and complications
of typhoid fever vary widely in different series and may be related to age, geographic
area, the causative organism, or the time at which patients seek medical care.
Gastrointestinal manifestations — Reports in the pre-antibiotic era
suggested that constipation occurred more frequently than diarrhea [24]. Subsequent reports suggest that these symptoms occur with
approximately equal frequency or that diarrhea may be more common, particularly
in young children and in adults with HIV infection [31,32]. Specifically, the incidence of diarrhea in children with culture
proven typhoid fever was 78 percent in a series from Australia [33] and 50 percent in a report from Vietnam [34]. Constipation occurs in approximately 30 percent of individuals [34,35], perhaps more frequently in adults. Among 552 patients with
culture-confirmed typhoid fever in Bangladesh, abdominal tenderness or
distension (57 percent) and rectal bleeding (9 percent) were equally
distributed across age groups .
Intestinal
perforation generally occurs more frequently among adults than children and is
associated with high mortality rates. Among 105 adults with typhoid fever in
India, this complication was observed in 10 percent of patients [37]. In the Bangladesh study, intestinal perforation was observed in three
percent of patients overall, but in 25 percent of patients over 31 years old [36]. An outbreak of typhoid fever in Uganda was detected specifically
because of a high incidence of intestinal perforation, seen in patients of all
ages [38]. Over an 18-month period, 249 cases with a median age of 16 years were
identified and 18 percent of them died.
Neurological manifestations — Although headache is a frequent
symptom reported in 44 to 94 percent of cases [34,35,38,39], other neurological manifestations including disordered sleep
patterns, acute psychosis, myelitis, and rigidity have been observed but are
uncommon [40], as are meningitis and focal central nervous infections with S. typhi
[41]. An outbreak of typhoid fever at the Malawi-Mozambique border was
notable for a relatively high incidence of associated neurological findings,
found in 40 of 303 cases (13 percent) [39]. These included signs of upper motor neuron disease (eg,
hyperreflexia, spasticity, sustained clonus), ataxia, and Parkinsonism.
Patients with
severe typhoid fever may develop “typhoid encephalopathy,” with altered
consciousness, delirium, and confusion. This has been observed in up to 17
percent of patients, with no clear frequency difference between children and
adults [36]. In one study of 38 patients in Indonesia with typhoid fever,
delirium, obtundation, and stupor were grave prognostic signs, with a mortality
rate as high as 55 percent [26]. In this study, intravenous dexamethasone was administered in a randomized placebo-controlled fashion as an
adjunctive to antibiotic therapy; a reduction in mortality from 55 to 10
percent was observed. In another series of 23 cases of typhoid encephalopathy
from Bangladesh, the mortality rate was 13 percent; in a retrospective analysis
of this series, survivors were more likely to have received IV dexamethasone [42].
Other extraintestinal manifestations — Other
protean symptoms have been reported to varying degrees. Cough is not rare and
has been observed in approximately 20 to 45 percent; arthralgias and myalgias
occur in about 20 percent [34,35,38,39]. Focal extraintestinal manifestations including involvement of the
hepatobiliary, cardiovascular, respiratory, genitourinary, musculoskeletal, and
central nervous systems have been described as a result of bacteremic seeding,
but are observed infrequently [43].
Laboratory abnormalities — Patients with typhoid fever frequently
have anemia and either leukopenia or leukocytosis; leukopenia with left shift
is typically seen in adults while leukocytosis is more common in children. If
observed in the third week of illness, leukocytosis should prompt suspicion for
intestinal perforation.
Abnormal liver
function tests are frequently observed [27,44]. In an outbreak in 34 patients, abnormal liver function tests were
observed in all but one patient [27]. In some patients, the clinical and laboratory picture may be
suggestive of acute viral hepatitis [45]. In one study comparing 27 patients with Salmonella hepatitis to 27
cases of viral hepatitis, Salmonella hepatitis was more frequently associated
with bradycardia (42 versus 4 percent) and fever >40ºC (44 versus 4
percent); serum aminotransferases also tended to be lower (peak serum ALT 296
versus 3234 IU/L). A potential diagnostic challenge in patients presenting with
abnormal liver function tests is that the two infections may be present at
once.
Cerebrospinal
fluid studies are usually normal or reveal a mild pleocytosis (<35 cells="" mm="" sup="">3
),
even in patients with neuropsychiatric symptoms [41].
Special populations
Children — Certain clinical manifestations associated with typhoid
fever occur with different frequency in children compared with adults; age
differences were specifically examined in a review of 552 culture-confirmed
cases in Bangladesh [36]. Pneumonia and febrile seizures were overall infrequent but occurred
more commonly in children, whereas intestinal perforation was not seen in
patients under five years old. Younger patients also tended to have higher WBC
counts; 14 of the 15 patients with a WBC count >20 x103/mm3 were
younger than five years old.
Even among
infants, there is variability in the severity of the disease. In a series from
Chile, febrile infants with typhoid fever had relatively mild illnesses not
requiring hospitalization [46], while a study from Bangladesh noted a fatality rate of 11 percent [36].
HIV-infected patients — The severity of enteric fever does not appear to be
markedly increased in the setting of HIV infection, although nontyphoidal
salmonellosis is known to be more complicated in HIV infection. However, there
is some evidence that immunocompromised patients fare poorly with typhoidal
infections. One study of four individuals with AIDS in Peru described
atypically severe diarrhea or colitis [31]. In a Tanzanian series of 104 cases of intestinal perforations due to
typhoid fever treated surgically at a university hospital, mortality was
associated with HIV-positivity and low CD4 count at admission, among other
factors [47]. Other case reports have documented unusual manifestations of S. typhi
infection such as arteritis [48] or chorioamnionitis [49] in HIV-infected patients.
Chronic carriers — In general, chronic carriers do not develop recurrent
symptomatic disease. They appear to reach an immunologic equilibrium in which
they are chronically colonized and may excrete large numbers of organisms, but
have a high level of immunity and do not develop clinical disease [12,50-52]. Chronic carriers frequently have high serum antibody titers against
the Vi antigen, which is a clinically useful test for rapid identification of
such patients [13,53].
DIAGNOSIS — The diagnosis of typhoid fever is made by culture of the
causative microorganism in the setting of a compatible clinical illness.
Typhoid fever should be considered in a patient living in, traveling from, or
visiting from an endemic area who presents with abdominal pain, fever, and
chills. In addition, autochthonous cases or outbreaks can occur due to
transmission via chronic carriers [54-56]. Serologic tests are of limited clinical utility. In resource-limited
settings, the diagnosis of typhoid fever is often based upon clinical
manifestations alone.
The
differential diagnosis is broad and includes malaria, amebiasis, dengue fever,
leishmaniasis, and other causes of bacterial gastroenteritis.
Culture — Blood cultures are positive in 40 to 80 percent of
patients, depending upon the series and culture techniques used. Blood cultures
may require several days of incubation. The diagnosis can also be made by
culture of stool, urine, rose spots, or duodenal contents (via string capsule)
[57]. Stool culture is positive in up to 30 to 40 percent of cases, but is
often negative by the time that systemic symptoms bring patients to medical
attention [46].
Bone marrow
culture is the most sensitive routinely available diagnostic tool [58]. This may be particularly important in complicated cases or when
antimicrobial therapy has already been initiated and the diagnosis remains
uncertain. Bone marrow cultures may be positive in as many as 50 percent of
patients after as many as five days of antibiotics [32]. In one series of 44 patients with typhoid fever, S. typhi was
isolated from 98 percent of bone marrow cultures compared with 70 percent of
blood cultures [59].
S. typhi
isolates should be screened for resistance to nalidixic acid, or have formal
sensitivity testing for the clinically used fluoroquinolones [60,61]. Organisms with nalidixic acid resistance should be anticipated to
have reduced susceptibility to fluoroquinolones, even if fluoroquinolone
sensitivity is reported by the laboratory.
Serology — Serologic tests such as the Widal test are of limited
clinical utility in endemic areas because positive results may represent
previous infection. The Widal test detects anti-S. typhi antibodies, and the
minimal titers defined as positive for the O (surface polysaccharide) antigens
and H (flagellar) antigens must be determined for individual geographic areas;
they are higher in developing regions than in the United States [62]. When paired acute and convalescent samples are studied, a fourfold or
greater increase is considered positive. Positive results have been reported in
46 to 94 percent of cases [63]. In a study of healthy blood donors performed in central India,
seropositivity for typhoid fever using the S. typhi O antigen or S. typhi H
antigen was observed in 8 and 14 percent, respectively [63].
Newer serologic
assays using enzyme-linked immunosorbent assay (ELISA) and dipstick techniques
perform somewhat better than the Widal test, but sensitivity and specificity
are not adequate for routine diagnostic use [64]. An ELISA for antibodies to the capsular polysaccharide Vi antigen is
useful for detection of carriers, but not for the diagnosis of acute illness [13,53].
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