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Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis

Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis
Literature review current through: Jan 2024.
This topic last updated: May 08, 2023.

INTRODUCTION — Enteric fever is characterized by severe systemic illness with fever and abdominal pain [1]. The organism classically responsible for the enteric fever syndrome is Salmonella enterica serotype Typhi (formerly S. typhi). Other Salmonella serotypes, particularly S. enterica serotypes 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]. Humans are the only reservoir for S. Typhi and S. Paratyphi A. The term "enteric fever" is a collective term that refers to both typhoid and paratyphoid fever, and "typhoid" and "enteric fever" are often used interchangeably.

The epidemiology, microbiology, clinical manifestations, and diagnosis of enteric fever will be reviewed here. The pathogenesis, treatment and prevention of enteric fever are discussed separately. (See "Pathogenesis of enteric (typhoid and paratyphoid) fever" and "Enteric (typhoid and paratyphoid) fever: Treatment and prevention" and "Immunizations for travel".)

EPIDEMIOLOGY

Worldwide — Worldwide, enteric fever is most prevalent in impoverished areas that are overcrowded with poor access to sanitation.

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) [3-6]. As an example, in a prospective study performed in India between 2017 and 2020, weekly surveillance for acute febrile illness was performed among more than 24,000 children ages 6 months to 14 years in three urban sites and one rural site [7]. The risk of typhoid fever (confirmed by blood culture) was greater in urban areas; at the three urban sites, the incidence ranged from 576 to 1173 cases per 100,000 child-years; at the rural site, the incidence was 35 cases per 100,000 child-years. The risk was greater in larger households with fewer assets and without a sanitary toilet.

Other regions of Asia and Africa, some parts of 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. Contemporary population-based studies from Latin America, in particular, are lacking, and surveillance suggests that rates have declined substantially over the past 30 years, though intermittent outbreaks continue to occur [8]. Furthermore, subsequent data from Africa have revealed substantial heterogeneity between countries, with some Southern and Northern African countries having very low rates (<5 cases per 100,000 person-years) while several countries in Eastern and West Africa have rates >100 per 100,000 [9]. S. Paratyphi A remains uncommon in Africa [9], but accounts for a substantial proportion of enteric fever cases in areas of South Asia [10].

United States — Approximately 400 to 500 cases of enteric fever are reported in the United States each year, with S. Typhi causing approximately 80 percent of infections [11]. Over 80 percent of these cases occur among travelers to countries where enteric fever is endemic, particularly countries in South-Central Asia, but domestic acquisition still occurs [11,12]. In a study of 428 cases of enteric fever reported among travelers from resource-rich countries through the multinational GeoSentinel Surveillance Network between 2006 and 2011, 67 percent of cases were acquired in south-central Asia (34, 13, 7, and 6 percent of total from India, Nepal, Pakistan, and Bangladesh, respectively) (figure 1) [13]. Individuals visiting relatives in endemic countries accounted for 28 percent of the typhoid cases.

Risk factors — For individuals outside of endemic areas, a history of travel to settings in which sanitation is poor or contact with a known typhoid case or carrier is useful; however, a specific source or contact is identified in a minority of cases [14]. Among individuals residing in endemic areas, enteric fever is more common in children and young adults than in older patients [15].

Many travelers who develop enteric fever have not received appropriate vaccination. Among 580 cases of vaccine-preventable diseases among returned international travelers reported to the 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 [16]. 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. (See "Immunizations for travel", section on 'Typhoid vaccine'.)

Risk factors for the development of enteric fever due to S. Typhi or S. Paratyphi 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), while 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) [17].

Some data suggest that S. Paratyphi may be more likely to be transmitted by food, while S. Typhi may spread more via contaminated water supply [18].

S. Paratyphi appears to be an increasing cause of enteric fever among vaccinated travelers, as the Vi polysaccharide typhoid vaccine is ineffective against most S. Paratyphi [19,20], which lack the Vi antigen targeted by the vaccine. Vaccines for S. Typhi induce detectable immune responses to S. Paratyphi in vitro, but the clinical significance of this finding is unknown [21,22]. There are mixed field data concerning the protection of the oral Ty21a against S. Paratyphi infections [23,24].

Issues related to the epidemiology of drug resistance are discussed separately. (See "Enteric (typhoid and paratyphoid) fever: Treatment and prevention".)

MICROBIOLOGY — The organism classically responsible for the enteric fever syndrome is S. enterica serotype Typhi (formerly S. typhi). Other human-adapted S. enterica serotypes also known as typhoidal Salmonella that cause enteric fever include [25]:

Salmonella Paratyphi A

Salmonella Paratyphi B

Salmonella Paratyphi C

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. (See "Pathogenesis of enteric (typhoid and paratyphoid) fever".)

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 S. Paratyphi species (also called Salmonella 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 A is commonly identified as a cause of enteric fever in Asia [10], and like S. Typhi, it only causes disease in humans. 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 [26].

"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 Salmonella typhimurium) were isolated in 7 percent of cases [27]. In Africa, bacteremia with nontyphoidal Salmonellae is often associated with underlying human immunodeficiency virus (HIV) infection, which should be considered in such patients. Mortality is generally higher from nontyphoidal Salmonella bacteremia, antimicrobial resistance patterns differ, and these infections should generally be considered distinct from typhoid. (See "Nontyphoidal Salmonella bacteremia and extraintestinal infection", section on 'Epidemiology'.)

CLINICAL FEATURES — Enteric fever 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. (See "Pathogenesis of enteric (typhoid and paratyphoid) fever", section on 'Infectious dose'.)

The majority of patients with enteric fever present with abdominal pain, fever, and chills.

Classic presentation — Classic reports described the characteristic stages of enteric fever in untreated individuals [28]. In the first week of illness, rising ("stepwise") fever and bacteremia develop [29]. While chills are typical, frank rigors are rare [19]. 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 (picture 1). 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 [30]. In the absence of acute complications or death from overwhelming sepsis, symptoms gradually resolve over weeks to months.

The clinical features of enteric fever have changed dramatically in the antibiotic era. When case series from the United States in 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 [31]. Intestinal bleeding was also less frequent.

The impact of antimicrobial therapy on mortality is discussed elsewhere. (See "Enteric (typhoid and paratyphoid) fever: Treatment and prevention", section on 'Outcomes'.)

Other clinical manifestations — The symptoms, signs, and complications of enteric 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 [28]. 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 [32,33]. Specifically, the incidence of diarrhea in children with culture proven typhoid fever was 78 percent in a series from Australia [34] and 50 percent in a report from Vietnam [35]. Constipation occurs in approximately 30 percent of individuals [35,36], 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 [37]. (See "Pathogenesis of enteric (typhoid and paratyphoid) fever", section on 'Gastrointestinal infection'.)

Intestinal perforation generally occurs more frequently among adults than children and is associated with high mortality rates. Although this complication was observed in 10 percent of 105 adults with enteric fever in a study from India [38], this high rate from a hospital-based study is likely not representative of the general natural history of typhoid. An outbreak of typhoid fever in Uganda was detected specifically because of a high incidence of intestinal perforation, seen in patients of all ages [39]. Over an 18-month period, 249 patients with perforation were identified; the median age was 16 years, and 18 percent died. In a systematic review of studies published over 20 years, the estimated case fatality rate among over 4600 typhoid patients hospitalized with intestinal perforation was approximately 15 percent, although regional differences were noted [40].

Typhoid intestinal perforation usually occurs in the ileum during the third week of febrile illness and is due to necrosis of the Peyer's patches in the antimesenteric bowel wall [41]. Affected patients present with increasing abdominal pain, distension, peritonitis, and sometimes secondary bacteremia with enteric aerobic and anaerobic microorganisms.

Neurologic manifestations — Although headache is a frequent symptom reported in 44 to 94 percent of cases [35,36,39,42,43], other neurological manifestations including disordered sleep patterns, acute psychosis, myelitis, and rigidity have been observed but are uncommon [44], as are meningitis and focal central nervous infections with S. Typhi [45]. An outbreak of typhoid fever at the Malawi-Mozambique border was notable for a relatively high incidence of associated neurologic findings, found in 40 of 303 cases (13 percent) [42]. These included signs of upper motor neuron disease (eg, hyperreflexia, spasticity, sustained clonus), ataxia, and Parkinsonism.

Patients with severe enteric 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 [37]. 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 [30]. 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 intravenous dexamethasone [46]. (See "Enteric (typhoid and paratyphoid) fever: Treatment and prevention".)

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 [35,36,39,42,43]. 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 [47].

Laboratory abnormalities — Patients with enteric 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 of intestinal perforation.

Abnormal liver function tests are frequently observed [31,48]. In an outbreak in 34 patients, abnormal liver function tests were observed in all but one patient [31]. In some patients, the clinical and laboratory picture may be suggestive of acute viral hepatitis [49]. 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 international units/L). A potential diagnostic challenge in patients presenting with abnormal liver function tests is that the two infections may be present at once.

Although nonspecific, serum C-reactive protein (CRP) is often elevated in patients with enteric fever [50].

Cerebrospinal fluid studies are usually normal or reveal a mild pleocytosis (<35 cells/mm3), even in patients with neuropsychiatric symptoms [45].

Special populations

Children — Certain clinical manifestations associated with enteric fever occur with different frequency in children compared with adults [51]; age differences were specifically examined in a review of 552 culture-confirmed cases in Bangladesh [37]. 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 white blood cell (WBC) counts; 14 of the 15 patients with a WBC count >20 x103/mm3 were younger than five years old. In a systematic review, higher case fatality rates were reported among children under five years of age compared with older children and adolescents [52].

Even among infants, there is variability in the severity of the disease. In a series from Chile, febrile infants with enteric fever had relatively mild illnesses not requiring hospitalization [53], while a study from Bangladesh noted a fatality rate of 11 percent [37].

Patients with HIV infection — The severity of enteric fever does not appear to be markedly increased in the setting of HIV infection, in contrast to nontyphoidal salmonellosis, in which higher complication rates are seen with HIV coinfection. However, there is some evidence that immunocompromised patients fare poorly with typhoidal infections. One study of four individuals with acquired immunodeficiency syndrome (AIDS) in Peru described atypically severe diarrhea or colitis [32]. In a Tanzanian series of 104 cases of intestinal perforations due to enteric fever treated surgically at a university hospital, mortality was associated with HIV-positivity and low CD4 count at admission, among other factors [54]. Other case reports have documented unusual manifestations of S. Typhi infection such as arteritis [55] or chorioamnionitis [56] in patients with HIV.

Chronic carriers — 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 [1,57,58]. Chronic carriage occurs more frequently in females and in patients with cholelithiasis or other biliary tract abnormalities [59,60]. Chronic carriage in the urine is rare and almost always associated with an abnormality in the urinary tract (eg, urolithiasis, prostatic hyperplasia) or concurrent bladder infection with Schistosoma [61].

Chronic carriers appear to reach an immunologic equilibrium in which they are chronically colonized (usually in the biliary tract) and may excrete large numbers of organisms but do not develop clinical disease [57,62-64]. Chronic carriers frequently have high serum antibody titers against the Vi antigen; however, the evidence for the utility of this test for identifying carriers is mixed [58,65,66]. (See "Pathogenesis of enteric (typhoid and paratyphoid) fever", section on 'Chronic carriage'.)

Asymptomatic chronic carriers are asymptomatic 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 [67], especially in areas of lower transmission. For this reason, eradication of carriage when identified should be attempted. This is discussed further separately. (See "Enteric (typhoid and paratyphoid) fever: Treatment and prevention", section on 'Post-acute shedding and chronic carriage'.)

The S. Typhi carrier state may be an independent risk factor for carcinoma of the gallbladder as well as other cancers [68,69]. (See "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis".)

DIAGNOSIS

Clinical approach — The possibility of enteric fever should be considered in a febrile patient living in, traveling from, or visiting from an endemic area. Duration of fever for more than three days or accompanying gastrointestinal symptoms (abdominal pain, diarrhea, or constipation) should heighten the suspicion.

When enteric fever is suspected, blood and stool culture should be performed. A high volume of blood sampled (eg, two to three 20 mL blood cultures in adults [70]) optimizes the yield of blood cultures. Other specimens can be cultured, including bone marrow, which yields the most sensitive culture but is invasive and usually not warranted. Evaluation of suspected enteric fever also includes consideration of other potential causes of fever, in particular malaria, amebiasis, rickettsial infections, leptospirosis, dengue fever, and other causes of bacteremia (including typhoidal tularemia) or bacterial gastroenteritis. The differential diagnosis is broad; less common causes include leishmaniasis, Q fever, and melioidosis. (See "Evaluation of fever in the returning traveler".)

The diagnosis of enteric fever is made by isolating S. Typhi or Paratyphi from a culture specimen in the setting of a compatible clinical illness. However, culture of most specimens is not highly sensitive, and other diagnostic tests (such as culture-independent methods and serology) are of limited clinical utility. Furthermore, even positive cultures usually require several days to incubate.

Thus, when cultures are negative or not available, as in some resource-limited settings, the diagnosis of enteric fever is often made presumptively on the basis of a protracted febrile illness without other explanation. Empiric therapy is often appropriate in the absence of an alternative diagnosis because of the risk for severe sequelae with untreated enteric fever; nevertheless, it is important to recognize that the clinical syndrome of enteric fever is nonspecific, and the positive predictive value of a clinical diagnosis even in high-burden settings is typically less than 50 percent.

Diagnostic tools

Culture and susceptibility testing — Blood cultures are positive in 50 to 70 percent of patients with typhoid, depending upon the series and culture techniques used [71]. 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) [72]. 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 [53]. Polymerase chain reaction-based diagnostics have had limited sensitivity in most studies given the low concentration of bacteria during bacteremia [73].

Bone marrow culture is the most sensitive diagnostic modality but is rarely indicated in routine clinical practice [74]. It may be reserved for complicated cases, including suspected treatment nonresponse due to antimicrobial resistance. Bone marrow cultures are positive in >90 percent of patients and may remain positive in as many as 50 percent of patients after as many as five days of antibiotics [33]. In a systematic review of 10 studies in which 635 individuals were tested by both blood and bone marrow cultures, the sensitivity of blood culture was 66 percent when bone marrow culture results were used as the reference [71].

S. Typhi isolates should be screened for sensitivity to clinically used fluoroquinolones [75,76], third-generation cephalosporins, ampicillin, trimethoprim-sulfamethoxazole, and azithromycin; the majority of isolates from areas of South Asia are fluoroquinolone nonsusceptible. An outbreak of extensively drug-resistant (XDR) S. Typhi, resistant to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, fluoroquinolones, and third-generation cephalosporins, was recognized in November 2016 in Pakistan and is ongoing [77]. (See "Enteric (typhoid and paratyphoid) fever: Treatment and prevention", section on 'Fluoroquinolone resistance'.)

Limitations of serology

Widal test − The Widal test detects anti-S. Typhi antibodies; this assay is of limited clinical utility in endemic areas because positive results may represent previous infection. The minimum 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 [78]. 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 [79]. 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 [79]. In many other settings, specificity of Widal testing has been lower [80,81].

Rapid antibody-based tests − Rapid antibody-based diagnostic tests have only moderate diagnostic accuracy in field testing [82-84]. A 2017 Cochrane review and meta-analysis concluded that rapid diagnostic tests are not sufficiently accurate to replace blood culture [84]. Tubex, which measures immunoglobulin (Ig)M antibodies to S. Typhi lipopolysaccharide, had sensitivity and specificity of 78 and 87 percent, respectively. Typhidot, which measures IgM or IgG responses to an outer membrane protein, had overall average sensitivity and specificity of 84 and 79 percent, respectively.

Newer approaches are in development; antibody tests to detect serum IgA against hemolysin E are promising [85,86].

Enzyme-linked immunosorbent assay − An enzyme-linked immunosorbent assay for antibodies to the capsular polysaccharide Vi antigen may be useful for detection of carriers in high-risk populations [58] but has had limited success in identifying carriers in community-based screens due to high-background prevalence of Vi-antibody levels in endemic populations [66,87]. Anti-Vi antibodies are not useful for the diagnosis of acute illness [58,65].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute diarrhea in adults" and "Society guideline links: Acute diarrhea in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Enteric (typhoid and paratyphoid) fever (The Basics)")

SUMMARY

General principles – Enteric fever is an invasive bacterial infection acquired through consumption of contaminated food or water. The organisms classically responsible for the enteric fever syndrome are Salmonella enterica serotypes Typhi (formerly S. typhi) and Paratyphi A, B, and C. Humans are the only reservoir for S. Typhi and S. Paratyphi A. (See 'Introduction' above.)

Epidemiology – In endemic settings, enteric fever is more common in children and young adults than in older patients. Humans are the only reservoir for S. enterica serotype Typhi. In resource-rich settings, most cases of enteric fever occur in patients who have traveled to endemic regions, particularly south-central Asia. A history of travel to settings in which sanitation is poor or history of contact with a known typhoid case or carrier is useful for identifying patients at risk of infection, although a specific contact is identified in a minority of cases. (See 'Epidemiology' above.)

Clinical features

Classic presentation – Enteric fever usually presents with abdominal pain, fever, and chills approximately 5 to 21 days after ingestion of the causative microorganism. Classic manifestations include relative bradycardia, pulse-temperature dissociation, and "rose spots" (faint salmon-colored macules on the trunk and abdomen). Hepatosplenomegaly, intestinal bleeding, and perforation may occur, leading to secondary bacteremia and peritonitis. Laboratory findings may include anemia, leukopenia, leukocytosis, and abnormal liver function tests. (See 'Classic presentation' above.)

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. Chronic carriage occurs more frequently in females and in patients with cholelithiasis or other biliary tract abnormalities. Chronic carriers represent an infectious risk to others, particularly in the setting of food preparation. (See 'Chronic carriers' above.)

Diagnosis – Enteric fever should be suspected in a febrile patient living in, traveling from, or visiting from an endemic area, particularly if the duration of fever is more than three days or if the patient also has gastrointestinal symptoms. The diagnosis of enteric fever is made by culture of the causative microorganism in the setting of a compatible clinical illness. The organism can be cultured from blood, stool, urine, rose spots, duodenal contents, or bone marrow, but most cultures are not highly sensitive. In many cases, the diagnosis of enteric fever is made presumptively in patients with protracted fever without alternative explanation. (See 'Diagnosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Elizabeth L Hohmann, MD, and Edward T Ryan, MD, DTMH, who contributed to earlier versions of this topic review.

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