Enteric (typhoid) fever is a systemic disease characterized by fever and abdominal pain and caused by dissemination of S. typhi or S. paratyphi. The disease was initially called typhoid fever because of its clinical similarity to typhus. 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. In 1869, given the anatomic site of infection, the term enteric fever was proposed as an alternative designation to distinguish typhoid fever from typhus. However, to this day, the two designations are used interchangeably.
In contrast to other Salmonella serotypes, the etiologic agents of enteric fever—S. typhi and S. paratyphi serotypes A, B, and C—have no known hosts other than humans. Most commonly, food-borne or waterborne transmission results from fecal contamination by ill or asymptomatic chronic carriers. Sexual transmission between male partners has been described. Health care workers occasionally acquire enteric fever after exposure to infected patients or during processing of clinical specimens and cultures.
With improvements in food handling and water/sewage treatment, enteric fever has become rare in developed nations. Worldwide, however, there are an estimated 27 million cases of enteric fever, with 200,000–600,000 deaths annually. The annual incidence is highest (>100 cases/100,000 population) in south-central and Southeast Asia; medium (10–100 cases/100,000) in the rest of Asia, Africa, Latin America, and Oceania (excluding Australia and New Zealand); and low in other parts of the world (Fig. 62-1). A high incidence of enteric fever correlates with poor sanitation and lack of access to clean drinking water. In endemic regions, enteric fever is more common in urban than rural areas and among young children and adolescents than among other age groups. Risk factors include contaminated water or ice, flooding, food and drinks purchased from street vendors, raw fruits and vegetables grown in fields fertilized with sewage, ill household contacts, lack of hand washing and toilet access, and evidence of prior Helicobacter pylori infection (an association probably related to chronically reduced gastric acidity). It is estimated that there is one case of paratyphoid fever for every four cases of typhoid fever, but the incidence of infection associated with S. paratyphi A appears to be increasing, especially in India; this increase may be a result of vaccination for S. typhi.
Annual incidence of typhoid fever per 100,000 population. (Adapted from JA Crump et al: The global burden of typhoid fever. Bull World Health Organ 82:346, 2004.)
Multidrug-resistant (MDR) strains of S. typhi emerged in the 1980s in China and Southeast Asia and have since disseminated widely. These strains contain plasmids encoding resistance to chloramphenicol, ampicillin, and trimethoprim—antibiotics long used to treat enteric fever. With the increased use of fluoroquinolones to treat MDR enteric fever in the 1990s, strains of S. typhi and S. paratyphi with decreased ciprofloxacin susceptibility (DCS; minimal inhibitory concentration [MIC], 0.125–0.5 μg/mL) or ciprofloxacin resistance (MIC, ≥1 μg/mL) have emerged on the Indian subcontinent, in southern Asia, and (most recently) in sub-Saharan Africa and have been associated with clinical treatment failure. Testing of isolates for resistance to the first-generation quinolone nalidixic acid detects many but not all strains with reduced susceptibility to ciprofloxacin and is no longer recommended. Strains of S. typhi and S. paratyphi producing extended-spectrum β-lactamases have emerged recently, primarily in India and Nepal.
Approximately 300 cases of typhoid and 150 cases of paratyphoid fever are reported annually in the United States. Of 1902 cases of S. typhi–associated enteric fever reported to the Centers for Disease Control and Prevention in 1999–2006, 79% were associated with recent international travel, most commonly to India (47%), Pakistan (10%), Bangladesh (10%), Mexico (7%), and the Philippines (4%). Only 5% of travelers diagnosed with enteric fever had received S. typhi vaccine. Overall, 13% of S. typhi isolates in the United States were resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole (TMP-SMX), and the proportion of DCS isolates increased from 19% in 1999 to 58% in 2006. Infection with DCS S. typhi was associated with travel to the Indian subcontinent. Of the 25–30% of reported cases of enteric fever in the United States that are domestically acquired, the majority are sporadic, but outbreaks linked to contaminated food products and previously unrecognized chronic carriers continue to occur.
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 >75% of cases, abdominal pain is reported in only 30–40%. Thus, a high index of suspicion for this potentially fatal systemic illness is necessary when a person presents with fever and a history of recent travel to a developing country.
The incubation period for S. typhi averages 10–14 days but ranges from 5 to 21 days, depending on the inoculum size and the host’s health and immune status. The most prominent symptom is prolonged fever (38.8°–40.5°C; 101.8°–104.9°F), which can continue for up to 4 weeks if untreated. S. paratyphi A is thought to cause milder disease than S. typhi, with predominantly gastrointestinal symptoms. However, a prospective study of 669 consecutive cases of enteric fever in Kathmandu, Nepal, found that the infections caused by these organisms were clinically indistinguishable. In this series, symptoms reported on initial medical evaluation included headache (80%), chills (35–45%), cough (30%), sweating (20–25%), myalgias (20%), malaise (10%), and arthralgia (2–4%). Gastrointestinal manifestations included anorexia (55%), abdominal pain (30–40%), nausea (18–24%), vomiting (18%), and diarrhea (22–28%) more commonly than constipation (13–16%). Physical findings included coated tongue (51–56%), splenomegaly (5–6%), and abdominal tenderness (4–5%).
Early physical findings of enteric fever include rash (“rose spots”; 30%), hepatosplenomegaly (3–6%), epistaxis, and relative bradycardia at the peak of high fever (<50%). Rose spots (Fig. 62-2; see also Fig. 14-9) make up a faint, salmon-colored, blanching, maculopapular rash located primarily on the trunk and chest. The rash is evident in ~30% of patients at the end of the first week and resolves without a trace after 2–5 days. Patients can have two or three crops of lesions, and Salmonella can be cultured from punch biopsies of these lesions. The faintness of the rash makes it difficult to detect in highly pigmented patients.
“Rose spots,” the rash of enteric fever due to Salmonella typhi or Salmonella paratyphi.
The development of severe disease (which occurs in ~10–15% of patients) depends on host factors (immunosuppression, antacid therapy, previous exposure, and vaccination), strain virulence and inoculum, and choice of antibiotic therapy. Gastrointestinal bleeding (10–20%) and intestinal perforation (1–3%) most commonly occur in the third and fourth weeks of illness and result from hyperplasia, ulceration, and necrosis of the ileocecal Peyer’s patches at the initial site of Salmonella infiltration (Fig. 62-3). Both complications are life-threatening and require immediate fluid resuscitation and surgical intervention, with broadened antibiotic coverage for polymicrobial peritonitis (Chap. 29) and treatment of gastrointestinal hemorrhages, including bowel resection. Neurologic manifestations occur in 2–40% of patients and include meningitis, Guillain-Barré syndrome, neuritis, and neuropsychiatric symptoms (described as “muttering delirium” or “coma vigil”), with picking at bedclothes or imaginary objects.
Typical ileal perforation associated with Salmonella typhi infection. (From JM Saxe, R Cropsey: Is operative management effective in treatment of perforated typhoid? Am J Surg 189:342, 2005.)
Rare complications whose incidences are reduced by prompt antibiotic treatment include disseminated intravascular coagulation, hematophagocytic syndrome, pancreatitis, hepatic and splenic abscesses and granulomas, endocarditis, pericarditis, myocarditis, orchitis, hepatitis, glomerulonephritis, pyelonephritis and hemolytic-uremic syndrome, severe pneumonia, arthritis, osteomyelitis, endophthalmitis, and parotitis. Up to 10% of patients develop mild relapse, usually within 2–3 weeks of fever resolution and in association with the same strain type and susceptibility profile.
Up to 10% of untreated patients with typhoid fever excrete S. typhi in the feces for up to 3 months, and 1–4% develop chronic asymptomatic carriage, shedding S. typhi in either urine or stool for >1 year. Chronic carriage is more common among women, infants, and persons who have biliary abnormalities or concurrent bladder infection with Schistosoma haematobium. The anatomic abnormalities associated with the latter conditions presumably allow prolonged colonization.
Because the clinical presentation of enteric fever is relatively nonspecific, the diagnosis needs to be considered in any febrile traveler returning from a developing region, especially the Indian subcontinent, the Philippines, or Latin America. Other diagnoses that should be considered in these travelers include malaria, hepatitis, bacterial enteritis, dengue fever, rickettsial infections, leptospirosis, amebic liver abscesses, and acute HIV infection (Chap. 6). Other than a positive culture, no specific laboratory test is diagnostic for enteric fever. In 15–25% of cases, leukopenia and neutropenia are detectable. Leukocytosis is more common among children, during the first 10 days of illness, and in cases complicated by intestinal perforation or secondary infection. Other nonspecific laboratory findings include moderately elevated values in liver function tests and muscle enzyme levels.
The definitive diagnosis of enteric fever requires the isolation of S. typhi or S. paratyphi from blood, bone marrow, other sterile sites, rose spots, stool, or intestinal secretions. The sensitivity of blood culture is only 40–80%, probably because of high rates of antibiotic use in endemic areas and the small number of S. typhi organisms (i.e., <15/mL) typically present in the blood. Because almost all S. typhi organisms in blood are associated with the mononuclear cell/platelet fraction, centrifugation of blood and culture of the buffy coat can substantially reduce the time to isolation of the organism but do not increase sensitivity.
Bone marrow culture is 55–90% sensitive, and, unlike that of blood culture, its yield is not reduced by up to 5 days of prior 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 is >90%. Stool cultures, although negative in 60–70% of cases during the first week, can become positive during the third week of infection in untreated patients.
Serologic tests, including the classic Widal test for “febrile agglutinins,” and rapid tests to detect antibodies to outer-membrane proteins or O:9 antigen are available for detection of S. typhi in developing countries but have lower positive predictive values than blood culture. More sensitive antigen and nucleic acid amplification tests have been developed to detect S. typhi and S. paratyphi in blood but are not yet commercially available and remain impractical in many areas where enteric fever is endemic.
TREATMENT Enteric (Typhoid) Fever
Prompt administration of appropriate antibiotic therapy prevents severe complications of enteric fever and results in a case-fatality rate of <1%. The initial choice of antibiotics depends on the susceptibility of the S. typhi and S. paratyphi strains in the area of residence or travel (Table 62-1). For treatment of drug-susceptible typhoid fever, fluoroquinolones are the most effective class of agents, with cure rates of ~98% and relapse and fecal carriage rates of <2%. Experience is most extensive with ciprofloxacin. Short-course ofloxacin therapy is similarly successful against infection caused by quinolone-susceptible strains. However, the increased incidence of DCS S. typhi in Asia, which is probably related to the widespread availability of fluoroquinolones over the counter, is now limiting the use of this drug class for empirical therapy. Patients infected with DCS S. typhi strains should be treated with ceftriaxone, azithromycin, or high-dose ciprofloxacin. A 7-day course of high-dose fluoroquinolone therapy for DCS enteric fever has been associated with delayed resolution of fever and high rates of fecal carriage during convalescence. Thus, for DCS strains, a 10- to 14-day course of high-dose ciprofloxacin is preferred.
Ceftriaxone, cefotaxime, and (oral) cefixime are effective for treatment of MDR enteric fever, including that caused by DCS and fluoroquinolone-resistant strains. These agents clear fever in ~1 week, with failure rates of ~5–10%, fecal carriage rates of <3%, and relapse rates of 3–6%. Oral azithromycin results in defervescence in 4–6 days, with rates of relapse and convalescent stool carriage of <3%. Against DCS strains, azithromycin is associated with lower rates of treatment failure and shorter durations of hospitalization than are fluoroquinolones. Despite efficient in vitro killing of Salmonella, first- and second-generation cephalosporins as well as aminoglycosides are ineffective in the treatment of clinical infections.
Most patients with uncomplicated enteric fever can be managed at home with oral antibiotics and antipyretics. Patients with persistent vomiting, diarrhea, and/or abdominal distension should be hospitalized and given supportive therapy as well as a parenteral third-generation cephalosporin or fluoroquinolone, depending on the susceptibility profile. Therapy should be administered for at least 10 days or for 5 days after fever resolution.
In a randomized, prospective, double-blind study of critically ill patients with enteric fever (i.e., those with shock and obtundation) in Indonesia in the early 1980s, the administration of dexamethasone (an initial dose of 3 mg/kg followed by eight doses of 1 mg/kg every 6 h) with chloramphenicol was associated with a substantially lower mortality rate than was treatment with chloramphenicol alone (10% vs 55%). Although this study has not been repeated in the “post-chloramphenicol era,” severe enteric fever remains one of the few indications for glucocorticoid treatment of an acute bacterial infection.
The 1–5% of patients who develop chronic carriage of Salmonella can be treated for 4–6 weeks with an appropriate oral antibiotic. Treatment with oral amoxicillin, TMP-SMX, ciprofloxacin, or norfloxacin is ~80% effective in eradicating chronic carriage of susceptible organisms. However, in cases of anatomic abnormality (e.g., biliary or kidney stones), eradication often requires both antibiotic therapy and surgical correction.
TABLE 62-1ANTIBIOTIC THERAPY FOR ENTERIC FEVER IN ADULTS ||Download (.pdf) TABLE 62-1 ANTIBIOTIC THERAPY FOR ENTERIC FEVER IN ADULTS
|INDICATION ||AGENT ||DOSAGE (ROUTE) ||DURATION, DAYS |
|Empirical Treatment |
| ||Ceftriaxonea ||2 g/d (IV) ||10–14 |
| ||Azithromycinb ||1 g/d (PO) ||5 |
|Fully Susceptible |
|Optimal treatment ||Ciprofloxacinc ||500 mg bid (PO) or 400 mg q12h (IV) ||5–7 |
| ||Azithromycin ||1 g/d (PO) ||5 |
|Alternative treatment ||Amoxicillin ||1 g tid (PO) or 2 g q6h (IV) ||14 |
| ||Chloramphenicol ||25 mg/kg tid (PO or IV) ||14–21 |
| ||Trimethoprim-sulfamethoxazole ||160/800 mg bid (PO) ||7–14 |
|Optimal treatment ||Ceftriaxonea ||2 g/d (IV) ||10–14 |
| ||Azithromycin ||1 g/d (PO) ||5 |
|Alternative treatment ||Ciprofloxacin ||500 mg bid (PO) or 400 mg q12h (IV) ||5–14 |
|Optimal treatment ||Ceftriaxone ||2 g/d (IV) ||10–14 |
| ||Azithromycin ||1 g/d (PO) ||5 |
|Alternative treatment ||High-dose ciprofloxacin ||750 mg bid (PO) or 400 mg q8h (IV) ||10–14 |
Theoretically, it is possible to eliminate the salmonellae that cause enteric fever because they survive only in human hosts and are spread by contaminated food and water. However, given the high prevalence of the disease in developing countries that lack adequate sewage disposal and water treatment, this goal is currently unrealistic. Thus, travelers to developing countries should be advised to monitor their food and water intake carefully and to strongly consider immunization against S. typhi.
Two typhoid vaccines are commercially available: (1) Ty21a, an oral live attenuated S. typhi vaccine (given on days 1, 3, 5, and 7, with a booster every 5 years); and (2) Vi CPS, a parenteral vaccine consisting of purified Vi polysaccharide from the bacterial capsule (given in a single dose, with a booster every 2 years). The old parenteral whole-cell typhoid/paratyphoid A and B vaccine is no longer licensed, largely because of significant side effects, especially fever. An acetone-killed whole-cell vaccine is available only for use by the U.S. military. The minimal age for vaccination is 6 years for Ty21a and 2 years for Vi CPS. In a recent meta-analysis of vaccines for preventing typhoid fever in populations in endemic areas, the cumulative efficacy was 48% for Ty21a at 2.5–3.5 years and 55% for Vi CPS at 3 years. Although data on typhoid vaccines in travelers are limited, some evidence suggests that efficacy rates may be substantially lower than those for local populations in endemic areas. Currently, there is no licensed vaccine for paratyphoid fever.
Vi CPS typhoid vaccine is poorly immunogenic in children <5 years of age because of T cell–independent properties. In the more recently developed Vi-rEPA vaccine, Vi is bound to a nontoxic recombinant protein that is identical to Pseudomonas aeruginosa exotoxin A. In 2- to 4-year-olds, two injections of Vi-rEPA induced higher T cell responses and higher levels of serum IgG antibody to Vi than did Vi CPS in 5- to 14-year-olds. In a two-dose trial in 2- to 5-year-old children in Vietnam, Vi-rEPA provided 91% efficacy at 27 months and 89% efficacy at 46 months and was very well tolerated. This vaccine is not yet commercially available in the United States. Efforts to improve the immunogenicity and reduce the number of doses of live attenuated oral vaccines are ongoing.
Typhoid vaccine is not required for international travel, but it is recommended for travelers to areas where there is a moderate to high risk of exposure to S. typhi, especially those who are traveling to southern Asia and other developing regions of Asia, Africa, the Caribbean, and Central and South America and who will be exposed to potentially contaminated food and drink. Typhoid vaccine should be considered even for persons planning <2 weeks of travel to high-risk areas. In addition, laboratory workers who deal with S. typhi and household contacts of known S. typhi carriers should be vaccinated. Because the protective efficacy of vaccine can be overcome by the high inocula that are commonly encountered in food-borne exposures, immunization is an adjunct and not a substitute for the avoidance of high-risk foods and beverages. Immunization is not recommended for adults residing in typhoid-endemic areas or for the management of persons who may have been exposed in a common-source outbreak.
Enteric fever is a notifiable disease in the United States. Individual health departments have their own guidelines for allowing ill or colonized food handlers or health care workers to return to their jobs. The reporting system enables public health departments to identify potential source patients and to treat chronic carriers in order to prevent further outbreaks. In addition, because 1–4% of patients with S. typhi infection become chronic carriers, it is important to monitor patients (especially child-care providers and food handlers) for chronic carriage and to treat this condition if indicated.