Enteric fever, or typhoid fever, is a severe systemic disease that is classically caused by Salmonella ser.Typhi (Salmonella typhi) and is found mainly in developing countries, but it is encountered worldwidebecause of international travel.181.2Enteric FeverEtiology.Enteric fever, or typhoid fever, is caused by S. ser Typhi, S. ser. Paratyphi A, S. ser. Paratyphi B(Schottmuelleri), and S. ser. Paratyphi C (Hirschfeldii). Rarely, other Salmonella serotypes cancause a similar prolonged febrile illness. Typhoid fever is a systemic disease characterized by fever and abdominal pain and caused bydissemination of S. Typhi or S. Paratyphi. The disease was initially called typhoid fever because of itsclinical similarity to typhus. However, in the early 1800s, typhoid fever was clearly defined pathologicallyas a unique illness on the basis of its association with enlarged Peyers patches and mesenteric lymphnodes. In 1869, given the anatomic site of infection, the term enteric fever was proposed as analternative designation to distinguish typhoid fever from typhusEpidemiology.The incidence, mode of transmission, and consequences of enteric fever differ significantly indeveloped and developing countries. The incidence has decreased markedly in developedcountries. In developing countries, S. ser. Typhi is often the most common Salmonella isolate,with an incidence that can reach 500 cases/ 100,000 population (0.5%) and a high mortality rate.The World Health Organization has estimated that at least 12.5 million cases occur annuallyworldwide.Because humans are the only natural reservoir of S. ser. Typhi, direct or indirect contact with aninfected person (sick or chronic carrier) is necessary for infection. Ingestion of foods or watercontaminated with human feces is the most common mode of transmission. Water-borneoutbreaks due to poor sanitation and direct fecal-oral spread due to poor personal hygiene areencountered, mainly in developing countries. Oysters and other shellfish cultivated in watercontaminated by sewage are also a source of widespread infection. Congenital transmission ofenteric fever can occur by transplacental infection from a bacteremic mother to her fetus.Intrapartum transmission is also possible, occurring by a fecal-oral route from a carrier mother.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.Pathogenesis.In younger children, the morphologic changes of S. ser. Typhi infection are less prominent thanin older children and adults. Hyperplasia of Peyer patches with necrosis and sloughing ofoverlying epithelium produces ulcers that may bleed. The mucosa and lymphatic tissue of theintestinal tract are severely inflamed and necrotic. Ulcers heal without scarring. Strictures andintestinal obstruction virtually never occur after typhoid fever. The inflammatory lesion mayoccasionally penetrate the muscularis and serosa of the intestine and produce perforation. The
mesenteric lymph nodes, liver, and spleen are hyperemic and generally reveal areas of focalnecrosis. Hyperplasia of reticuloendothelial tissue with proliferation of mononuclear cells is thepredominant finding. A mononuclear response may be seen in the bone marrow in associationwith areas of focal necrosis. Inflammation of the gallbladder is focal, inconstant, and modest inproportion to the extent of local bacterial multiplication. Bronchitis is common. Inflammationalso may be observed in the form of localized abscesses, pneumonia, septic arthritis,osteomyelitis, pyelonephritis, endophthalmitis, and meningitis.The inoculum size required to cause enteric fever in volunteers is 105–109 S. ser. Typhiorganisms. These estimates may be higher than in naturally acquired infection because thevolunteers ingested the organisms in milk; stomach acidity is an important determinant ofsusceptibility to Salmonella. The bacteria invade through the Peyer patches. Organisms aretransported to intestinal lymph nodes, where multiplication takes place within the mononuclearcells. Monocytes, unable to destroy the bacilli early in the disease process, carry these organismsinto the mesenteric lymph nodes. Organisms then reach the bloodstream through the thoracicduct, causing a transient bacteremia. Circulating organisms reach the reticuloendothelial cells inthe liver, spleen, and bone marrow and may seed other organs. After proliferation in thereticuloendothelial system, bacteremia recurs. The gallbladder is particularly susceptible to beinginfected. Local multiplication in the walls of the gallbladder produces large numbers ofsalmonellae, which reach the intestine through the bile.Several virulence factors seem to be important. Invasion of Peyer patches is encoded by genesclosely related to the invasion genes of Shigella and enteroinvasive E. coli. However, S. ser.Typhi possesses a number of additional genes not found in Shigella that are responsible for thefeatures of typhoid fever. The surface Vi capsular antigen found in S. ser. Typhi interferes withphagocytosis by preventing the binding of C3 to the surface of the bacterium. The ability oforganisms to survive within macrophages after phagocytosis is an important virulence traitencoded by the phoP regulon; it may be related to metabolic effects on host cells. Circulatingendotoxin, a lipopolysaccharide component of the bacterial cell wall, is thought to cause theprolonged fever and toxic symptoms of enteric fever, although its levels in symptomatic patientsare low. Alternatively, endotoxin-induced cytokine production by human macrophages maycause the systemic symptoms. The occasional occurrence of diarrhea may be explained bypresence of a toxin related to cholera toxin and E. coli heat-labile enterotoxin.Cell-mediated immunity is important in protecting the human host against typhoid fever.Decreased numbers of T lymphocytes are found in patients who are critically ill with typhoidfever. Carriers show impaired cellular reactivity to S. ser. Typhi antigens in the leukocytemigration inhibition test. In carriers, a large number of virulent bacilli pass into the intestinedaily and are excreted in the stool, without entering the epithelium of the host.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 inonly 30–40%. Thus, a high index of suspicion for this potentially fatal systemic illness is necessary when aperson 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 3 to 21 days, with the durationlikely reflecting the inoculum size and the hosts health and immune status. The most prominentsymptom is prolonged fever (38.8°–40.5°C; 101.8°–104.9°F), which can continue for up to 4 weeks ifuntreated. S. Paratyphi A is thought to cause milder disease than S. Typhi, with predominantlygastrointestinal symptoms. However, a prospective study of 669 consecutive cases of enteric fever inKathmandu, Nepal, found that the infections were clinically indistinguishable. In this series, symptomsreported on initial medical evaluation included headache (80%), chills (35–45%), cough (30%), sweating(20–25%), myalgias (20%), malaise (10%), and arthralgia (2–4%). Gastrointestinal symptoms includedanorexia (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"), hepatosplenomegaly (3–6%),epistaxis, and relative bradycardia at the peak of high fever. Rose spots (Fig. 146-2) make up a faint,salmon-colored, blanching, maculopapular rash located primarily on the trunk and chest. The rash isevident 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 ofthese lesions. The faintness of the rash makes it difficult to detect in highly pigmented patients.The development of severe disease (which occurs in ~10–15% of patients) depends on hostfactors (immunosuppression, antacid therapy, previous exposure, and vaccination), strainvirulence 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 illnessand result from hyperplasia, ulceration, and necrosis of the ileocecal Peyers patches at the initialsite of Salmonella infiltration. Both complications are life-threatening and require immediatefluid resuscitation and surgical intervention, with broadened antibiotic coverage forpolymicrobial peritonitis (Chap. 121) and treatment of gastrointestinal hemorrhages, includingbowel resection. Neurologic manifestations occur in 2–40% of patients and include meningitis,Guillain-Barré syndrome, neuritis, and neuropsychiatric symptoms (described as "mutteringdelirium" or "coma vigil"), with picking at bedclothes or imaginary objects.Rare complications whose incidences are reduced by prompt antibiotic treatment includedisseminated intravascular coagulation, hematophagocytic syndrome, pancreatitis, hepatic andsplenic abscesses and granulomas, endocarditis, pericarditis, myocarditis, orchitis, hepatitis,glomerulonephritis, pyelonephritis and hemolytic uremic syndrome, severe pneumonia, arthritis,osteomyelitis, and parotitis. Up to 10% of patients develop mild relapse, usually within 2–3weeks 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 3months, and 1–4% develop chronic asymptomatic carriage, shedding S. Typhi in either urine orstool for >1 year. Chronic carriage is more common among women, infants, and persons withbiliary abnormalities or concurrent bladder infection with Schistosoma haematobium. The
anatomic abnormalities associated with the latter conditions presumably allow prolongedcolonization.Clinical Manifestations.The incubation period is usually 7–14 days, but it may range from 3–30 days, depending mainlyon the size of the ingested inoculum. The clinical manifestations of enteric fever depend on age.SCHOOL-AGED CHILDREN AND ADOLESCENTS.The onset of symptoms is insidious. Initial symptoms of fever, malaise, anorexia, myalgia,headache, and abdominal pain develop over 2–3 days. Although diarrhea having a pea soupconsistency may be present during the early course of the disease, constipation later becomes amore prominent symptom. Cough and epistaxis may ensue. Severe lethargy may develop insome children. Temperature, which increases in a stepwise fashion, becomes an unremitting andhigh fever within 1 wk, often reaching 40°C.During the 2nd week of illness, high fever is sustained, and fatigue, anorexia, cough, andabdominal symptoms increase in severity. Patients appear acutely ill, disoriented, and lethargic.Delirium and stupor may be observed. Physical findings include a relative bradycardia, which isdisproportionate to the high fever. Hepatomegaly, splenomegaly, and distended abdomen withdiffuse tenderness are very common. In about 50% of patients with enteric fever, a macular ormaculopapular rash (rose spots) appears on about the 7th–10th day. Lesions are usually discrete,erythematous, and 1–5 mm in diameter; the lesions are slightly raised and blanch on pressure.They appear in crops of 10–15 lesions on the lower chest and abdomen and last 2–3 days. Theyleave a slight brownish discoloration of the skin on healing. Cultures of the lesions have a 60%yield for Salmonella organisms. Rhonchi and scattered rales may be heard on auscultation of thechest. Nausea and vomiting if occurring in the 2nd or 3rd week suggest a complication. If nocomplications occur, the symptoms and physical findings gradually resolve within 2–4 wk, butmalaise and lethargy may persist for an additional 1–2 mo. Patients may be emaciated by the endof the illness. Enteric fever caused by nontyphoidal Salmonella is usually milder, with a shorterduration of fever and a lower rate of complications.INFANTS AND YOUNG CHILDREN (<5 YR).Enteric fever is relatively rare in this age group in endemic areas. Although clinical sepsis canoccur, the disease is surprisingly mild at presentation, making the diagnosis difficult. Mild feverand malaise, misinterpreted as a viral syndrome, occur in infants with culture-proven typhoidfever. Diarrhea is more common in young children with typhoid fever than in adults, leading to adiagnosis of acute gastroenteritis.NEONATES.In addition to its ability to cause abortion and premature delivery, enteric fever during latepregnancy may be transmitted vertically. The neonatal disease usually begins within 3 days ofdelivery. Vomiting, diarrhea, and abdominal distention are common. Temperature is variable but
may be as high as 40.5°C. Seizures may occur. Hepatomegaly, jaundice, anorexia, and weightloss can be marked.Complications.Severe intestinal hemorrhage and intestinal perforation occur in 1–10% and 0.5–3% of thepatients, respectively. These and most other complications usually occur after the 1st week of thedisease. Hemorrhage, which usually precedes perforation, is manifested by a decrease intemperature and blood pressure and an increase in the pulse rate. Perforations, which are usuallypinpoint size but may be as large as several centimeters, typically occur in the distal ileum andare accompanied by a marked increase in abdominal pain, tenderness, vomiting, and signs ofperitonitis. Sepsis with various enteric aerobic gram-negative bacilli and anaerobes may develop.Although disturbed liver function test results are found for many patients with enteric fever,overt hepatitis and cholecystitis are considered complications. An increase in serum amylaselevels may sometimes accompany clinically obvious pancreatitis.Pneumonia caused by superinfection with organisms other than Salmonella is more common inchildren than in adults. In children, pneumonia or bronchitis is common (approximately 10%).Toxic myocarditis with fatty infiltration and necrosis of the myocardium may be manifested byarrhythmias, sinoatrial block, ST-T changes on the electrocardiogram, or cardiogenic shock.Thrombosis and phlebitis occur rarely. Neurologic complications include increased intracranialpressure, cerebral thrombosis, acute cerebellar ataxia, chorea, aphasia, deafness, psychosis, andtransverse myelitis. Peripheral and optic neuritis have been reported. Permanent sequelae arerare. Other reported complications include fatal bone marrow necrosis, pyelonephritis, nephroticsyndrome, meningitis, endocarditis, parotitis, orchitis, and suppurative lymphadenitis. Althoughosteomyelitis and suppurative arthritis can occur in a normal host, they are more common inchildren with hemoglobinopathies.Diagnosis.Culturing the Salmonella strain involved is usually the basis for confirming the diagnosis.Results of blood cultures are positive in 40–60% of the patients seen early in the course of thedisease, and stool and urine cultures become positive after the 1st week. The stool culture resultis also occasionally positive during the incubation period. Because of the intermittent and low-level bacteremia, repeated blood cultures should be obtained in suspect cases. Cultures of bonemarrow often yield positive results during later stages of the disease, when blood cultures may besterile; although seldom obtained, cultures of mesenteric lymph nodes, liver, and spleen may alsohave positive results at this point. A culture of bone marrow is the single most sensitive methodof diagnosis (positive in 85–90%) and is less influenced by prior antimicrobial therapy. Stool andsometimes urine cultures are positive in chronic carriers. In suspected cases with negative resultsof stool cultures, a culture of aspirated duodenal fluid or of a duodenal string capsule may behelpful in confirming infection. However, the duodenal string culture test cannot be performedon those too young or too ill to cooperate.Direct detection of S. ser. Typhi-specific antigens in the serum or S. ser. Typhi Vi antigen in theurine has been attempted by immunologic methods, often using monoclonal antibodies.Polymerase chain reaction has been used to amplify specific genes of S. ser. Typhi in the blood
of patients, enabling diagnosis within a few hours. This method is specific and more sensitivethan blood cultures, given the low level of bacteremia in enteric fever. Serology is of little helpin establishing the diagnosis, but it may be useful in epidemiologic studies. The classic Widaltest measures antibodies against O and H antigens of S. ser. Typhi. Because many false-positiveand false-negative results occur, diagnosis of typhoid fever by Widal test alone is prone to error.A normochromic, normocytic anemia often develops after several weeks of illness and is relatedto intestinal blood loss or bone marrow suppression. Blood leukocyte counts are frequently lowin relation to the fever and toxicity, but there is a wide range in counts; leukopenia, usually notless than 2,500 cells/mm3, is often found after the 1st or 2nd week of illness. When pyogenicabscesses develop, leukocytosis may reach 20,000–25,000/mm3. Thrombocytopenia may bestriking and persist for as long as 1 wk. Liver function test results are often disturbed. Proteinuriais common. Fecal leukocytes and fecal blood are very common.DiagnosisSince the clinical presentation of enteric fever is relatively nonspecific, the diagnosis needs to beconsidered in any febrile traveler returning from a developing country, especially the Indiansubcontinent, the Philippines, or Latin America. Other diagnoses that should be considered inthese travelers include malaria, hepatitis, bacterial enteritis, dengue fever, rickettsial infections,leptospirosis, amebic liver abscesses, and acute HIV infection (Chap. 117). Other than a positiveculture, no specific laboratory test is diagnostic for enteric fever. In 15–25% of cases, leukopeniaand neutropenia are detectable. Leukocytosis is more common among children, during the first10 days of illness, and in cases complicated by intestinal perforation or secondary infection.Other nonspecific laboratory findings include moderately elevated liver function tests andmuscle enzyme levels.The definitive diagnosis of enteric fever requires the isolation of S. Typhi or S. Paratyphi fromblood, bone marrow, other sterile sites, rose spots, stool, or intestinal secretions. The yield ofblood cultures is quite variable; sensitivity is as high as 90% during the first week of infectionand decreases to 50% by the third week. A low yield in infected patients is related to lownumbers of salmonellae (<15 organisms/mL) and/or to recent antibiotic treatment. Since almostall 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 isolationof the organism but does not increase sensitivity.Unlike blood culture, bone marrow culture remains highly (90%) sensitive despite 5 days ofantibiotic therapy. Culture of intestinal secretions (best obtained by a noninvasive duodenalstring test) can be positive despite a negative bone marrow culture. If blood, bone marrow, andintestinal secretions are all cultured, the yield is >90%. Stool cultures, while negative in 60–70%of cases during the first week, can become positive during the third week of infection inuntreated patients.Several serologic tests, including the classic Widal test for "febrile agglutinins," are available.None of these tests is sufficiently sensitive or specific to replace culture-based methods for the
diagnosis of enteric fever in developed countries. Polymerase chain reaction and DNA probeassays to detect S. Typhi in blood are being developed.DIFFERENTIAL DIAGNOSIS.During the initial stage of enteric fever, the clinical diagnosis may mistakenly be gastroenteritis,viral syndrome, bronchitis, or bronchopneumonia. Subsequently, the differential diagnosisincludes sepsis with other bacterial pathogens; infections caused by intracellularmicroorganisms, such as tuberculosis, brucellosis, tularemia, leptospirosis, and rickettsialdiseases; viral infections, such as infectious mononucleosis and anicteric hepatitis; andmalignancies, such as leukemia and lymphoma.Treatment.Antimicrobial therapy is essential in treating enteric fever. Because of increasing antibioticresistance, however, choosing the appropriate empirical therapy is problematic and controversial.Although antibiotic resistance of S. ser. Typhi isolates in the United States is relatively low (3–4%), most infections are acquired abroad, where resistance occurs. Increasing rates of plasmid-mediated antibiotic resistance of S. ser. Typhi have been reported from Southeast Asia, Mexico,and certain countries in the Middle East. Reports from India describe multiresistance tochloramphenicol, ampicillin, and TMP-SMX in 49–83% of S. ser. Typhi isolates. Resistantstrains are usually susceptible to third-generation cephalosporins. Quinolones are efficacious butare not approved for children. Most antibiotic regimens are associated with a 5–20% recurrencerisk. Chloramphenicol (50 mg/kg/24 hr divided qid PO or 75 mg/kg/24 hr divided q 6 hrIV), ampicillin (200 mg/kg/24 hr divided q 4–6 hr IV), amoxicillin (100 mg/kg/24 hrdivided tid PO), and trimethoprim-sulfamethoxazole (10 mg of TMP and 50 mg ofSMZ/kg/24 hr divided bid PO) have demonstrated good clinical efficacy. Althoughchloramphenicol therapy is associated with a more rapid defervescence and sterilization ofblood, the rate of relapse is somewhat higher, and this agent can cause potentially seriousadverse effects. Most children become afebrile within 7 days; treatment of uncomplicated casesshould be continued for at least 14 days, or 5–7 days after defervescence. Data suggest that veryshort courses of therapy may be adequate with oral cefixime (20 mg/kg/24 hr divided bid for 7days), ceftriaxone (50 mg/kg/24 hr once daily IM for 5 days) or oral ofloxacin(15 mg/kg/24 hr for 2 days). Chloramphenicol remains the gold standard.In adults, ciprofloxacin at a dose of 500 mg bid for 7–10 days is effective and associated with alow relapse rate. In children with suspected resistant strains, empirical therapy with ceftriaxone(or cefotaxime) is appropriate until antibiotic susceptibility patterns are available.In addition to antibiotic therapy, a short course of dexamethasone (3 mg/kg for the initial dose,followed by 1 mg/kg q 6 hr for 48 hr) improves the survival rate of patients with shock,obtundation, stupor, or coma. Supportive treatment and maintenance of appropriate fluid andelectrolyte balance are essential. When intestinal hemorrhage is severe, blood transfusion isneeded. Surgical intervention and broad-spectrum antibiotics are recommended for intestinalperforation. Surgical resection of 10 cm on each side of the perforation has been reported toimprove survival. Platelet transfusions have been suggested for the treatment of
thrombocytopenia that is sufficiently severe to cause intestinal hemorrhage in patients for whomsurgery is contemplated.Although attempts to eradicate chronic carriage of S. ser. Typhi are recommended for publichealth considerations, eradication is difficult despite in vitro susceptibility to the usualantibiotics. A course of 4–6 wk of high-dose ampicillin (or amoxicillin) plus probenecid orTMP-SMZ results in an approximately 80% cure rate of carriers if no biliary tract disease ispresent. Ciprofloxacin has been used successfully in adults. In the presence of cholelithiasis orcholecystitis, antibiotics alone are unlikely to be successful; cholecystectomy within 14 days ofantibiotic treatment is recommended.Enteric (Typhoid) Fever: TreatmentPrompt administration of appropriate antibiotic therapy prevents severe complications of entericfever and results in a case-fatality rate of <1%. The initial choice of antibiotics depends on thesusceptibility of the S. Typhi and S. Paratyphi strains in the area of residence or travel (Table146-1). For treatment of drug-susceptible typhoid fever, fluoroquinolones are the most effectiveclass of agents, with cure rates of ~98% and relapse and fecal carriage rates of <2%. Experienceis most extensive with ciprofloxacin. Short-course ofloxacin therapy is similarly successfulagainst infection caused by nalidixic acid–susceptible strains. However, the increased incidenceof nalidixic acid–resistant (NAR) S. Typhi in Asia, which is probably related to the widespreadavailability of fluoroquinolones over the counter, is now limiting the use of this drug class forempirical therapy. Patients infected with NAR S. Typhi strains should be treated withceftriaxone, azithromycin, or high-dose ciprofloxacin. However, high-dose fluoroquinolonetherapy for NAR enteric fever has been associated with delayed resolution of fever and highrates of fecal carriage during convalescence.Ceftriaxone, cefotaxime, and (oral) cefixime are effective for treatment of MDR enteric fever,including NAR and fluoroquinolone-resistant strains. These agents clear fever in ~1 week, withfailure rates of ~5–10%, fecal carriage rates of <3%, and relapse rates of 3–6%. Oralazithromycin results in defervescence in 4–6 days, with rates of relapse and convalescent stoolcarriage of <3%. Despite efficient in vitro killing of Salmonella, first- and second-generationcephalosporins as well as aminoglycosides are ineffective in treating clinical infections.Patients with persistent vomiting, diarrhea, and/or abdominal distension should be hospitalizedand given supportive therapy as well as a parenteral third-generation cephalosporin orfluoroquinolone, depending on the susceptibility profile. Therapy should be administered for atleast 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 ofdexamethasone (3-mg initial dose followed by eight doses of 1 mg/kg every 6 h) withchloramphenicol was associated with a substantially lower mortality rate than treatment withchloramphenicol 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 glucocorticoidtreatment of an acute bacterial infection.
The 1–5% of patients who develop chronic carriage of Salmonella can be treated for 4–6 weekswith an appropriate oral antibiotic. Treatment with oral amoxicillin, trimethoprim-sulfamethoxazole (TMP-SMX), ciprofloxacin, or norfloxacin is ~80% effective in eradicatingchronic carriage of susceptible organisms. However, in cases of anatomic abnormality (e.g.,biliary or kidney stones), eradication often requires both antibiotic therapy and surgicalcorrection.Prognosis.The prognosis for a patient with enteric fever depends on prompt therapy, the age of the patient,previous state of health, the causative Salmonella serotype, and the appearance of complications.In developed countries, with appropriate antimicrobial therapy, the mortality rate is less than 1%.In developing countries, the mortality rate is higher than 10%, usually because of delays indiagnosis, hospitalization, and treatment. Infants and children with underlying debilitatingdisorders are at higher risk. The appearance of complications, such as gastrointestinal perforationor severe hemorrhage, meningitis, endocarditis, and pneumonia, is associated with highmorbidity and mortality rates.Relapse after the initial clinical response occurs in 4–8% of the patients who are not treated withantibiotics. In patients who have received appropriate antimicrobial therapy, the clinicalmanifestations of relapse become apparent about 2 wk after stopping antibiotics and resemble theacute illness. The relapse, however, is usually milder and of shorter duration. Numerous relapsesmay occur. Individuals who excrete S. ser. Typhi for ≥3 mo after infection usually becomechronic carriers. The risk of becoming a carrier is low in children and increases with age; of allpatients with typhoid fever, 1–5% become chronic carriers. The incidence of biliary tractdiseases is higher in chronic carriers than in the general population. Although chronic urinarycarriage may also occur, it is rare and found mainly in individuals with schistosomiasis.Multidrug-resistant (MDR) strains of S. Typhi emerged in 1989 in China and Southeast Asia andhave since disseminated widely (Fig. 146-1). These strains contain plasmids encoding resistanceto chloramphenicol, ampicillin, and trimethoprim—antibiotics long used to treat enteric fever.With the increased use of fluoroquinolones to treat MDR enteric fever, strains of S. Typhi and S.Paratyphi with reduced susceptibility to ciprofloxacin [minimal inhibitory concentration (MIC),0.125–1.0 g/mL] have emerged in India and Vietnam and have been associated with clinicaltreatment failure. Testing of isolates for resistance to the first-generation quinolone nalidixic aciddetects most but not all strains with reduced susceptibility to ciprofloxacin.Prevention.In endemic areas, improved sanitation and clean running water are essential to control entericfever. To minimize person-to-person transmission and food contamination, personal hygienemeasures, handwashing, and attention to food preparation practices are necessary. Efforts toeradicate S. ser. Typhi from carriers are recommended, because humans are the only reservoir ofS. ser. Typhi. When such efforts are unsuccessful, carriers should be prevented from working infood- or water-processing activities, in kitchens, and in occupations related to patient care. These
individuals should be made aware of the potential contagiousness of their condition and of theimportance of handwashing and attentive personal hygiene.VACCINE.Two vaccines against S. ser. Typhi are commercially available in the United States. An oral, live-attenuated preparation of the Ty21a strain of S. ser. Typhi have been shown to have goodefficacy (67–82%). Four enteric-coated capsules are given on alternate days, and the entire seriesis repeated every 5 yr. Significant adverse effects are rare. The oral vaccine is recommended forpersons ≥6 yr of age. Infants and toddlers do not develop immune responses with thispreparation. It should not be used in persons with immunodeficiency syndromes. The Vi capsularpolysaccharide can be used in persons ≥2 yr of age. It is given as a single intramuscular dose,with a booster every 2 yr.Typhoid vaccination is recommended to travelers to endemic areas, especially Latin America,Southeast Asia, and Africa. Such travelers need to be cautioned that the vaccine is not asubstitute for personal hygiene and careful selection of foods and drinks, because none of thevaccines has efficacy approaching 100%. Vaccination is also recommended to individuals withintimate exposure to a documented carrier and for control of outbreaks.Prevention and ControlTheoretically, it is possible to eliminate the salmonellae that cause enteric fever since theysurvive only in human hosts and are spread by contaminated food and water. However, given thehigh prevalence of the disease in developing countries that lack adequate sewage disposal andwater treatment, this goal is currently unrealistic. Thus, travelers to developing countries shouldbe advised to monitor their food and water intake carefully and to consider vaccination.Two typhoid vaccines are commercially available: (1) Ty21a, an oral live attenuated S. Typhivaccine (given on days 1, 3, 5, and 7, with a booster every 5 years); and (2) Vi CPS, a parenteralvaccine consisting of purified Vi polysaccharide from the bacterial capsule (given in 1 dose, witha booster every 2 years). The old parenteral whole-cell typhoid/paratyphoid A and B vaccine isno longer licensed, largely because of significant side effects (see below). An acetone-killedwhole-cell vaccine is available only for use by the U.S. military. The minimal age forvaccination is 6 years for Ty21a and 2 years for Vi CPS. Currently, there is no licensed vaccinefor paratyphoid fever.A large-scale meta-analysis of vaccine trials comparing whole-cell vaccine, Ty21a, and Vi CPSin populations in endemic areas indicates that, while all three vaccines are similarly effective forthe first year, the 3-year cumulative efficacy of the whole-cell vaccine (73%) exceeds that ofboth Ty21a (51%) and Vi CPS (55%). In addition, the heat-killed whole-cell vaccine maintainsits efficacy for 5 years, whereas Ty21a and Vi CPS maintain their efficacy for 4 and 2 years,respectively. However, the whole-cell vaccine is associated with a much higher incidence of sideeffects (especially fever: 16% vs 1–2%) than the other two vaccines.Vi CPS typhoid vaccine is poorly immunogenic in children <5 years of age because of T cell–independent properties. In the 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 IgGantibody to Vi than did Vi CPS in 5- to 14-year-olds. In a two-dose trial in 2- to 5-year-oldchildren in Vietnam, Vi-rEPA provided 91% efficacy at 27 months and 88% efficacy at 43months and was very well tolerated. Similar results were obtained in a trial in Cambodia. Thisvaccine is not yet commercially available in the United States. At least three new live vaccinesare in clinical development and may prove more efficacious and longer-lasting than previous livevaccines.Although data on typhoid vaccines in travelers are limited, some evidence suggests that efficacyrates may be substantially lower than those for local populations in endemic areas. Both the CDCand the World Health Organization recommend typhoid vaccination for travelers to typhoid-endemic countries. Recent analyses from the CDC found that 16% of travel-associated casesoccurred among persons who stayed at their travel destination for 2 weeks. Thus,vaccination should be strongly considered even for persons planning short-term travel to high-risk areas such as the Indian subcontinent. In the United States, persons who have intimate orhousehold contact with a chronic carrier or laboratory workers who frequently deal with S. Typhialso should receive typhoid vaccine.Enteric fever is a notifiable disease in the United States. Individual health departments have theirown guidelines for allowing ill or colonized food handlers or health care workers to return totheir jobs. The reporting system enables public health departments to identify potential sourcepatients and to treat chronic carriers in order to prevent further outbreaks. In addition, since 1–4% of patients with S. Typhi infection become chronic carriers, it is important to monitorpatients (especially child-care providers and food handlers) for chronic carriage and to treat thiscondition if indicated.sMorphology. Infection causes Peyers patches in the terminal ileum to enlarge into sharplydelineated, plateau-like elevations up to 8 cm in diameter. Draining mesenteric lymph nodes arealso enlarged. Neutrophils accumulate within the superficial lamina propria, and macrophagescontaining bacteria, red blood cells, and nuclear debris mix with lymphocytes and plasma cells inthe lamina propria. Mucosal shedding creates oval ulcers, oriented along the axis of the ileum,that may perforate. The draining lymph nodes also harbor organisms and are enlarged due tophagocyte accumulation.The spleen is enlarged and soft, with uniformly pale red pulp, obliterated follicular markings,and prominent phagocyte hyperplasia. The liver shows small, randomly scattered foci ofparenchymal necrosis in which hepatocytes are replaced by macrophage aggregates, calledtyphoid nodules, that may also develop in the bone marrow and lymph nodes.