Enteric fever is a systemic clinical syndrome produced by certain Salmonella organisms. It encompasses the terms typhoid fever, caused by S. typhi, and paratyphoid fever, caused by S. paratyphi A, S. schottmuelleri (formerly S. paratyphi B), S. hirschfeldii (formerly S. paratyphi C), and occasionally other Salmonella serotypes. Typhoid fever, the most frequent and best studied type of enteric fever, tends to be more severe than the other forms.
EPIDEMIOLOGY. The incidence, mode of transmission, and consequences of enteric fever differ significantly in developed and developing countries. The incidence has decreased markedly in developed countries. In the
United States, about 400 cases of typhoid fever are reported each year, giving an annual incidence of less than 0.2 per 100,000, which is similar to that in Western Europe and . In Japan Southern Europe, the annual incidence is 4.3–14.5 per 100,000. In developing countries, S. typhi is often the most common Salmonella isolate, with an incidence than can reach 500 per 100,000 (0.5%) and a high mortality rate. The World Health Organization has estimated that 12.5 million cases occur annually worldwide (excluding ). China
Because humans are the only natural reservoir of S. typhi, direct or indirect contact with an infected person (sick or chronic carrier) is necessary for infection. Ingestion of foods or water contaminated with human feces is the most common mode of transmission. Waterborne outbreaks due to poor sanitation and direct fecal-oral spread due to poor personal hygiene are seen, mainly in developing countries. Oysters and other shellfish cultivated in water contaminated by sewage are also a source of widespread infection. In the
, about 65% of the cases result from international travel. Travel to Asia (especially to United States India) and Central or South America (especially ) is usually implicated. Domestically acquired enteric fever is most frequent in the southern and western Mexico and is usually caused by consumption of foods contaminated by individuals who are chronic carriers. Congenital transmission of enteric 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. United States
PATHOLOGY. In younger children, the morphologic changes of S. typhi infection are less prominent than in older children and adults. Hyperplasia of Peyer patches with necrosis and sloughing of overlying epithelium, producing ulcers, is typical. The mucosa and lymphatic tissue of the intestinal tract are severely inflamed and necrotic. Ulceration that heals without scarring is common. Strictures and intestinal obstruction virtually never occur after typhoid fever. Hemorrhages may occur. The inflammatory lesion may occasionally 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 focal necrosis. Hyperplasia of reticuloendothelial tissue with proliferation of mononuclear cells is the predominant finding. A mononuclear response may be seen in the bone marrow associated with areas of focal necrosis. Inflammation of the gallbladder is focal, inconstant, and modest in proportion to the extent of local bacterial multiplication. Bronchitis is common. Inflammation also may be observed in the form of localized abscesses, pneumonia, septic arthritis, osteomyelitis, pyelonephritis, endophthalmitis, and meningitis.
PATHOGENESIS. Bloodstream invasion by S. typhi or occasionally by other serotypes is necessary to produce the enteric fever syndrome. The inoculum size required to cause disease in volunteers is 105–109 S. typhi organisms. These estimates may be higher than in naturally acquired infection because the volunteers ingested the organisms in milk; stomach acidity is an important determinant of susceptibility to salmonella. After attachment to the microvilli of the ileal brush borders, the bacteria invade intestinal epithelium, apparently through the Peyer patches. Organisms are transported to intestinal lymph follicles, where multiplication takes place within the mononuclear cells. Monocytes, unable to destroy the bacilli early in the disease process, carry these organisms into the mesenteric lymph nodes. Organisms then reach the bloodstream through the thoracic duct, causing a transient bacteremia. Circulating organisms reach the reticuloendothelial cells in the liver, spleen, and bone marrow and may seed other organs. After proliferation in the reticuloendothelial system, the bacteremia recurs. The gallbladder is particularly susceptible to being infected from the bloodstream or through the biliary system. Local multiplication in the walls of the gallbladder produces large numbers of salmonellae, which secondarily reach the intestine through the bile.
Several virulence factors seem to be important. A surface Vi capsular antigen is found in most S. typhi and some other serotypes; it interferes with phagocytosis by preventing the binding of C3 to the surface of the bacterium and correlates with invasion capability. The sequence of the gene (viaB) encoding Vi has been defined. The ability of organisms to survive within macrophages after phagocytosis is an important virulence trait encoded by the phoP regulon; it may be related to metabolic effects on host cells. Circulating endotoxin, a lipopolysaccharide component of the bacterial cell wall, is thought to cause the prolonged fever and toxic symptoms of enteric fever, although its levels in symptomatic patients are low. Alternatively, endotoxin-induced cytokine production by human macrophages may cause the systemic symptoms. The occasional occurrence of diarrhea may be explained by presence 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 typhoid fever. Carriers show impaired cellular reactivity to S. typhi antigens in the leukocyte migration inhibition test. In carriers, a large number of virulent bacilli pass into the intestine daily and are excreted in the stool, without entering the epithelium of the host.
CLINICAL MANIFESTATIONS. The incubation period is usually 7–14 days, but it may range from 3–30 days, depending mainly on the size of the ingested inoculum. The clinical manifestations of enteric fever depend on age.
School-Age 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 soup consistency may be present during the early course of the disease, constipation later becomes a more prominent symptom. Nausea and vomiting are uncommon and suggest a complication, particularly if occurring in the 2nd or 3rd wk. Cough and epistaxis may be seen. Severe lethargy may develop in some children. The fever, which rises in a step-wise fashion, becomes unremittent and high within 1 wk, often reaching 40º C (104º F).
During the 2nd wk of illness, high fever is sustained, and fatigue, anorexia, cough, and abdominal symptoms increase in severity. The patient appears acutely ill, disoriented, and lethargic. Delirium and stupor may be observed. Physical findings include a relative bradycardia, which is disproportionate to the high fever. Hepatomegaly, splenomegaly, and distended abdomen with diffuse tenderness are very common. In about 50% of patients with enteric fever, a macular (i.e., rose spots) or maculopapular rash appears on about the 7th to 10th day. Lesions are usually discrete, erythematous, and 1 to
5 mm in diameter; the lesions are slightly raised, and blanch on pressure. They appear in crops of 10 to 15 lesions on the lower chest and abdomen and last 2 or 3 days. They leave 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 the chest. If no complications occur, the symptoms and physical findings gradually resolve within 2–4 wk, but malaise and lethargy may persist for an additional 1–2 mo. The patients may be emaciated by the end of the illness. Enteric fever caused by nontyphoidal Salmonella is usually milder, with a shorter duration of fever and a lower rate of complications.
Infants and Young Children (<5 yr). Enteric fever is relatively rare in this age group. Although clinical sepsis can occur, the disease is surprisingly mild at presentation, making the diagnosis difficult and underdiagnosis possible. Mild fever and malaise, misinterpreted as a viral syndrome, are seen in infants with culture-proven typhoid fever. Diarrhea is more common in young children with typhoid fever than in adults, leading to a diagnosis of acute gastroenteritis. Others may present with signs and symptoms of lower respiratory tract infection.
Neonates. In addition to its ability to cause abortion and premature delivery, enteric fever during late pregnancy may be transmitted vertically. The neonatal disease usually begins within 3 days of delivery. Vomiting, diarrhea, and abdominal distention are common. Temperature is variable but may be as high as 40.5º C (105º F). Seizures may occur. Hepatomegaly, jaundice, anorexia, and weight loss can be marked.
LABORATORY FINDINGS. A normochromic, normocytic anemia is often seen after several weeks of illness and is related to intestinal blood loss or bone marrow suppression. Blood leukocyte counts are frequently low in relation to the fever and toxicity, but there is a wide range in counts; leukopenia, usually not below 2500 cells/mm3, is often seen after the 1st or 2nd wk of illness. When pyogenic abscesses develop, leukocytosis may reach 20,000–25,000/mm3. Thrombocytopenia may be striking and persist for as long as 1 wk. Liver function test results are often disturbed. Proteinuria is common. Fecal leukocytes and fecal blood are very common.
COMPLICATIONS. Common complications include intestinal perforation, myocarditis, and central nervous system manifestations. Severe intestinal hemorrhage and intestinal perforation occur in 1–10% and 0.5–3% of the patients, respectively. These and most other complications usually occur after the 1st wk of the disease. Hemorrhage, which usually precedes perforation, is manifested by a drop in temperature and blood pressure and an increase in the pulse rate. Perforations, which are usually pinpoint size but may be as large as several centimeters, typically occur in the distal ileum and are accompanied by a marked increase in abdominal pain, tenderness, vomiting, and signs of peritonitis. 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 amylase levels may be seen sometimes with clinically obvious pancreatitis.
Pneumonia often caused by superinfection with organisms other than Salmonella is more common in children than in adults. In children, pneumonia or bronchitis is common (approximately 10%). Toxic myocarditis may be manifested by arrhythmias, sinoatrial block, ST-T changes on the electrocardiogram, cardiogenic shock, fatty infiltration, and necrosis of the myocardium. Thrombosis and phlebitis occur rarely. Neurologic complications include increased intracranial pressure, cerebral thrombosis, acute cerebellar ataxia, chorea, aphasia, deafness, psychosis, and transverse myelitis. Peripheral and optic neuritis have been reported. Permanent sequelae are rare. Other reported complications are fatal bone marrow necrosis, pyelonephritis, nephrotic syndrome, meningitis, endocarditis, parotitis, orchitis, and suppurative lymphadenitis. Although osteomyelitis and septic arthritis can occur in a normal host, they are more frequently seen in children with hemoglobinopathies.
DIAGNOSIS. Culturing the Salmonella strain involved is usually the basis for the diagnosis. Blood cultures are positive in 40–60% of the patients seen early in the course of the disease, and stool and urine cultures become positive after the 1st wk. The stool culture is also occasionally positive during the incubation period. Because of the intermittent and low-level bacteremia, repeated blood cultures should be obtained. Cultures of bone marrow are often positive during later stages of the disease, when blood cultures may be sterile; although seldom obtained, cultures of mesenteric lymph nodes, liver, and spleen may also be positive at this point. A culture of bone marrow is the single most sensitive method of diagnosis (positive in 85–90%) and is less influenced by prior antimicrobial therapy. Stool and sometimes urine cultures are positive in chronic carriers. In suspected cases with negative stool cultures, a culture of aspirated duodenal fluid or of a duodenal string capsule may be helpful in confirming infection.
Because identification of S. typhi from culture usually takes at least 3 days, several methods for earlier diagnosis are being developed. Direct detection of S. typhi–specific antigens in the serum or S. typhi Vi antigen in the urine has been attempted by immunologic methods, often using monoclonal antibodies. Polymerase chain reaction (PCR) has been used to amplify specific genes of S. typhi in the blood of patients, enabling diagnosis within a few hours. This method is specific and more sensitive than blood cultures given the low level of bacteremia in enteric fever. More experience with these new methods is needed before they can be endorsed.
Serology is of little help in establishing the diagnosis, but it may be useful in epidemiologic studies. The classic Widal test measures antibodies against O and H antigens of S. typhi. Because many false-positive and false-negative results occur, diagnosis of typhoid fever by Widal test alone is prone to error. Experience is still limited with new serologic assays.
DIFFERENTIAL DIAGNOSIS. During the initial stage of enteric fever, the clinical diagnosis may mistakenly be gastroenteritis, viral syndrome, bronchitis, or bronchopneumonia. Subsequently, the differential diagnosis includes sepsis with other bacterial pathogens; infections caused by intracellular microorganisms, such as tuberculosis, brucellosis, tularemia, leptospirosis, and rickettsial diseases; viral infections, such as infectious mononucleosis and anicteric hepatitis; and malignancies, such as leukemia and lymphoma.
PREVENTION. In endemic areas, improved sanitation and clean, running water are essential to control enteric fever. To minimize person-to-person transmission and food contamination, personal hygiene measures, handwashing, and attention to food preparation practices are necessary. Efforts to eradicate S. typhi from carriers are recommended, because humans are the only reservoir of S. typhi. When such efforts are unsuccessful, carriers should be prevented from working in food- or water-processing plants, in kitchens, and in occupations related to patient care. These individuals should be made aware of the potential contagiousness of their condition and the importance of handwashing and personal hygiene.
Several vaccines against S. typhi are available. A parenteral heat-phenol–inactivated vaccine confers limited protection (51–76% efficacy) and is associated with adverse effects, including fever, local reactions, and headache in at least 25% of recipients. Two doses of 0.5 mL administered subcutaneously 4 wk or more apart have been recommended for children 10 yr or older; 0.25 mL per dose is recommended for younger children. A second newly licensed vaccine (Vivotif) is an oral, live-attenuated preparation of the Ty21a strain of S. typhi. Several large studies have shown efficacy (67–82%). Significant adverse effects are rare. Four enteric-coated capsules on alternate days are given. The oral vaccine is not recommended for children younger than 6 yr because of limited experience. Infants and toddlers do not develop immune responses with this preparation. It should not be used in persons with immunodeficiency syndromes. Vaccines against typhoid fever made from the Vi capsular polysaccharide, with or without protein conjugation, are under investigation.
A typhoid vaccine 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 a substitute for personal hygiene and careful selection of foods and drinks, because neither vaccine has efficacy approaching 100%. Vaccination is also recommended to individuals with intimate exposure to a documented carrier and for control of outbreaks.
Antimicrobial therapy is essential in treating enteric fever, especially for typhoid fever. Because of increasing antibiotic resistance, however, choosing the appropriate empiric therapy is problematic and sometimes controversial. Most antibiotic regimens are associated with a 5–20% recurrence risk. Chloramphenicol (50 mg/kg/24 hr orally or 75 mg/kg/24 hr, intravenously in four equal doses), ampicillin (200 mg/kg/24 hr, intravenously in four to six doses), amoxicillin (100 mg/kg/24 hr, orally in three doses), and trimethoprim-sulfamethoxazole (10 mg of TMP and 50 mg of SMX/kg/24 hr, orally in two doses) have demonstrated good clinical efficacy. Although chloramphenicol therapy is associated with a more rapid defervescence and sterilization of blood, the rate of relapse is somewhat higher, and this agent can cause potentially serious adverse effects. Most children become afebrile within 7 days; treatment of uncomplicated patients should be continued for at least 14 days or 5–7 days after defervescence. In children with underlying disturbances, including severe malnutrition, extending antibiotic therapy for 21 days may reduce the rate of complications.
Although antibiotic resistance of S. typhi isolates in the
is relatively low (3–4%), most infections are acquired abroad, where resistance occurs. Increasing rates of plasmid-mediated antibiotic resistance of S. typhi have been reported from United States Southeast Asia, Mexico, and certain countries in the Middle East. Reports from describe multiresistance to chloramphenicol, ampicillin, and TMP-SMX in 49–83% of S. typhi isolates. Resistant strains are usually susceptible to third-generation cephalosporins. Cefotaxime (200 mg/kg/24 hr, intravenously in three to four doses) and ceftriaxone (100 mg/kg/24 hr, intravenously in one to two doses) have been successfully used to treat typhoid fever caused by resistant strains, although the response to ceftriaxone was somewhat better. Aztreonam has also been successfully used. Fluoroquinolones are efficacious, but they are not approved for children. In adults, ciprofloxacin at a dose of 500 mg twice daily for 7–10 days is effective and associated with a low relapse rate. In patients with suspected resistant strains, we recommend empirical therapy with ceftriaxone (or cefotaxime) until antibiotic susceptibility patterns are available. India
In addition to antibiotic therapy, a short course of dexamethasone, using 3 mg/kg for the initial dose, followed by 1 mg/kg every 6 hr for 48 hr, improves the survival rate of patients with shock, obtundation, stupor, or coma. This does not increase the incidence of complications if antibiotic therapy is adequate. Supportive treatment and maintenance of appropriate fluid and electrolyte balance are essential. When intestinal hemorrhage is severe, blood transfusion is needed. Surgical intervention with broad-spectrum antibiotics is recommended for intestinal perforation. Platelet transfusions have been suggested for the treatment of thrombocytopenia that is sufficiently severe to cause intestinal hemorrhage in patients for whom surgery is contemplated.
Although attempts to eradicate chronic carriage of S. typhi are recommended for public health considerations, eradication is difficult despite in vitro susceptibility to the antibiotic used. A course of 4–6 wk of high-dose ampicillin (or amoxicillin) plus probenecid or TMP-SMX results in an approximately 80% cure rate of carriers if no biliary tract disease is present. Ciprofloxacin has been used successfully in adults. In the presence of cholelithiasis or cholecystitis, antibiotics alone are unlikely to be successful; cholecystectomy within 14 days of antibiotic treatment is recommended.
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 below 1%. In developing countries, the mortality rate is higher than 10%, usually because of delays in diagnosis, hospitalization, and treatment. Infants younger than 1 yr of age and children with underlying debilitating disorders are at higher risk. S. typhi causes a more severe disease, with higher rates of complications and death, than other serotypes. The appearance of complications, such as gastrointestinal perforation or severe hemorrhage, meningitis, endocarditis, and pneumonia, are associated with high morbidity and mortality rates.
Relapse after the initial clinical response occurs in 4–8% of the patients who are not treated with antibiotics. In patients who have received appropriate antimicrobial therapy, the clinical manifestations of relapse become apparent about 2 wk after stopping antibiotics and resemble the acute illness. The relapse, however, is usually milder and of shorter duration. Multiple relapses may occur. Individuals who excrete S. typhi 3 mo or longer after infection are usually excretors at 1 yr and defined as chronic carriers. The risk of becoming a carrier is low in children and increases with age; of all patients with typhoid fever, 1–5% become chronic carriers. The incidence of biliary tract diseases is higher in chronic carriers than in the general population. Although chronic urinary carriage may also occur, it is rare and found mainly in individuals with schistosomiasis.
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