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 can cause a similar prolonged febrile illness. EPIDEMIOLOGY In the United States, about 400 cases of typhoid fever are reported each year, giving an annual incidence of less than 0.2 cases/100,000 population, which is similar to that in Western Europe and Japan. In Southern Europe, the annual incidence is 4.3-14.5 cases/100,000 population. 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 annually worldwide. Because humans are the only natural reservoir of S. ser. 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. Water-borne outbreaks due to poor sanitation and direct fecal-oral spread due to poor personal hygiene are encountered, mainly in developing countries. Oysters and other shellfish cultivated in water contaminated by sewage are also a source of widespread infection 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 PATHOGENESIS In younger children, the morphologic changes of S. ser. Typhi infection are less prominent than in older children and adults Hyperplasia of Peyer patches with necrosis and sloughing of overlying epithelium produces ulcers that may bleed The mucosa and lymphatic tissue of the intestinal tract are severely inflamed and necrotic Ulcers heal without scarring Strictures and intestinal obstruction virtually never occur after typhoid fever 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 in association 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. 5 9 The inoculum size required to cause enteric fever in volunteers is 10 -10 S. ser. Typhi organisms The bacteria invade through the Peyer patches Organisms are transported to intestinal lymph nodes, 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, bacteremia recurs The gallbladder is particularly susceptible to being infected Local multiplication in the walls of the gallbladder produces large numbers of salmonellae, which reach the intestine through the bile Virulence factors seem to be important. Invasion of Peyer patches is encoded by genes closely 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 the features of typhoid fever The surface Vi capsular antigen found in S. ser. Typhi interferes with phagocytosis by preventing the binding of C3 to the surface of the bacterium The ability of organisms to survive within macrophages after phagocytosis is an important virulence trait encoded by the phoP regulon 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 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. ser. 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-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 diarrhea having a pea soup consistency may be present during the early course of the disease constipation later becomes a more prominent symptom Cough and epistaxis may ensue Severe lethargy may develop in some children Temperature, which increases in a stepwise fashion, becomes an unremitting and high fever within 1 wk, often reaching 40C During the 2nd week of illness, high fever is sustained, and fatigue, anorexia, cough, and abdominal symptoms increase in severity Patients appear 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 or maculopapular 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 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 Nausea and vomiting if occurring in the 2nd or 3rd week suggest a complication. If no complications occur, the symptoms and physical findings gradually resolve within 2-4 wk Patients may be emaciated by the end of the illness

Infants and Young Children (<5 Years Old) Enteric fever is relatively rare in this age group in endemic areas Mild fever and malaise, misinterpreted as a viral syndrome, occur 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

Neonates Able 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 40.5C Seizures may occur. Hepatomegaly, jaundice, anorexia, and weight loss can be marked

Complications 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 week of the disease. Hemorrhage, which usually precedes perforation, is manifested by a decrease 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 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 sometimes accompany clinically obvious pancreatitis. Pneumonia 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 with fatty infiltration and necrosis of the myocardium may be manifested by arrhythmias, sinoatrial block, ST-T changes on the electrocardiogram, or cardiogenic shock 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 osteomyelitis and suppurative arthritis can occur in a normal host, they are more common in children 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 the disease stool and urine cultures become positive after the 1st week The stool culture result is 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 bone marrow often yield positive results during later stages of the disease, when blood cultures may be sterile 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 results of stool cultures, a culture of aspirated duodenal fluid or of a duodenal string capsule may be helpful in confirming infection duodenal string culture test cannot be performed on 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 the urine 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 sensitive than blood cultures, given the low level of bacteremia in enteric fever 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. ser. Typhi. Because many false-positive and 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 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 3 range in counts; leukopenia, usually not less than 2,500 cells/mm , is often found after the 1st or 2nd week of illness 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

DIFFERENTIAL DIAGNOSIS During the initial stage of enteric fever, the clinical diagnosis may mistakenly be: Gastroenteritis viral syndrome bronchitis bronchopneumonia Subsequently, the differential diagnosis includes: sepsis with other bacterial pathogens tuberculosis brucellosis tularemia leptospirosis

TREATMENT Antimicrobial therapy is essential in treating enteric fever. Because of increasing antibiotic resistance, however, choosing the appropriate empirical therapy is problematic and controversial. 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 to chloramphenicol, ampicillin, and TMP-SMX in 49-83% of S. ser. Typhi isolates Resistant strains are usually susceptible to third-generation cephalosporins Quinolones are efficacious but are not approved for children. Most antibiotic regimens are associated with a 5-20% recurrence risk The following have demonstrated good clinical efficacy: Chloramphenicol (50 mg/kg/24 hr divided qid PO or 75 mg/kg/24 hr divided q 6 hr IV) ampicillin (200 mg/kg/24 hr divided q 4-6 hr IV) amoxicillin (100 mg/kg/24 hr divided tid PO) trimethoprim-sulfamethoxazole (10 mg of TMP and 50 mg of SMZ/kg/24 hr divided bid PO) 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 cases should be continued for at least 14 days, or 5-7 days after defervescence Data suggest that very short courses of therapy may be adequate with oral cefixime (20 mg/kg/24 hr divided bid for 7 days), 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

PREVENTION In endemic areas, improved sanitation and clean running water are essential to control enteric fever handwashing, and attention to food preparation practices

Vaccines Two vaccines against S. ser. Typhi are commercially available in the United States. An oral, liveattenuated preparation of the Ty21a strain of S. ser. Typhi have been shown to have good efficacy (6782%). Four enteric-coated capsules are given on alternate days, and the entire series is repeated every 5 yr. Significant adverse effects are rare. The oral vaccine is recommended for persons 6 yr of age. Infants and toddlers do not develop immune responses with this preparation. It should not be used in persons with immunodeficiency syndromes. The Vi capsular polysaccharide can be used in persons 2 yr of age. It is given as a single intramuscular dose, with a booster every 2 yr.

Source: Nelson Textbook of Pediatrics, 19th Ed