INTRODUCTION	Section 2 of 9
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Bibliography

Background: Typhoid fever, also known as enteric fever, is a systemic infection by Salmonella typhi or by the related but less virulent Salmonella paratyphi. Since ancient times, these bacteria have thrived during wartime and during the breakdown of basic sanitation. Archeologists have found S typhi in Athenian mass graves from the era of the Peloponnesian Wars, implicating it as the cause of the Great Plague of Athens. S typhi persists mostly in developing nations where sanitation is generally poor. Although sporadic outbreaks occur in developed nations, most individuals with typhoid fever in such areas have recently returned from travel to an endemic region.

Of all Salmonella serotypes, only S typhi and S paratyphi are pathogenic exclusively in humans. Typhoid fever is a severe multisystemic illness characterized by the classic prolonged fever, sustained bacteremia without endothelial or endocardial involvement, and bacterial invasion of and multiplication within the mononuclear phagocytic cells of the liver, spleen, lymph nodes, and Peyer patches. Typhoid fever is potentially fatal if untreated.

People are typically infected with S typhi and S paratyphi through food and beverages contaminated by a chronic stool carrier. Less commonly, carriers may shed the bacteria in urine. Individuals may also be infected by drinking sewage-contaminated water or by eating contaminated shellfish or faultily canned meat.

Salmonella is a genus in the family Enterobacteriaceae that has more than 2300 serotypes previously described in the Kauffman-White schema. Salmonellae are gram-negative, flagellate, nonsporulating, facultative anaerobic bacilli that ferment glucose, reduce nitrate to nitrite, and synthesize peritrichous flagella when motile. All but S typhi produce gas upon sugar fermentation.

Salmonellae are grouped based on the somatic O antigen and further divided into serotypes based on flagellar H and surface virulence (Vi) antigens. In particular, S typhi, the cause of typhoid fever, has O and H antigens, an envelope (K) antigen, and a lipopolysaccharide macromolecular complex called endotoxin that forms the outer portion of the cell wall. S typhi, S paratyphi C, and Salmonella Dublinare the only Salmonella serotypes that carry Vi antigen. Based on DNA studies, all salmonellae are now considered one of two species: Salmonella enterica (formerly called Salmonella choleraesuis) and Salmonella bongori. S enterica has 6 subspecies (I, II, IIIa, IIIb, IV, VI); S bongori has one (V). S typhi and S paratyphi are S enterica I subspecies, serotypes typhi and paratyphi.

Pathophysiology: After ingestion by the host, S typhi invades through the gut and multiplies within the mononuclear phagocytic cells in the liver, spleen, lymph nodes, and Peyer patches of the ileum.

In studies of healthy, previously unvaccinated men, ingestion of 10⁷ S typhi bacilli caused disease in 50% of volunteers. Investigations of outbreaks seem to indicate that an inoculum of as few as 200 organisms may lead to the disease. Perhaps such a discrepancy exists because many who ingest S typhi are not healthy men and have any one of a number of risk factors (see below). As the number of organisms increases, the incubation period decreases. The number of bacilli ingested does not change the subsequent clinical syndrome.

After successfully passing through the stomach, any Salmonella subspecies may be phagocytized by the gut's intraluminal dendritic cells, causing inflammation that leads to diarrhea. Only the subspecies S enterica causes severe disease in the rest of the body. Its specialized fimbriae adhere to the epithelium that overlies Peyer patches. Peyer patches are grossly visible aggregates of 5-100 lymphoid follicles in the small bowel submucosa; these patches are larger and more numerous distally. They are the primary mechanism for sampling antigens in the gut and initiating response. S enterica enters them via 1 of 3 pathways.

Intraluminal dendritic cells may infiltrate through the gut epithelium while carrying the bacterium. M cells may transport it as well. Immobile and interspersed among regular enterocytes in Peyer patches, M cells are epithelial cells that mature into professional phagocytes. They phagocytize bacteria such as S enterica and present them to macrophages and T cells in the lamina propria. Most interestingly, S enterica may convert normally nonphagocytic epithelial cells into bacterially-mediated endocytosis (BME).

In BME, Salmonella uses a type III secretion system—macromolecular channels that gram-negative bacteria such as Salmonella insert into eukaryotic cells and intracellular membranes to inject virulence proteins—to inject proteins SipA and SipC into the epithelial cell. These disrupt the normal brush border and force the cell to form membrane ruffles. The ruffles engulf the bacilli and create vesicles that carry them across the epithelial cell cytoplasm and the basolateral membrane. Salmonella pathogenicity island 1 (SPI-1) in the genome encodes the elements of BME.

In the submucosa, Salmonella enters macrophages via bacteria-triggered pinocytosis or via macrophage receptor–mediated phagocytosis. The intravacuolar environment activates the PhoP/PhoQ regulon, leading to modification of protein and lipopolysaccharide elements of the bacterial inner and outer membranes. Thus, Salmonella resists lysis and decreases host proinflammatory signaling. The bacterium also produces homocysteine to inactivate nitric oxide and enzymes against other microbicides. Finally, with the Vi antigen, a polysaccharide capsule, S typhi and S paratyphi further protect themselves from lysis within the macrophage and from neutrophils and complement without.

The newly described Salmonella pathogenicity island 2 (SPI-2) encodes a type III secretion system that carries bacterial proteins across the vacuole membrane and into the cytosol. Other virulence factors from SPI-2 prevent or alter fusion of the Salmonella-containing vacuole with other intracellular compartments, rearrange the actin cytoskeleton around the vacuole, and may prevent the implantation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and nitric oxide synthase into the vacuole membrane.

The infected macrophage provides Salmonella a vehicle safe from other elements of the immune system and in which it can multiply and travel. It passes through the mesenteric lymph nodes into the thoracic duct and the lymphatics beyond to seed the reticuloendothelial tissues—liver, spleen, bone marrow, and lymph nodes. In these havens, it multiplies until some critical density is reached. It causes the apoptosis in the macrophages and enters the bloodstream to attack the rest of the body. At this stage, the Vi antigen comes into play. It forms a capsule to protect the bacterium from complement and from phagocytic immune cells.

From blood or from the liver via bile ducts, it infects the gallbladder and reenters the gastrointestinal tract in the bile, spreading to other hosts via stool. In addition, it occasionally invades the urinary tract and spreads via urine.

After primary intestinal infection, further seeding of the Peyer patches occurs through infected bile. They may become hyperplastic and necrotic with infiltration of mononuclear cells and neutrophils, forming ulcers that may hemorrhage through eroded blood vessels or perforate the bowel wall, causing peritonitis.

The host recognizes the invader with toll-like receptors 2, 4, and 5. These induce cytokines such as interferon alpha, interleukin (IL)–12, and tumor necrosis factor-alpha, which recruit macrophages and cause the high fevers of the disease. Macrophages and neutrophils suppress the active infection. Later, humoral and CD4 T-cell–mediated immunity clears it.

Risk factors

Salmonella has mechanisms against acidic environments, but a pH level of 1.5 or less kills most of the bacilli. People who continually ingest antacids, histamine-2 receptor antagonists (H2 blockers), or proton pump inhibitors; who have undergone gastrectomy; or who have achlorhydria due to aging or other factors require fewer bacilli to produce clinical disease. Acquired immune deficiencies or hereditary deficiencies in immune modulars such as IL-12 and IL-23 increase risk for infection, complications, and death.

Frequency:

• In the US: From 1900-1960, the incidence of typhoid fever declined steadily and has remained low in the United States. Improved sanitation and successful antibiotic treatment led to this decline. An average of 245 cases have been reported annually, with an incidence of 0.2 per 100,000 population since 1985 compared with 35,994 reported cases in 1920. More than 70% of cases occurred within 30 days of returning from international travel, mostly to the Indian subcontinent and Latin America. The rare outbreaks of typhoid fever due to transmission within the United States are generally traceable to imported food or a food handler from an endemic region.

• Internationally: S typhi and S paratyphi infections occur worldwide but primarily in developing nations where sanitary conditions are poor. Typhoid and paratyphoid fevers are endemic in Asia, Africa, Latin America, the Caribbean, and Oceania. Typhoid fever affects 13-17 million people yearly and kills an estimated 600,000.

Mortality/Morbidity: Early antibiotic therapy has transformed a previously life-threatening illness of several weeks' duration with an overall mortality rate approaching 20% into a short-term febrile illness with negligible mortality. Case fatality rates of 10-50% have been reported from endemic countries when diagnosis is delayed.

Race: No racial predilection exists.

Sex: No sex-related predilection exists.

Age: In endemic areas, children aged 1-5 years are at the highest risk of infection, morbidity, and mortality because of waning passively acquired maternal antibody and a lack of acquired immunity. In young children, the clinical syndrome is often a nonspecific febrile illness that is not recognized as typhoid fever. In more recent years, prospective studies have shown that, although the incidence of classic typhoid fever in patients is highest in adolescents and young adults, the overall incidence of blood culture–confirmed disease is generally highest in children aged 3-9 years and declines significantly in late adolescence.

	CLINICAL	Section 3 of 9
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Bibliography

History: Untreated typhoid fever lasts at least 4 weeks. Most of the classic signs and symptoms of typhoid fever are prevented with prompt treatment. Clinical response begins about 2 days after starting antibiotics, and the patient's condition markedly improves within 4-5 days.

The incubation period of typhoid fever varies with the size of the infecting dose and averages 7-14 (range, 3-60) days. In paratyphoid infection, the incubation period ranges from 1-10 days. During the incubation period, 10-20% of patients have transient diarrhea (enterocolitis) that usually resolves before the onset of the full-fledged disease.

As bacteremia develops, the incubation period ends. Patients often experience chills, diaphoresis, anorexia, dry cough, a dull frontal headache, and myalgias before the onset of a high fever. About 20-40% of patients present with abdominal pain. In immunocompetent adults, constipation is common and is most likely due to hypertrophy of Peyer patches. Young children and individuals with AIDS are more likely to have diarrhea that is probably due to blunted secondary immunity. The incidence of constipation versus diarrhea varies geographically, perhaps because of local differences in diet or S typhi strains or genetic variation.

Unusual modes of onset include isolated severe headaches that may mimic meningitis. S typhi infection may cause an acute lobar pneumonia. In the early stages of the disease, rigors are rare unless the person also has malaria. This is not an unusual pairing of diseases. Patients may present with arthritis only, urinary symptoms, severe jaundice, or fever. Some patients, especially in India and Africa, may present with confusion and delirium or report parkinsonian symptoms or spastic rigidity. This regional variety in neuropsychiatric presentation may be due to the same factors that cause the variation in gastrointestinal symptoms.

Physical: The classic signs of enteric fever include fever, toxemia, delirium, abdominal pain, constipation, and hepatosplenomegaly.

Fever occurs in 75-85% of patients in the first week and is often initially remittent but becomes steady. The individual's temperature often rises to as high as 103-104°F (39-40°C) by the beginning of week 2. Constipation often develops early and is likely due to obstruction at the ileocecal valve by swollen Peyer patches. It may last for the entire duration of illness.

At approximately the end of the first week of illness, about a third of patients develop bacterial emboli to the skin known as rose spots. These are considered a classic symptom in typhoid fever, but they occasionally appear in shigellosis and nontyphoidal salmonellosis. Rose spots constitute a subtle, extremely sparse (often <5 spots), salmon-colored, blanching, truncal, maculopapular rash with 1- to 4-cm lesions that generally resolve within 2-5 days. Relative bradycardia and a dicrotic pulse are also common during this stage of illness.

During the second week of illness, the patient is toxic-appearing and apathetic with sustained fever. The abdomen is slightly distended, and soft splenomegaly is common.

In the third week, the patient grows more toxic and anorexic with significant weight loss. The patient may have a thready pulse, tachypnea, conjunctivitis, and crackles over the lung bases. Pyrexia persists. The patient may enter into a typhoid state of apathy, confusion, and even psychosis. Patients may develop polyneuropathy. Abnormal cerebrospinal fluid should prompt a search for a different cause.

Meanwhile, the patient commonly has pronounced abdominal distension. Some individuals may produce liquid, foul, green-yellow diarrhea (pea soup diarrhea). At this stage, the patient may die from overwhelming toxemia, myocarditis, intestinal hemorrhage, or perforation due to necrotic Peyer patches. Rare complications of enteric fever include pancreatitis, meningitis, orchitis, and osteomyelitis.

During the fourth week, the fever, mental state, and abdominal distension slowly improve over a few days, but intestinal complications may still occur in surviving untreated individuals. Weight loss and debilitating weakness last months. Relapses occur in 10% of patients, mostly during the first 2-3 weeks of convalescence.

Chronic carrier state

One to four percent of untreated patients become chronic carriers, defined as individuals who excrete Salmonella for more than 1 year. Some individuals may continue to excrete the bacterium for decades. Bladder infection with Schistosoma haematobium predisposes to urinary carriage. The parasite itself becomes a carrier. Stool carriage is more frequent in people with preexisting biliary abnormalities, perhaps because S enterica survives in gallstones, and these people have a greater incidence of cholecystitis. Chronic carriers have a greater risk for carcinoma of the gallbladder and other gastrointestinal malignancies; chronic carriers had a 6-fold increase in the risk of death due to hepatobiliary cancer. This may be due to chronic inflammation caused by the bacterium.