Etiology
The main causative agent of enteric fever is Salmonella enterica, serotype typhi, which, in most regions, accounts for 60% to 80% of cases.[2][11][25] The other Salmonella enterica serovars are paratyphi, species A, B and C, which differ in their geographic distribution. S paratyphi A is a common pathogen in the Indian subcontinent, while S paratyphi B is found in Indonesia, Malaysia, the Mediterranean region, and South America and S paratyphi C is found in Africa.[26][27][28][29][30] All of these species are restricted human pathogens that, unlike many other salmonellae, do not infect poultry, reptiles, or mammalian livestock.
S paratyphi A was considered to be of a minor epidemiologic importance. However, among travelers, the incidence of disease caused by Salmonella paratyphi was found to be significant. In one study from Nepal, the ratio of S paratyphi A to S typhi was 70% versus 30% among travelers, while this ratio was reversed, as expected, in the local population.[31]
The disproportionate number of cases of S paratyphi organisms may be due to a vaccine effect, which gives protection only for S typhi.[13] This has been clearly shown among Israeli travelers where, among vaccinated patients, 29% were caused by S paratyphi A, while among nonimmunized patients only 4% were caused by S paratyphi A.[14] This has also been seen in several Asian countries. For example, S paratyphi A was found in 64% of culture-positive cases in Hechi China (where typhoid vaccine is part of routine immunization), in 15% to 25% of cases in Kolkata (India) and Karachi (Pakistan), and accounted for 44% of cases in one study in Nepal.[32][33]
Pathophysiology
The first step in establishing infection is adhesion to and invasion of the gut wall. About 1,000,000 bacterial cells are needed to cause infection. Low gastric acidity (as in older people or use of antacid drugs) can decrease the infective dose to 1000, while prior vaccination can increase it to 1,000,000,000.[34]
The organisms spread throughout the reticuloendothelial system, mainly to the liver, spleen, and bone marrow, multiplying intracellularly within macrophages; then the bacteria appear in the blood stream and a symptomatic bacteremic phase ensues.[13]
The incubation time from ingestion of Salmonella enterica, serotype S typhi or S paratyphi, to the beginning of fever is usually 2 to 3 weeks (range 3-60 days). At this early stage of the infection and until the establishment of bacteremia, there are usually no symptoms or clinical signs. However, because there is often coinfection with other pathogens with fecal-oral spread, gastrointestinal complaints, primarily diarrhea, may exist.
After the incubation period, secondary metastatic foci may occur, including splenic abscesses and even endocarditis. Important loci of secondary infection are the Peyer patches: areas where intestinal bleeding and perforation (the main cause of mortality in the pre-antibiotic era) occur.[13]
It is probably during this phase that infection of the gallbladder also occurs. In some patients this leads to long-term (frequently lifelong) carriage of S typhi and S paratyphi in bile and secretion to the stool.
Relapse may occur, even with appropriate antimicrobial therapy, in both S typhi and S paratyphi infections.[14] This reflects the difficulty of eradicating the organism.
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