A 42-year-old man comes to the office due to 2 weeks of progressive fever, chills, abdominal discomfort, and loose stools, which began during a trip to Southeast Asia. He received no pretravel vaccinations and did not strictly follow food and water safety precautions during the trip. The patient has no chronic medical conditions; however, he had an episode of Salmonella Enteritidis gastroenteritis last year, and it resolved with symptomatic care. Temperature is 39.4 C (102.9 F), blood pressure is 110/64 mm Hg, pulse is 62/min, and respirations are 18/min. Physical examination shows a faint macular rash on the trunk. There is mild tenderness to palpation in the lower abdominal quadrants with no guarding or rebound tenderness. Hepatosplenomegaly is present. Blood culture grows gram-negative, non–lactose-fermenting rods. Which of the following pathogenic mechanisms best explains this patient's prolonged and severe disease course compared to his prior episode of bacterial gastroenteritis?
Salmonella infection | ||
Nontyphoidal Salmonella | Typhoidal Salmonella | |
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GI = gastrointestinal; HSM = hepatosplenomegaly; RES = reticuloendothelial system. | ||
This patient most likely has typhoid fever, an invasive Salmonella infection. Salmonella species are gram-negative, non–lactose-fermenting, motile enteric rods divided into nontyphoidal and typhoidal strains. Both strains penetrate enterocytes, where they travel in vacuoles from the apical to the basolateral end of the cell and invade the lamina propria. However, the pathogenesis then diverges, as follows:
Nontyphoidal strains (eg, S Enteritidis) are phagocytosed by neutrophils and macrophages in the lamina propria and induce a massive inflammatory response with neutrophilic infiltration. This cytokine-mediated response causes gastroenteritis (eg, watery diarrhea, abdominal pain, fever), which usually self-resolves, as in this patient's prior history.
In contrast, typhoidal strains contain specialized virulence factors (eg, Vi capsular antigen) that inhibit neutrophil recruitment and phagocytosis, limiting the acute inflammatory response that helps contain nontyphoidal species. It also inhibits macrophages from generating an oxidative burst to destroy the bacteria, allowing the pathogen to undergo extensive, unchecked intraphagocytic replication and dissemination through the lymphatic and reticuloendothelial system. This results in typhoid fever, as seen in this patient.
Manifestations begin approximately a week after transmission of the typhoidal strain, which typically occurs via consumption of food or water contaminated by human feces in regions of poor sanitation. Initial symptoms include an escalating fever that is often associated with relative bradycardia (pulse-temperature dissociation). A week later, patients typically develop abdominal pain, diarrhea or constipation, hepatosplenomegaly, and transient salmon-colored macules (rose spots) on the trunk. Blood culture is diagnostic.
(Choice A) Contact between Entamoeba histolytica and the host cell results in insertion of an amebic channel-forming protein in the host cell membrane, causing cell death. Symptoms include bloody diarrhea and/or extraintestinal manifestations (eg, liver abscess). Rash is uncommon, and blood cultures would not show gram-negative rods.
(Choice B) Campylobacter infection causes acute, self-limited diarrhea (<7 days) and may result in cross-reacting antibodies to ganglioside GM1, leading to Guillain-Barré syndrome. Rose spots, hepatosplenomegaly, and pulse-temperature dissociation would not be expected.
(Choice D) Rotavirus and Giardia damage intestinal villi, leading to intestinal malabsorption due to villous blunting and decreased levels of brush border enzymes (eg, maltase, lactase).
Educational objective:
Typhoidal strains of Salmonella contain a capsular antigen (Vi) and other virulence factors that inhibit neutrophil phagocytosis, neutrophil recruitment, and macrophage-mediated destruction. Therefore, typhoidal Salmonella undergoes extensive replication in macrophages and is able to spread through the lymphatic and reticuloendothelial system, leading to widespread systemic disease (typhoid fever).