What is the pathophysiology of typhoid (Typhoid) fever?

From the Guidelines

Typhoid fever is a systemic infection caused by Salmonella enterica serotype Typhi, which invades the intestinal epithelium, survives within macrophages, and disseminates to various organs, leading to a complex pathophysiological progression. The infection begins when the bacteria are ingested through contaminated food or water and survive the acidic environment of the stomach 1. Upon reaching the small intestine, S. Typhi invades the intestinal epithelium, particularly through specialized M cells overlying Peyer's patches. The bacteria then enter macrophages where they survive and replicate within Salmonella-containing vacuoles, protected from the host's immune system.

Key Pathophysiological Steps

• Invasion of the intestinal epithelium
• Survival and replication within macrophages
• Dissemination to the liver, spleen, and bone marrow via the lymphatic system
• Reentry into the bloodstream, coinciding with the onset of clinical symptoms
• Production of endotoxin, triggering the release of cytokines and causing fever and systemic inflammation

From there, they disseminate via the lymphatic system to the liver, spleen, and bone marrow during the primary bacteremia phase. In these organs, S. Typhi continues to multiply before reentering the bloodstream (secondary bacteremia), which coincides with the onset of clinical symptoms including the characteristic step-ladder fever pattern 1. The bacteria produce an endotoxin (lipopolysaccharide) that triggers the release of cytokines, causing fever and systemic inflammation. S. Typhi also expresses Vi capsular antigen, which helps it evade host immune detection.

Clinical Presentation and Complications

• Fever is almost invariable, with other symptoms and signs being non-specific
• Complications such as gastrointestinal bleeding, intestinal perforation, and typhoid encephalopathy occur in 10-15% of patients
• Vaccination provides incomplete protection against typhoid fever and does not protect from paratyphoid

The bacteria eventually reach the gallbladder, where they can establish persistent infection, and are excreted back into the intestines, causing inflammation and ulceration of Peyer's patches that may lead to intestinal hemorrhage or perforation in severe cases. Treatment typically involves intravenous ceftriaxone as a first-line agent, especially in patients returned from Asia, due to increasing reports of fluoroquinolone-resistant isolates 1. Understanding this pathophysiology explains why typhoid fever presents as a systemic illness rather than primarily a gastrointestinal disease, and why treatment requires antibiotics that can penetrate intracellular spaces and reach all affected organs.

From the Research

Pathophysiology of Typhoid Fever

• Typhoid fever is a bacterial infection caused by the Gram-negative bacterium Salmonella enterica subspecies enterica serovar Typhi (S. Typhi) 2
• The disease is prevalent in many low- and middle-income countries, and in high-income territories, it is predominantly travel-related 2
• The emergence of multidrug resistance and decreased ciprofloxacin susceptibility (DCS) in S. Typhi have rendered older drugs ineffective or suboptimal for typhoid fever 3

Treatment of Typhoid Fever

• The World Health Organization (WHO) currently recommends treatment with azithromycin, ciprofloxacin, or ceftriaxone due to widespread resistance to older, first-line antimicrobials 4
• Fluoroquinolones, such as gatifloxacin, may be more effective than ciprofloxacin and ofloxacin for patients infected with bacteria showing DCS 3
• Cephalosporins, such as ceftriaxone, may be an effective treatment for adults and children with enteric fever, with few adverse effects 4
• Azithromycin meets the criteria for effective treatment better than other drugs, including causing defervescence within 1 week, rendering blood and stool cultures sterile, and preventing relapse 3

Antibiotic Resistance

• Resistance patterns vary in different locations and are changing over time 4
• Fluoroquinolone resistance in South Asia often precludes the use of ciprofloxacin 4
• Extensively drug-resistant strains of enteric fever have emerged in Pakistan 4
• Clinicians need to take into account current, local resistance patterns in addition to route of administration when choosing an antimicrobial 4

Vaccination Strategies

• Vaccination is an effective way to prevent typhoid fever, especially for people living in typhoid-endemic regions 2
• There are several vaccines available to prevent typhoid fever, including oral and injectable vaccines 2
• Vaccine recommendations for people living in typhoid-endemic regions and travelers to these regions are available 2