Typhoid Fever: Pathophysiology and Risk Factors


Typhoid fever, also known as enteric fever, is a potentially fatal multisystem disease caused mainly by enteric Salmonella.

The protean manifestations of typhoid fever make this disease a real challenge in its diagnosis.

The classic presentation includes fever, malaise, diffuse abdominal pain, and constipation.

Without treatment, typhoid fever is a severe disease that can progress to delirium, intestinal bleeding, intestinal perforation, and even death within the first month of onset.

Survivors may be left with long-term or permanent neuropsychiatric complications.

This fever has been an important human pathogen for thousands of years, thriving in sanitation conditions, overcrowding, and social chaos. He may have been responsible for the Great Plague of Athens at the end of the Peloponnese War.


As anecdotal data, its name derives from the ancient Greek typhus, an ethereal smoke or cloud that is believed to cause disease and madness.

In the advanced stages of typhoid fever, the level of consciousness of the patient is cloudy.

Although antibiotics have markedly reduced the frequency of typhoid fever in the developed world, it is still endemic in developing countries because it causes the same syndrome. It may be taking the place of typhus, in part, due to naïveness among the population and incomplete coverage by vaccines that target this condition.

Pathophysiology of Typhoid Fever

When present in the intestine, all the pathogenic Salmonella species are swallowed by phagocytic cells, which then pass them through the mucosa and present them to the macrophages of the lamina propria.

Nontyphoidal salmonellae are phagocytosed along the distal ileum and colon. Macrophages recognize molecular patterns associated with pathogens, such as flagella and lipopolysaccharides, with the toll-like receptor.

Macrophages and intestinal epithelial cells attract T cells and neutrophils with interleukin 8, causing inflammation and suppressing infection.

In contrast to nontyphoidal salmonellae, the so-called paratyphi enters the host system mainly through the distal ileum.

They have specialized fimbria that adheres to the epithelium on clusters of lymphoid tissue in the ileum (Peyer patches), the main point of reentry of the macrophages that travel from the intestine to the lymphatic system. The bacteria then induce their host macrophages to attract more macrophages.

The enteric Salmonella has a capsular antigen that masks the PAMPs, avoiding neutrophil-based inflammation, while the more common paratyphi, the serovar, the paratyphi A, does not.

This may explain the greater infectivity of the syndrome compared to most of its cousins.

Typhoid salmonella co-opts the cellular machinery of macrophages for its reproduction. They are carried through the mesenteric lymph nodes to the thoracic duct and the lymphatics and then to the reticuloendothelial tissues of the liver, spleen, bone marrow, and lymph nodes.

Once there, they stop and continue multiplying until reaching a critical density. Subsequently, the bacteria induce the apoptosis of the macrophages, leaving the bloodstream to invade the rest of the body.

The bacteria then infect the gallbladder through bacteremia or direct spread of the infected bile.

The result is that the organism re-enters the gastrointestinal tract of the bile and reinfects Peyer’s patches. Bacteria that do not reinfect the host usually throw themselves in the stool and are then available to infect other hosts.

Is this disease necessarily, of immediate appearance?

Chronic carriers are responsible for much of the transmission of the organism. While they are asymptomatic, they can continue to shed bacteria in their feces for decades.

The organisms sequester themselves as a biofilm in gallstones or epithelium of the gallbladder or, perhaps, intracellularly, within the epithelium itself.

Bacteria excreted by a single carrier can have multiple genotypes, making it challenging to locate an outbreak at its source.

Risk factors with the bacteria causing Typhoid Fever

Typhoid salmonella has no non-human vectors. An inoculum is as tiny as 100,000 typhus organisms and causes infection in more than 50% of healthy volunteers. It requires a much higher inoculum to infect and is less endemic in rural areas. Therefore, the transmission patterns are slightly different.

The following are modes of transmission of typhoid salmonella:

  • Oral transmission through food or beverages handled by an often asymptomatic individual – a carrier – who chronically spills the bacteria through the stool or, less commonly, the urine
  • Hand-to-mouth transmission after using a contaminated bath and neglecting hand hygiene
  • Oral transmission through water contaminated with wastewater or shellfish (especially in developing countries).

This Salmonella is most commonly transmitted in foods of street vendors. It is believed that some of these foods provide a friendly environment for microbes.

Paratyphi is more common among newcomers to urban areas, probably because they tend to be immunologically unsafe to it. In addition, travelers receive little or no protection against it through vaccines.

Bacteria such as Typhoid Salmonella can survive in a stomach with a pH as low as 1.5. Antacids, histamine-2 receptor blockers (H2 blockers), proton pump inhibitors, gastrectomy, and achlorhydria decrease stomach acidity and facilitate S. Typhi infection.

HIV / AIDS is associated with an increased risk of non-steroidal Salmonella infection; however, the data and opinions in the literature about whether this is true for S. typhi or paratyphi infection are conflicting.

If there is an association, it is probably smaller.

Other risk factors for typhoid fever include various genetic polymorphisms. These risk factors often also predispose to other intracellular pathogens.

For example, PARK2 and PACGR are part of a code for an aggregate of proteins essential for breaking down bacterial signaling molecules that moisten the response of macrophages.

Polymorphisms in their shared regulatory region are disproportionately found in people infected with Mycobacterium leprae and S Typhi.

On the other hand, protective mutations of the host also exist. The fimbriae of S Typhi bind in vitro to the transmembrane cystic fibrosis conductance receptor (CFTR), expressed in the intestinal membrane.

In conclusion, body and environmental hygiene will always play a key and integral role in effectively neutralizing typhoid fever’s age-old destructive and infectious power.