Typhoid fever is a substantive global health problem with wide geographic distribution and significant morbidity and mortality. Typhoid fever should not be confused with typhus, which is a vector-borne rickettsial disease covered previously at Infection Landscapes. The clinical presentation is, however, somewhat similar with respect to neurologic symtpoms, which led to their similar nomenclature when early physicians would have difficulty distinguishing based on signs and symptoms alone. Nevertheless, these two diseases are otherwise quite distinct with respect to the causative organism, pathogenicity, mode of transmission, and landscape epidemiology. In fact, typhoid fever is more correctly known as enteric fever, though the former term is still very much in wide use.
The Pathogen. The causative agent for enteric fever is another serovar of Salmonella enterica enterica. The serovar responsible for enteric fever is Salmonella Typhi, while Salmonella Paratyphi causes a milder form of enteric fever (often referred to as paratyphoid fever). This organism is a gram negative bacillus with paritrichous flagella:
The bacteria target epithelial cells and microfold cells of the small intestine in the distal ileum in close proximity to the the Peyer's patches, which are important lymphoid tissue in the gut. Much like the other Salmonella serovars discussed previously, Salmonella Typhi employs a type III secretion system to inject proteins into the host cell, altering its cytoskeletal structure and inducing the uptake of the bacterium into the cytoplasm of the host cell. However, this serovar's pathogenicity is more invasive. Because of the location of infection in the small intestine, Salmonella Typhi typically invades the Peyer's patches and thereby accesses the lymphatic system, which ultimately leads to more widespread dissemination by way of the general circulation. Once in circulation, these Salmonellae can target cells in multiple organ systems. Most importantly, they infect macrophages, in which they replicate and are able to disseminate throughout the reticuloendothelial system.
The Disease. The clinical manifestation of enteric fever presents a diagnostic puzzle. Most of the symptoms are non-specific and often mimic other infections even when complicated. Indeed, the cognate, typhus, describes a very different infection, but nevertheless shares some similarities with the neurologic involvement and rash of enteric fever and thus the historical confusion between the two. Both typhoid and typhus are derived from the Greek word meaning stupor.
There are four clinical stages of enteric fever, each roughly one weak, though not all (or any) stages need present in a particular infection.
The first stage, when infection is symptomatic, may include malaise, dry coughing, headache, myalgia, and a fever of steadily increasing temperature. However, the other symptoms will often precede the fever. While fever is a classic symptom of enteric fever, it will not always occur in symptomatic cases, which can further complicate the diagnosis.
In the second stage of symptomatic infection, the fever typically levels off at a high temperature (between 39 and 40 degrees C) and is maintained over a prolonged period, often until the fourth week of infection. During this stage, hepatomegaly and/or splenomegaly appear with or without associated abdominal pain. Diarrhea and/or constipation are common gastroenteritis signs in the second stage, though diarrhea is more common in children and constipation is more common in adults. Delirium is also a frequent characteristic of enteric fever that usually manifests around the second week of infection in about 20% of symptomatic cases. In about 30% of cases, a mild rash consisting of flat rose spots appears on the chest and abdomen. Elevated liver enzymes, leukopenia, thrombocytopenia, and anemia are common laboratory findings by this stage.
The third stage, if it occurs, typically coincides with the 3rd week of infection. This is the time when more serious complications can present. A more intensive delirium is a common complication with individuals demonstrating increasing agitation and advanced stupor. Intestinal bleeding is common (up to 20% of cases), and intestinal perforation, while not as common (up to 3% of cases), is associated with high case-fatality because of the septicemia that follows. Encephalitis, meningitis, osteitis, endocarditis, and pericarditis are all potential complications of enteric fever, reflecting the wide dissemination and broad tropism exhibited by Salmonella Typhi.
The fourth stage is characterized by recovery. The fever and delirium begin to recede during this stage at week four (or even toward the end of the third week) in a slow progressive convalescence, which can last up to 2 or more months.
The chart below depicts some typical clinical symptoms of enteric fever, all of which are non-specific:
The Epidemiology and the Landscape. Enteric fever constitutes a significant global burden of disease with approximately 22 million cases per year and 200,000 deaths, which is substantively more than the burden represented by cholera. The case-fatality of untreated enteric fever is approximately 15%, but with appropriate antibiotic therapy it is, on average, less than 1%. However, in some parts of Asia and Africa where advanced resistance to antibiotic treatment has emerged, current case-fatality may be as high as 30%. The map below from CHU Rouen shows the global distribution of enteric fever with the brown and red shades highlighting endemic and hyperendemic countries, respectively.
The high risk regions typically experience greater than 100 incident cases per 100,000 persons in the population each year, while medium risk regions experience between 10 and 100 incident cases per 100,000 persons each year. Unlike most of the global burden of diarrheal disease covered at Infection Landscapes, enteric fever's greatest burden is not experienced by the youngest children in at risk populations. Rather, the disease is concentrated in older children aged 5 to 19 years. Nevertheless, in hyperendemic regions children aged 1 to 5 years can still experience a significant burden of disease. In addition, when enteric fever does occur in young children, especially those younger than 1 year of age, complications are much more common in the clinical course and the mortality is higher.
Humans are the only reservoir for both Samonella Typhi and Salmonella Paratyphi. Once infected, individuals are infectious beginning at some point during the subclinical period before symptoms present, and until the first week of recovery (i.e. stage 4 described above). However, 10% of those infected who do not receive treatment will continue shedding viable bacteria for up to 3 months following recovery. Up to 5% of untreated infected persons become chronic carries, potentially shedding Salmonella Typhi for the rest of their lives. This extended pathogen carriage following recovery, whether for the sizable proportion who shed bacteria for several months or the smaller proportion who shed bacteria for much of their lives, is one of the critical epidemiologic characteristics of enteric fever. Extended carriage ensures an ongoing source of contamination and, thus, maintains the primary mode of transmission in those regions where this disease is endemic.
Transmission is through the fecal-oral route, and ingestion of feces-contaminated water and food is the primary mode of transmission in most settings where enteric fever is endemic. Direct person to person contact can also be an important mode of transmission, but contaminated water and/or food is consistently the major source of new infections in endemic regions. As such, the geography of endemicity follows the lines of poverty, which, as with other gut infections we have covered at Infection Landscapes, are delineated by areas of poor sanitation and poor water infrastructure.
Control and Prevention. Control and prevention of enteric fever begins by following the usual guidelines: improving sanitation in resource poor areas and maintaining vigilance in personal hygiene. In most settings in the world where enteric fever is endemic, improved infrastructure that can maintain adequate water resources is a first priority in prevention.
Secondarily, personal hygiene at the individual level, especially in the context of food preparation, can also be very important in preventing enteric fever: consistent hand washing, boiling water, and thoroughly cooking food are all important in stopping the chain of transmission.
Vaccination against enteric fever should also be an important component to control and prevention in endemic regions. There are currently 2 vaccines recommended by the World Health Organization. The Ty21a is a live attenuated vaccine that is administered orally, and the Vi antigen vaccine is an inactivated vaccine that is administered intramuscularly or subcutaneously. The live vaccine induces both humoral and cell-mediated immunity and requires a 3 to 4 dose schedule, whereas the inactivated vaccine is a one-time injection and induces only a humoral response with significant antibody production, but no memory cells. The efficacy of the live vaccine approaches 80%, but some studies have shown it to be as low as 50%. The range of efficacy for the inactivated vaccine is similar (55% to 77%). As expected, the immunity from the live vaccine is longer lived (approximately 5 years) than that induced by the inactivated vaccine (approximately 2 years), necessitating booster vaccines in both when immunity wanes.
Here is a good summary of prevention strategy from a Kenyan physician: