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Examining Salmonella Typhi and Typhoid Fever

by Dr. Jaclynn Moskow

Typhoid fever refers to the disease caused by Salmonella typhi (Salmonella enterica subsp. enterica serovar Typhi), a facultative anaerobic Gram-negative bacillus. Both typhoid fever and its close relative paratyphoid fever are sometimes referred to as “enteric fever.” As the name enteric fever implies, the illness is often characterized by gastrointestinal symptoms and fever.

Green houseflies feeding on ripe mango using their labellum to suck the meat

Transmission

Humans are the only natural reservoir for Salmonella typhi, and transmission occurs via the fecal-oral route. Transmission may occur after eating food that was prepared by someone carrying the bacterium or after using a contaminated toilet and failing to follow proper hand hygiene. Transmission can also occur by drinking water contaminated by sewage, or by eating food prepared in contaminated water. Flies can carry the bacteria from sewage to food.

The average incubation period for typhoid fever is 15 to 21 days, but symptoms may develop as soon as 5 days post transmission or as late as 34 days. Both children and adults contract typhoid fever. In some outbreaks, typhoid fever has primarily affected school-aged children, with cases in infants and toddlers being quite rare. In recent years, very young children have also proven extremely susceptible to the disease.[1]

Chronic Carriers and the Case of Typhoid Mary

Salmonella typhi may continue to shed in feces after a patient has recovered from the disease, and such individuals may become asymptomatic carriers of the bacteria. Approximately five percent of people who contract Salmonella typhi infection will become chronic carriers. 25% of carriers experienced no signs or symptoms of the disease.[2]  Females are more likely than males to become chronic carriers.  In chronic carriers, Salmonella typhi takes refuge in macrophages [3] and the gall bladder.

The most infamous carrier of typhoid fever was Mary Mallon, also known as “Typhoid Mary.” Mary was born in Ireland and immigrated to New York at the turn of the 20th century. She worked as a cook for eight affluent families, seven of which contracted Typhoid Fever.[4] These high-profile infections eventually led to an investigation and to Mary’s forced quarantine. After her release, she defied orders and continued to work as a cook, using various aliases. She stopped working for private clients and worked instead at several public restaurants as well as at Sloane Maternity Hospital.

51 cases of typhoid fever were traced to Mary, including three fatalities. [5] It is likely that Mary actually infected and killed many times this amount. In 1915, she was located and detained a second time, eventually dying after a period of 23 years in forced quarantine. Mary never believed she was the source of any infections, as she had no symptoms of the disease.

Signs and Symptoms

Typhoid fever can have a very nonspecific clinical presentation. Generally, initial enterocolitis develops, without associated fever. Patients may experience constipation or diarrhea, associated with abdominal pain and vomiting. Hematochezia may occur. Hepatosplenomegaly is present in 50% of cases and jaundice may also develop. Some patients develop cholecystitis or pancreatitis.

A short asymptomatic phase may proceed with the onset of fever.  Once fever develops, it often follows a “step-ladder” pattern, rising and subsequently falling before rising again. Additional flu-like symptoms may include chills, diaphoresis, headache, sore throat, cervical lymphadenopathy, cough, and myalgia. Pneumonia may develop and bradycardia is often noted. During the second week of illness, 30% of patients develop a rash referred to as “rose spots.” Initial leukocytosis is often seen, followed by leukopenia. Thrombocytopenia, coagulopathy, and hepatic dysfunction may also be noted.

Some patients will go on to develop an intestinal perforation, generally in the 3rd or 4th week of illness. Intestinal perforation is more common in males than in females. Typhoid fever is dangerous for pregnant women, with 70% of untreated cases ending in miscarriage. Additionally, transmission from mother to fetus and subsequent neonatal typhoid can occur.

Systemic inflammation may lead to such complications as myocarditis, endocarditis, pericarditis, and mycotic aneurysm. Some patients develop meningitis or encephalitis. Spondylitis/spondylodiscitis, rhabdomyolysis, and hemophagocytic lymphohistiocytosis have also been seen – as have endophthalmitis, cranial nerve palsy, and Guillain-Barre syndrome.

Typhoid fever can induce neuropsychiatric symptoms. Encephalopathy occurs in 21% of cases. Psychosis or confusion occurs in 5 to 10%. Seizures and coma occur less commonly. The term “typhoid state” (from the Greek word “typhos” –  meaning “clouded”) is sometimes used to refer to changes in mental status.

Without treatment, symptoms of typhoid fever will generally resolve in approximately one month. About ten percent of patients with typhoid fever will experience relapse, more common among those who received treatment than those who did not. Typhoid fever is more severe among patients with HIV infection, malaria, and sickle cell anemia. Long-term carriers have a higher incidence of cancers of the gallbladder, pancreas, colon, and lung. The case-fatality rate for untreated typhoid fever is approximately 15% – vs. 0.8% with treatment.

Illustration of typhoid fever

Diagnosis and Treatment

Diagnosis is made via culture of blood, urine, sputum, or bone marrow. Stool cultures are often negative except in very late infection. Previously, the Widal test was used to detect serum antibody titers against Salmonella typhi O and H antigens. However, this test has a high rate of both false negatives and false positives and is thus unreliable. 

Both Ceftriaxone and Azithromycin can be used to treat typhoid fever. Fluoroquinolones are no longer recommended, in view of the emergence of resistant strains. Corticosteroids may be used when there is evidence of widespread systemic involvement. Health-care personnel should follow stool precautions. Most carriers can be cured with antibiotics. Carriers with cholelithiasis usually remain positive after antibiotic treatment and will require cholecystectomy.

Prevalence 

Over the last three decades, typhoid fever has affected between 11 to 21 million people per year, worldwide.  Incidence has been declining in many countries. 

Typhoid, estimated cases worldwide 1990 - today

The countries reporting most cases include Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, and Vietnam. High rates also occur in Africa and Central and South America. If you have a GIDEON account, click to explore the typhoid fever outbreak map. 

The CDC reports that approximately 350 people in the United States receive treatment for typhoid fever each year and that as many as 5,700 people are likely to be infected.[6]  Most cases in the United States result from travel to endemic areas. Occasionally, cases arise from other sources, such as from contaminated imported food. A review of outbreaks in the United States can be found here.

Prevention

Cases of typhoid fever and other waterborne diseases will decline as access to clean water increases and as sanitary conditions improve.  The CDC recommends receiving a typhoid fever vaccine prior to travel to countries with high incidence. Both oral and injectable vaccines are available – both with approximately 50 to 80% efficacy in preventing disease. When traveling, precautions should include adherence to proper hand hygiene, drinking only bottled water, and avoiding uncooked food.

Paratyphoid Fever and Typhus

Typhoid fever is clinically similar to Paratyphoid fever and some forms of Typhus. Paratyphoid fever is a form of enteric fever caused by a Salmonella paratyphi (Salmonella enterica serotypes Paratyphi A, Paratyphi B, or Paratyphi C). Clinically, it may be indistinguishable from typhoid fever and it is transmitted via the same routes. Salmonella paratyphi causes fewer cases of enteric fever than Salmonella typhi

Typhus refers to diseases caused by Rickettsia typhi, Rickettsia prowazekii, and Orientia tsutsugamushi.  Typhus is transmitted by fleas, mites, or lice. During the 19th century, typhoid and typhus were believed to be two forms of a single disease. Like typhoid fever, typhus usually causes flu-like symptoms and a rash, and often with gastrointestinal symptoms. The various forms of typhus are less common than typhoid – and are each reported in specific geographical regions. 

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References

[1] A Sinha, S Sazawal, R Kumar, et al., “Typhoid fever in children aged less than 5 years”, Lancet, vol. 28, num. 354, pp. 734-7, 1999. Available: 10.1016/S0140-6736(98)09001-1

[2] C Parry, T Hien, G Dougan, et al., “Typhoid fever”, N Engl J Med, vol. 347, num. 22, pp. 1770-82, 2002. Available: 10.1056/NEJMra020201

[3] N Eisele, T Ruby, A Jacobson et al., “Salmonella require the fatty acid regulator PPARδ for the establishment of a metabolic environment essential for long-term persistence”, Cell Host Microbe, vol. 14, num. 2, pp. 171-182, 2013. Available: 10.1016/j.chom.2013.07.010

[4] Marineli F, Tsoucalas G, Karamanou M, Androutsos G. Mary Mallon (1869-1938) and the history of typhoid fever. Ann Gastroenterol. 2013;26(2):132-134. [Online]. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959940/

[5] “’Typhoid Mary’ Dies Of A Stroke At 68. Carrier of Disease, Blamed for 51 Cases and 3 Deaths, but Immune”, The New York Times, November 12, 1938. [Online]. Available: https://www.nytimes.com/1938/11/12/archives/typhoid-mary-dies-of-a-stroke-at-68-carrier-of-disease-blamed-for.html

[6] Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Foodborne, Waterborne, and Environmental Diseases (DFWED), “Typhoid Fever and Paratyphoid Fever: Questions and Answers”. [Online]. Available: https://www.cdc.gov/typhoid-fever/sources.html 

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