Typhoid Fever


Clinical Description


A systemic bacterial disease with insidious onset of sustained fever, marked headache, malaise, anorexia, relative bradycardia, splenomegaly, nonproductive cough in the early stage of the illness, rose spots on the trunk in 25% of white-skinned patients and constipation more often than diarrhea in adults. The clinical picture varies from mild illness with low-grade fever to severe clinical disease with abdominal discomfort and multiple complications. Severity is influenced by factors such as strain virulence, quantity of inoculum ingested, duration of illness before adequate treatment, age and previous exposure to vaccination.

Unapparent or mild illnesses occur, especially in endemic areas; 60%–90% of patients with typhoid fever do not receive medical attention or are treated as outpatients. Mild cases show no systemic involvement; the clinical picture is that of a gastroenteritis. Nonsweating fevers, mental dullness, slight deafness and parotitis may occur. Peyer patches in the ileum can ulcerate, with intestinal hemorrhage or perforation (about 1% of cases), especially late in untreated cases. Severe forms with altered mental status have been associated with high casefatality rates. The case-fatality rate of 10%–20% observed in the preantibiotic era can fall below 1% with prompt antimicrobial therapy. Depending on the antimicrobials used, 15%–20% of patients may experience relapses (generally milder than the initial clinical illness).

Paratyphoid fever, caused by Salmonella enterica subsp. enterica serovars Paratyphi. A, B, and C (commonly S. Paratyphi A, B and C), presents a similar clinical picture. Serovar Paratyphi B refers to the invasive biotype that is associated with paratyphoid fever. A tartrate fermenting variant, referred to as serovar Paratyphi B var L(+) tartrate+, or var. Java, is associated with routine gastrointestinal disease. Since the distinction between these two biovars is currently based on a single phenotypic trait, they can be easily confused. The ratio of disease caused by Salmonella enterica subsp. enterica serovar Typhi (commonly S. Typhi, the latter not italicized) to that caused byS. Paratyphi A and B is estimated to be about 4:1. Relapses occur in approximately 3%–4% of cases. S. Paratyphi C infections are rare.

Infectious Agents

In the recently proposed nomenclature for Salmonella the agent formerly known as S. typhi is called S. enterica subsp. enterica serovar Typhi (commonly S. Typhi). Paratyphoid fever is caused mainly by S. Paratyphi A and Paratyphi B, but also by Paratyphi C in rare cases. Note that each of the Paratyphi serotypes belongs to a different O-group of Salmonella referred to in its name; S. Typhi belongs to O-group D.


The causal organisms can be isolated from blood early in the disease, and from urine and feces after the first week. Blood culture is the diagnostic mainstay for typhoid fever, but bone marrow culture provides the most sensitive method for bacteriological confirmation even in patients who have already received antimicrobials. Because of limited sensitivity and specificity, serological tests based on agglutinating antibodies (Widal) are generally of little diagnostic value. New rapid sero-diagnostic tests based upon the detection of specific antibodies appear very promising, but their current sensitivity and specificity limit usefulness in routine practice.


Mode of Transmission

Ingestion of food and water contaminated by feces and urine of patients and carriers. Important vehicles in some countries include shellfish (particularly oysters) from sewage-contaminated beds, raw fruit, vegetables fertilized by night soil and eaten raw, and contaminated milk/milk products (usually contaminated through hands of carriers). Flies may infect foods in which the organism then multiplies to infective doses (those are reportedly lower fortyphoid than for paratyphoid bacteria). Epidemiological data suggest that, while waterborne transmission of S. Typhi usually involves small inocula, food-borne transmission is associated with large inocula and high attack rates over short periods. Sexual transmission of typhoid fever from an asymptomatic carrier has been documented.

Incubation Period

Depends on inoculum size and on host factors; from 3 days to over 60 days—usual range 8–14 days; the incubation period for paratyphoid fever is 1–10 days.

Period of Communicability

As long as bacilli appear in excreta, usually from the first week throughout convalescence; variable thereafter (commonly 1–2 weeks for paratyphoid). About 10% of untreated typhoid fever patients discharge bacilli for 3 months after onset of symptoms; 2%–5% become permanent carriers. Fewer persons infected with paratyphoid organisms may become permanent gallbladder carriers.


Humans for both typhoid and paratyphoid; questionably, domestic animals for paratyphoid. Family contacts may be transient or permanent carriers. A carrier state may follow acute illness or mild or even sub-clinical infections. In most parts of the world, short-term fecal carriers are more common than urinary carriers. The chronic carrier state is most common (2%–5%) among persons infected during middle age, especially women; carriers frequently have biliary tract abnormalities including gallstones, with S. Typhi located in the gallbladder. The chronic urinary carrier state may occur with schistosome infections or kidney stones.


Susceptibility is general and is increased in individuals with gastric achlorhydria. One study has suggested that susceptibility may be increased in persons who are HIV-positive. Relative specific immunity follows recovery from clinical disease, unapparent infection and active immunization. In endemic areas, typhoid fever is most common in preschool children and children 5–19.


Worldwide, the annual estimated incidence of typhoid fever is about 22 million cases with approximately 200 000 deaths. Most of the burden of the disease occurs in the developing world. The burden is sporadic in industrialized countries; currently most cases in the industrialized world are acquired during travel in endemic areas. Paratyphoid fever occurs sporadically or in limited outbreaks, probably more frequently than reports suggest. Of the 3 serotypes, Paratyphi A is most common, Paratyphi B is less frequent, and Paratyphi C is extremely rare. In parts of China and Pakistan, more cases have been reported as caused by S. Paratyphi than by S. Typhi.

Prevention and Control

1)    Preventive measures:

Prevention is based on access to safe water and proper sanitation, as well as adherence to safe food-handling practices.

a)    Educate the public regarding the importance of hand-washing. Provide suitable hand-washing facilities, particularly for food handlers and attendants involved in the care of patients and children.

b)    Dispose of human feces safely, and maintain fly-proof latrines. Where culturally appropriate, encourage use of sufficient toilet paper to minimize finger contamination. Under field conditions, dispose of feces by burial at a site distant and downstream from the source of drinking water.

c)    Protect, purify and chlorinate public water supplies, provide safe private supplies, and avoid possible backflow connections between water and sewer systems. For individual and small group protection, and during travel or in the field, treat water chemically or by boiling.

d)    Control flies by screening and use of insecticidal baits and traps or, where appropriate, spraying with insecticides. Control fly-breeding through frequent garbage collection and disposal, and through fly control measures in latrine construction and maintenance.

e)    Use scrupulous cleanliness in food preparation and handling; refrigerate as appropriate. Pay particular attention to the storage of salads and other foods served cold. These provisions apply to home and public eating-places. If uncertain about sanitary practices, select foods that are cooked and served hot, and fruit that is peeled by the consumer.

f)    Pasteurize or boil all milk and dairy products. Supervise the sanitary aspects of commercial milk production, storage and delivery.

g)    Enforce suitable quality-control procedures in industries that prepare food and drink for human consumption. Use chlorinated water for cooling during canned food processing.

h)    Limit the collection and marketing of shellfish to supplies from approved sources. Boil or steam (for at least 10 minutes) before serving.

i)    Instruct the community, patients, convalescents and carriers in personal hygiene. Emphasize hand-washing as a routine practice after defecation and before preparing, serving or eating food.

j)    Encourage breast-feeding throughout infancy; boil all milk and water used for infant feeding.

k)    Typhoid carriers should be excluded from handling food and from providing patient care. Identify and supervise typhoid carriers; culture of sewage may help in locating them. Chronic carriers should not be released from supervision and restriction of occupation until local or state regulations are met, often not until 3 consecutive negative cultures are obtained from authenticated fecal specimens (and urine in areas endemic for schistosomiasis), at least 1 month apart and at least 48 hours after antimicrobial therapy has stopped. Fresh stool specimens are preferred to rectal swabs. It has been suggested that at least 1 of the 3 consecutive negative stool specimens should be obtained by purging.

Administration of 750 mg of ciprofloxacin or 400 mg of norfloxacin twice daily for 28 days provides successful treatment of carriers in 80–90% of cases. Limited studies have suggested 14–21 days of treatment to be equally efficacious. Follow-up cultures are necessary to confirm cure.

l)    Immunization for typhoid fever is not routinely recommended in non-endemic areas except for those subject to unusual occupational exposure to enteric infections (e.g. clinical microbiology technicians) and household members of known carriers. WHO recommends vaccination for people who travel to endemic high-risk areas and school-age children living in endemic areas where typhoid fever control is a priority. Vaccination of high-risk populations is considered the most promising strategy for the control of typhoid fever. No vaccines for paratyphoid fever are currently available.

An oral, live vaccine using S. Typhi strain Ty21a (requiring 3 or 4 doses, 2 days apart) and a parenteral vaccine containing the single dose polysaccharide Vi antigen are available; these are as protective as the whole cell bacteria vaccine (which has been removed from the market) and much less reactogenic. However, Ty21a should not be used in patients receiving antibiotics until 24 hours or more after the last antibiotic dose. Booster doses every 2 to 5 years, according to vaccine type, are desirable for those at continuing risk of infection. In field trials, oral Ty21a conferred partial protection against paratyphoid B, but not as well as it protected against typhoid. Neither vaccine is licensed for children less than 2 years old; Ty21a is only licensed for children 6 years old and older in the US, but is licensed for younger children in other countries.

A new Vi vaccine conjugated to a nontoxic recombinant Pseudomonas aeruginosa exotoxin A (rEPA) was shown in Vietnam to have more than 90% efficacy, and to be potentially immunogenic in younger children. This promising new vaccine has not yet been licensed.

2)    Control of patient, contacts and the immediate environment:

a)    Report to local health authority: Obligatory case report in most countries, Class 2.

b)    Isolation: Enteric precautions while ill; hospital care is desirable during acute illness. Release from supervision by local health authority based on not fewer than 3 consecutive negative cultures of feces (and urine in patients with schistosomiasis) at least 24 hours apart, at least 48 hours after any antimicrobials, and not earlier than 1 month after onset. If any of these is positive, repeat cultures at monthly intervals during the 12 months following onset until at least 3 consecutive negative cultures are obtained.

c)    Concurrent disinfection: Of feces, urine and articles soiled therewith. In communities with adequate sewage disposal systems, feces and urine can be disposed of directly into sewers without preliminary disinfection. Terminal cleaning.

d)    Quarantine: Not applicable.

e)    Immunization of contacts: Routine administration of typhoid vaccine is of limited value for family, household and nursing contacts who have been or may be exposed to active cases; it should be considered for those who may be exposed to carriers on a prolonged basis. There is no effective immunization for paratyphoid fever.

f)    Investigation of contacts and source of infection: Determine actual or probable source of infection of every case through search for unreported cases, carriers or contaminated food, water, milk or shellfish. All members of travel groups in which a case has been identified should be followed.

The presence of elevated antibody titers to purified Vi polysaccharide is highly suggestive of the typhoid carrier state, especially in the setting of an epidemiologically consistent history. Identification of the same phage type or molecular subtype in the carrier and in organisms isolated from patients suggests a possible chain of transmission.

Consideration should be given to obtaining 2 negative feces and urine cultures, taken at least 24 hours apart, from household and close contacts before allowing them to be employed in sensitive occupations (e.g. as food handlers).

g)    Specific treatment: Evidence suggests that fluoroquinolones are the drug of choice in adults. However, recent emergence of decreased susceptibility, and frank resistance to fluoroquinolones in both S. Typhi and S. Paratyphi A, restricts widespread and indiscriminate use in primary care facilities and mandates antimicrobial testing of all isolates. If local strains are known to be sensitive to traditional first-line antibiotics, oral chloramphenicol, amoxicillin or trimethoprim-sufoxazole (particularly in children) should be used in accordance with local antimicrobial sensitivity patterns. Ceftriaxone, a parenteral once-daily antibiotic, is useful in patients with dulled perceptions or those with complications such that oral antibiotics cannot be used. Shortterm, high-dose corticosteroid treatment, combined with specific antibiotics and supportive care, reduces mortality in critically ill patients (see 9A11 for treatment of carrier state). Patients with concurrent schistosomiasis must also be treated with praziquantel to eliminate possible schistosome carriage of S. Typhi. Patients with confirmed intestinal perforation need intensive care as well as surgical intervention. Early intervention is crucial, as morbidity rates increase with delayed surgery after perforation.

Strains resistant to chloramphenicol and other recommended antimicrobials have become prevalent in several areas of the world. Most isolates from southern and southeastern Asia, the Middle East and northeastern Africa in the 1990s carry an R factor plasmid encoding resistance to those antimicrobial agents that were previously the mainstay of oral treatment, including chloramphenicol, ampicillin and trimethoprim/sufamethoxazole. Resistance to fluoroquinolones continues to emerge rapidly, especially in Asia. For treatment of Salmonella infections resistant to Nalidixic Acid, Erythromycin seems to be effective.

3)    Epidemic measures:

a)    Search intensively for the case/carrier who is the source of infection, and for the vehicle (water or food) through which infection was transmitted.

b)    Selectively eliminate suspected contaminated food. Pasteurize or boil milk, or exclude milk supplies and other foods suspected on epidemiological evidence, until safety is ensured.

c)    Chlorinate suspected water supplies adequately under competent supervision, or avoid use. All drinking water must be chlorinated, treated with iodine, or boiled before use.

d)    Use of vaccine should be considered before or during an outbreak; a protective efficacy of over 70% was recently obtained among immunized school-age children during an outbreak in China.

4)    Disaster implications:

With disruption of usual water supply and sewage disposal, and of controls on food and water, transmission and large-scale outbreaks of typhoid fever may occur if there are active cases or carriers in a displaced population. Efforts are advised to restore safe drinking-water supplies and excreta disposal facilities. Selective immunization of stabilized groups such as school children, prisoners and utility, municipal or hospital personnel may be helpful.

5)    International measures:

a)    For typhoid fever: Immunization is advised for international travelers to endemic areas, especially if travel is likely to involve exposure to unsafe food and water, or close contact in rural areas to indigenous populations. Immunization is not a legal requirement for entry into any country.

b)    WHO Collaborating Centres provide support as required. More information can be found at: http://www.who.int/collaboratingcentres/database/en/

Source: Heymann (Ed.). (2008). Control of Communicable Diseases Manual, 19th edition. Washington, DC: American Public Health Association.

Available Vaccines

WHO-Prequalified Typhoid Fever Vaccines

Common Disease Taxonomy: