Typhoid Fever

Typhoid Fever

Definition
Typhoid fever is a severe infection caused by a bacterium, Salmonella typhi. S. typhi is in the same family of bacteria as the type spread by chicken and eggs, commonly known as salmonella poisoning or food poisoning. S. typhi bacteria do not have vomiting and diarrhea as the most prominent symptoms of their presence in humans. Instead, persistently high fever is the hallmark of S. typhi infection.

Description
S. typhi bacteria are passed into the stool and urine of infected patients. They may continue to be present in the stool of asymptomatic carriers, who are persons who have recovered from the symptoms of the disease but continue to carry the bacteria. This carrier state occurs in about 3% of all individuals recovered from typhoid fever.

Typhoid fever is passed from person to person through poor hygiene, such as incomplete or no hand washing after using the toilet. Persons who are carriers of the disease and who handle food can be the source of epidemic spread of typhoid. One such individual gave her name to the expression "Typhoid Mary," a name given to someone whom others avoid.

Typhoid fever is a particularly difficult problem in parts of the world with poor sanitation practices. There are about 16 million cases of typhoid reported around the world each year. In the United States, most patients who contract typhoid fever have recently returned from travel to another country where typhoid is much more common, including Mexico, Peru, Chile, India, and Pakistan. However, there have been reports in the early 2000s of typhoid outbreaks within the United States that were unrelated to recent travel. One such outbreak occurred in Queens, New York, and was traced to a worker in a local restaurant.

Causes and symptoms
S. typhi must be ingested to cause disease. Transmission often occurs when a person in the carrier state does not wash hands thoroughly (or not at all) after defecation and serves food to others. This pathway is sometimes called the fecal-oral route of disease transmission. In countries where open sewage is accessible to flies, the insects land on the sewage, pick up the bacteria, and then contaminate food to be eaten by humans.
After being swallowed, the S. typhi bacteria head down the digestive tract, where they are taken in by cells called mononuclear phagocytes. These phagocytes are cells of the immune system, whose job it is to engulf and kill invading bacteria and viruses. In the case of S. typhi, however, the bacteria are able to survive ingestion by the phagocytes, and multiply within these cells. This period of time, during which the bacteria are multiplying within the phagocytes, is the 10 to 14-day incubation period of typhoid fever. When huge numbers of bacteria fill an individual phagocyte, they spill out of the cell and into the bloodstream, where their presence begins to cause symptoms.
The presence of increasingly large numbers of bacteria in the bloodstream (bacteremia) is responsible for an increasingly high fever, which lasts throughout the four to eight weeks of the disease in untreated individuals. Other symptoms of typhoid fever include constipation (at first), extreme fatigue, headache, joint pain, and a rash across the abdomen known as rose spots.
The bacteria move from the bloodstream into certain tissues of the body, including the gallbladder and lymph tissue of the intestine (called Peyer's patches). The tissue's response to this invasion causes symptoms ranging from inflammation of the gallbladder (cholecystitis) to intestinal bleeding to actual perforation of the intestine. Perforation of the intestine refers to an actual hole occurring in the wall of the intestine, with leakage of intestinal contents into the abdominal cavity. This leakage causes severe irritation and inflammation of the lining of the abdominal cavity, which is called peritonitis. Peritonitis is a frequent cause of death from typhoid fever.
Other complications of typhoid fever include liver and spleen enlargement, sometimes so great that the spleen ruptures or bursts; anemia, or low red blood cell count due to blood loss from the intestinal bleeding; joint infections, which are especially common in patients with sickle cell anemia and immune system disorders; pneumonia caused by a bacterial infection—usually Streptococcus pneumoniae—which is able to take hold due to the patient's weakened state; heart infections; and meningitis and infections of the brain, which cause mental confusion and even coma. It may take a patient several months to recover fully from untreated typhoid fever.

Common risk factors in the development of typhoid fever are:

*Travel to endemic areas
*Poor hygiene habits
*Poor sanitation conditions
*Proximity to flying insects feeding on feces
*Contact with someone who recently suffered from typhoid fever
*Recent use of antibiotics
*Achlorhydria
*Immunosuppressive illnesses such as AIDS
*Crowded housing
*Consumption of raw fruits and vegetables contaminated with sewage
*Prolonged illness
*Being a health care worker
*Being a clinical microbiologists who *handles salmonella typhi
*Childhood

Protective factors
Presence of certain biological characteristics may confer protection against typhoid fever.

Transmission
The typhoid bacillus is transmitted by consumption of contaminated food or water. Occasionally, direct faecal–oral transmission may occur. Shellfish taken from sewage-polluted areas are an important source of infection; transmission also occurs through eating raw fruit and vegetables fertilized by human excreta and through ingestion of contaminated milk and milk products. Flies may cause human infection through transfer of the infectious agents to foods. Pollution of water sources may produce epidemics of typhoid fever when large numbers of people use the same source of drinking-water.

Nature of the disease
Typhoid fever is a systemic disease of varying severity. Severe cases are characterized by gradual onset of fever, headache, malaise, anorexia and insomnia. Constipation is more common than diarrhoea in adults and older children. Without treatment, some patients develop sustained fever, bradycardia, hepatosplenomegaly, abdominal symptoms and, occasionally, pneumonia. In white-skinned patients, pink spots, which fade on pressure, appear on the skin of the trunk in up to 20% of cases. In the third week, untreated cases may develop gastrointestinal and cerebral complications, which may prove fatal in up to 10–20% of cases. The highest casefatality rates are reported in children <4 years of age. Around 2–5% of those who contract typhoid fever become chronic carriers, as bacteria persist in the biliary tract after symptoms have resolved.

Geographical distribution
There is a higher risk of typhoid fever in countries or areas with low standards of hygiene and water supply facilities.

Risk for travellers
The risk for travellers is generally low, except in parts of northern and western Africa, in southern Asia, in parts of Indonesia and in Peru. Elsewhere, travellers are usually at risk only when exposed to low standards of hygiene. Even vaccinated travellers should take care to avoid consumption of potentially contaminated food and water as the vaccine does not confer 100% protection.

Diagnosis
In some cases, the doctor may suspect the diagnosis if the patient has already developed the characteristic rose spots, or if he or she has a history of recent travel in areas with poor sanitation. The diagnosis, however, is confirmed by a blood culture. Samples of a patient's stool, urine, and bone marrow can also be used to grow S. typhi in a laboratory for identification under a microscope. Cultures are the most accurate method of diagnosis. Blood cultures usually become positive in the first week of illness in 80% of patients who have not taken antibiotics.

Treatment
Antibiotics are the treatment of choice for typhoid fever. As of the early 2000s, the most frequently used drugs are ceftriaxone and cefoperazone. Ciprofloxacin is sometimes given as follow-up therapy.
Carriers of S. typhi must be treated even when they do not show any symptoms of the infection, because carriers are responsible for the majority of new cases of typhoid fever. Eliminating the carrier state is actually a fairly difficult task. It requires treatment with one or even two different medications over a period of four to six weeks. The antibiotics most commonly given are ampicillin (sometimes given together with probenecid) and amoxicillin. In the case of a carrier with gallstones, surgery may need to be performed to remove the gallbladder. This measure is necessary because typhoid bacteria are often housed in the gallbladder, where they may survive in spite of antibiotic treatment. In some patients, however, treatment with rifampin and trimethoprim-sulfamethoxazole is sufficient to eradicate the bacteria from the gallbladder without surgery.

Prognosis
The prognosis for recovery is good for most patients. In the era before effective antibiotics were discovered, about 12% of all typhoid fever patients died of the infection. Now, however, fewer than 1% of patients who receive prompt antibiotic treatment will die. The mortality rate is highest in the very young and very old, and in patients suffering from malnutrition. The most ominous signs are changes in a patient's state of consciousness, including stupor or coma.

Prevention
Hygienic sewage disposal systems in a community as well as proper personal hygiene are the most important factors in preventing typhoid fever. Immunizations are available for travelers who expect to visit countries where S. typhi is a known public health problem. Some of these immunizations provide only short-term protection (for a few months), while others may be effective for several years. Efforts are being made to develop vaccines that provide a longer period of protection with fewer side effects from the vaccine itself. The most commonly reported side effects are flu-like muscle cramps and abdominal pain. As of earlt 2004, these vaccines are also being studied as possible antibioterrorism agents.

Resources
Books
Beers, Mark H., MD, and Robert Berkow, MD., editors. "Enterobacteriaceae Infections." In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.
Periodicals
Begier,E.M., D. R. Burwen, P. Haber, et al. "Postmarketing Safety Surveillance for Typhoid Fever Vaccines from the Vaccine Adverse Event Reporting System, July 1990 through June 2002." Clinical Infectious Diseases 38 (March 15, 2004): 771-779.
Parry, C. M. "Typhoid Fever." Current Infectious Diseases Report 6 (February 2004): 27-33.
Yoon, J., S. Segal-Maurer, and J. J. Rahal. "An Outbreak of Domestically Acquired Typhoid Fever in Queens, NY." Archives of Internal Medicine 164 (March 8, 2004): 565-567.

Organizations
Centers for Disease Control and Prevention. 1600 Clifton Rd., NE, Atlanta, GA 30333. (800) 311-3435, (404) 639-3311. http://www.cdc.gov.

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INFECTIOUS AGENT
Salmonella enterica serotypes Typhi and Paratyphi A, Paratyphi B (tartrate negative), and Paratyphi C cause a potentially severe and occasionally life-threatening bacteremic illness referred to respectively as typhoid and paratyphoid fever, and collectively as enteric fever.

TRANSMISSION
Humans are the only source of these bacteria; no animal or environmental reservoirs have been identified. Typhoid and paratyphoid fever are most often acquired through consumption of water or food that has been contaminated by feces of an acutely infected or convalescent person or a chronic, asymptomatic carrier. Transmission through sexual contact, especially among men who have sex with men, has been documented rarely.

EPIDEMIOLOGY
An estimated 26 million cases of typhoid fever and 5 million cases of paratyphoid fever occur worldwide each year, causing 215,000 deaths. In the United States, approximately 300 culture-confirmed cases of typhoid fever and 80 cases of paratyphoid fever caused by S. enterica serotype Paratyphi A are reported each year. Cases of paratyphoid fever caused by serotypes Paratyphi B (tartrate negative) and Paratyphi C are rarely reported. Approximately 85% of typhoid fever and 90% of paratyphoid fever cases in the United States are among international travelers; of those, 75% of typhoid and 90% of paratyphoid fever cases are caused by serotype Paratyphi A acquired by travelers to southern Asia (such as India, Pakistan, or Bangladesh). Other high-risk regions for typhoid and paratyphoid fever include Africa and Southeast Asia; lower-risk regions include East Asia, South America, and the Caribbean.

Travelers who are visiting friends and relatives are at increased risk (see Chapter 8, Immigrants Returning Home to Visit Friends and Relatives [VFRs]). Although the risk of acquiring typhoid or paratyphoid fever increases with the duration of stay, travelers have acquired typhoid fever even during visits of <1 week to countries where the disease is highly endemic (such as India, Pakistan, or Bangladesh).

CLINICAL PRESENTATION
The incubation period of typhoid and paratyphoid infections is 6–30 days. The onset of illness is insidious, with gradually increasing fatigue and a fever that increases daily from low-grade to as high as 102°F–104°F (38°C–40°C) by the third to fourth day of illness. Headache, malaise, and anorexia are nearly universal, and abdominal pain, diarrhea, or constipation are common. Hepatosplenomegaly can often be detected. A transient, macular rash of rose-colored spots can occasionally be seen on the trunk. Fever is commonly lowest in the morning, reaching a peak in late afternoon or evening. This clinical presentation is often confused with malaria, and typhoid fever should be suspected in a person with a history of travel to an endemic area who is not responding to antimalarial medication. Untreated, the disease can last for a month. The serious complications of typhoid fever generally occur after 2–3 weeks of illness and may include life-threatening intestinal hemorrhage or perforation.

DIAGNOSIS
Infection with typhoid or paratyphoid fever results in a low-grade septicemia. Although blood culture is the mainstay of diagnosis in typhoid and paratyphoid fever, a single culture is positive in only approximately 50% of cases. Multiple cultures increase the sensitivity and may be required to make the diagnosis. Bone marrow culture increases the diagnostic yield to approximately 80% of cases and is relatively unaffected by prior or concurrent antibiotic use. Stool culture is not usually positive during the first week of illness, so blood culture is preferred. Urine culture has no higher diagnostic yield than stool culture for acute cases.

The Widal test is unreliable but is widely used in developing countries because of its low cost. It is a serologic assay that may react in patients with typhoid or paratyphoid fever, but is not specific and false positives may occur. Serologic assays are not an adequate substitute for blood, stool, or bone marrow culture.

Because there is no definitive serologic test for typhoid or paratyphoid fever, the initial diagnosis often has to be made clinically. The combination of a history of risk for infection and a gradual onset of fever that increases in severity over several days should raise suspicion of typhoid or paratyphoid fever. Typhoid fever is a nationally notifiable disease.

TREATMENT
Specific antimicrobial therapy shortens the clinical course of enteric fever and reduces the risk for death. Fluoroquinolones are recommended for empiric treatment of enteric fever in adults, but quinolone resistance is >80% for Typhi and Paratyphi A infections in travelers to South and Southeast Asia, which suggests that treatment failures will occur. Injectable third-generation cephalosporins are often the empiric drug of choice when the possibility of fluoroquinolone resistance is high. Azithromycin and ceftriaxone are increasingly used to treat typhoid fever or paratyphoid fever because of the emergence of multidrug-resistant strains, although increasing resistance to azithromycin in Typhi strains has been documented outside the United States. In contrast, no cases of ceftriaxone resistance have been reported among Typhi and Paratyphi A isolates tested by the CDC National Antimicrobial Monitoring System through 2013. Additional data on antimicrobial resistance among enteric fever cases in the United States can be found at www.cdc.gov/narmsnow.

Patients treated with an antibiotic may continue to have fever for 3–5 days, although the height of the fever generally decreases each day. Patients may actually feel worse during the several days it takes for the fever to end. If fever in a person with culture-confirmed typhoid or paratyphoid fever does not subside within 5 days, alternative antimicrobial agents or other foci of infection such as abscesses, bone or joint infections, and other extraintestinal sites should be considered.

PREVENTION
Food and Water
Safe food and water precautions and frequent handwashing (especially before meals) are important in preventing typhoid and paratyphoid fever (see Chapter 2, Food & Water Precautions). Although vaccines are recommended to prevent typhoid fever, they are not 100% effective; therefore, even vaccinated travelers should follow recommended food and water precautions. For paratyphoid fever, food and water precautions are the only prevention method, as no vaccines are available.

Vaccine
INDICATIONS FOR USE
CDC recommends typhoid vaccine for travelers to areas where there is an increased risk of exposure to S. enterica serotype Typhi. Destination-specific vaccine recommendations are available at the CDC Travelers’ Health website (www.cdc.gov/travel).

Two typhoid vaccines are available in the United States:

Vi capsular polysaccharide vaccine (ViCPS) (Typhim Vi, manufactured by Sanofi Pasteur) for intramuscular use
Oral live attenuated vaccine (Vivotif, manufactured from the Ty21a strain of serotypeTyphi by PaxVax)
Both typhoid vaccines protect 50%–80% of recipients; travelers should be reminded that typhoid immunization is not 100% effective, and typhoid fever could still occur. Available typhoid vaccines offer no protection against paratyphoid fever.

VACCINE ADMINISTRATION
Table 3-21 provides information on vaccine dosage, administration, and revaccination. The time required for primary vaccination differs for the 2 vaccines, as do the lower age limits.

Primary vaccination with ViCPS consists of one 0.5 mL (25 mg) dose administered intramuscularly. One dose should be given ≥2 weeks before travel. The manufacturer does not recommend the vaccine for infants and for children <2 years old. A booster dose is recommended every 2 years for people who remain at risk.

Primary vaccination with oral Ty21a vaccine consists of 4 capsules, 1 taken every other day. The capsules should be kept refrigerated (not frozen), and all 4 doses must be taken to achieve maximum efficacy. Each capsule should be taken with cool liquid no warmer than 98.6°F (37°C), approximately 1 hour before a meal and ≥2 hours after a previous meal. This regimen should be completed ≥1 week before potential exposure. What to do when a dose of the oral vaccine is missed or taken late is unclear. Some suggest that minor deviations in the dosing schedule, such as taking a dose one day late, may not have a large effect on how well the vaccine works. However, we are unaware of any studies showing the effect of such deviations; thus, if 4 doses are not completed as directed, optimal immune response may not be achieved. The vaccine manufacturer recommends that Ty21a not be administered to infants or to children aged <6 years. A booster dose is recommended every 5 years for people who remain at risk.

VACCINE SAFETY AND ADVERSE REACTIONS
Adverse reactions to Ty21a vaccine are rare and mainly consist of abdominal discomfort, nausea, vomiting, and rash. ViCPS vaccine is most often associated with headache (16%–20%) and injection-site reactions (7%). Adverse reactions should be reported to the Vaccine Adverse Event Reporting System by visiting https://vaers.hhs.gov/index or calling 1-800-822-7967Call: 1-800-822-7967.

PRECAUTIONS AND CONTRAINDICATIONS
No information is available on the safety of these vaccines in pregnancy; it is prudent on theoretical grounds to avoid vaccinating pregnant women. However, the benefits of vaccinating pregnant women may outweigh potential risks when the likelihood of typhoid exposure is high; the inactivated vaccine (ViCPS) may be considered in these situations. Live attenuated Ty21a vaccine should not be given to pregnant women or immunocompromised travelers, including those infected with HIV. The intramuscular vaccine presents a theoretically safer alternative for immunocompromised travelers. (The Advisory Committee on Immunization Practices does not recommend against vaccinating household contacts of immunocompromised people with Ty21a; although vaccine organisms can be shed transiently in the stool of vaccine recipients, secondary transmission of vaccine organisms has not been documented.) The only contraindication to vaccination with ViCPS vaccine is a history of severe local or systemic reactions after a previous dose. Neither vaccine should be given to people with an acute febrile illness.

Theoretical concerns have been raised about the immunogenicity of live, attenuated Ty21a vaccine in people concurrently receiving antimicrobial agents (including antimalarial chemoprophylaxis), viral vaccines, or immune globulin. The growth of the live Ty21a strain is inhibited in vitro by various antibacterial agents, and vaccination with Ty21a should be delayed for >72 hours after the administration of any antibacterial agent. Available data do not suggest that simultaneous administration of oral polio or yellow fever vaccine decreases the immunogenicity of Ty21a. If typhoid vaccination is warranted, it should not be delayed because of administration of viral vaccines. Simultaneous administration of Ty21a and immune globulin does not appear to pose a problem.