Typhoid Fever Follow-up

After discharge, patients should be monitored for relapse or complications for 3 months after treatment has commenced.

Five percent to 10% of patients treated with antibiotics experience relapse of typhoid fever after initial recovery. Relapses typically occur approximately 1 week after therapy is discontinued, but relapse after 70 days has been reported. In these cases, the blood culture results are again positive, and high serum levels of H, O, and Vi antibodies and rose spots may reappear.

A relapse of typhoid fever is generally milder and of shorter duration than the initial illness. In rare cases, second or even third relapses occur. Notably, the relapse rate is much lower after treatment with the new quinolone drugs, which have effective intracellular penetration.

Previous infection does not confer immunity. In any suspected relapse, infection with a different strain should be ruled out.

Depending on the antibiotic used, between 0% and 5.9% of treated patients become chronic carriers. In some cases, the organism evades antibiotics by sequestering itself within gallstones or Schistosoma haematobium organisms that are infecting the bladder. From there, it is shed in stool or urine, respectively. If present, these diseases must be cured before the bacterium can be eliminated.

Untreated survivors of typhoid fever may shed the bacterium in the feces for up to 3 months. Therefore, after disease resolution, 3 stool cultures in one-month intervals should be performed to rule out a carrier state. Concurrent urinary cultures should be considered.

If treated with well-selected antibiotics, patients with typhoid fever (enteric fever) should defervesce within 3-5 days. However, patients with complicated typhoid fever should finish their course intravenously and should remain in the hospital if unable to manage this at home.

Patients with complicated typhoid fever should be admitted through the acute phase of the illness. Uncomplicated cases are generally treated on an outpatient basis unless the patient is a public health risk or cannot be fully monitored outside the home.

Travelers to endemic countries should avoid raw unpeeled fruits or vegetables since they may have been prepared with contaminated water and should not buy food from street vendors; in addition, they should drink only boiled water.

In endemic countries, the most cost-effective strategy for reducing the incidence of typhoid fever is the institution of public health measures to ensure safe drinking water and sanitary disposal of excreta. The effects of these measures are long-term and reduce the incidence of other enteric infections, which are a major cause of morbidity and mortality in those areas.

Vaccines

In endemic areas, mass immunization with typhoid vaccines at regular intervals considerably reduces the incidence of infections.

Routine typhoid vaccination is not recommended in the United States but is indicated for travelers to endemic areas, persons with intimate exposure to a documented S typhi carrier (eg, household contacts of chronic carriers, defined as persons with excretion of S typhi in urine or stool ≥1 year), and microbiology laboratory personnel who frequently work with S typhi. In their 2015 recommendations, the Advisory Committee on Immunization Practices in the US recommends that travelers to countries with a high prevalence of typhoid and recognized risk for exposure to Styphi should be vaccinated against typhoid, even if they are staying with friends or relatives or only traveling for a short time. ^[55]

Vaccines are not approved for use in children younger than 2 years. The efficacy of typhoid fever vaccinations against paratyphi serovars has not been firmly established, but is markedly less than their efficacy against typhi. ^[56]

Travelers should be vaccinated at least one week prior to departing for an endemic area. Because typhoid vaccines lose effectiveness after several years, consultation with a specialist in travel medicine is advised if the individual is traveling several years after vaccination. In addition, clinicians should warn travelers to consume only safe foods and beverages, because typhoid vaccines offer only moderate protection, and large inocula of S t yphi can overcome vaccine-induced protection.

The only absolute contraindication to vaccination is a history of severe local or systemic reactions following a previous dose. The typhoid vaccines available in the United States have not been studied in pregnant women.

Currently, the 3 typhoid fever vaccines include injected Vi capsular polysaccharide (ViCPS; Typhim Vi, Pasteur Merieux) antigen, enteric Ty21a (Vivotif Berna, Swiss Serum and Vaccine Institute) live-attenuated vaccine, and an acetone-inactivated parenteral vaccine (used only in members of the armed forces). The efficacy of both vaccines available to the general public approaches 50%.

Vi capsular polysaccharide antigen vaccine

Vi capsular polysaccharide antigen vaccine is composed of purified Vi antigen, the capsular polysaccharide elaborated by S typhi isolated from blood cultures. The Vi antigen is absent in S paratyphi A, but this vaccine does provide some in vitro immunogenicity against S paratyphi A. This may be due to trace amounts of other, common antigens in the preparation. ^[57]

Primary vaccination with ViCPS consists of a single parenteral dose of 0.5 mL (25 µg IM) one week before travel. The vaccine manufacturer does not recommend the vaccine for children younger than 2 years. Booster doses are needed every 2 years to maintain protection if continued or renewed exposure is expected.

Adverse effects include fever, headache, erythema, and/or induration of 1 cm or greater. In a study conducted in Nepal, the ViCPS vaccine produced fewer local and systemic reactions than the control (the 23-valent pneumococcal vaccine). ^[58] Among school children in South Africa, ViCPS produced less erythema and induration than the control (bivalent vaccine).

A systemic review and meta-analysis of 5 randomized controlled trials on the efficacy and safety of ViCPS versus placebo or nontyphoid vaccine found a cumulative efficacy of 55% (95% CI, 30%-70%).

The efficacy of vaccination with ViCPS has not been studied among persons from areas without endemic disease who travel to endemic regions or among children younger than 5 years. ViCPS has not been given to children younger than 1 year.

Questions concerning Vi typhoid vaccine effectiveness in young children (ie, < 5 y) have inhibited its use in developing countries. Whether the vaccine is effective under programmatic conditions is also unclear.

^[59]

Ty21a

Ty21a is an oral vaccine that contains live attenuated S typhi Ty21a strains in an enteric-coated capsule. The vaccine elicits both serum and intestinal antibodies and cell-mediated immune responses.

In the United States, primary vaccination with Ty21a consists of one enteric-coated capsule taken on alternate days to a total of 4 capsules. The capsules must be refrigerated (not frozen), and all 4 doses must be taken to achieve maximum efficacy.

The optimal booster schedule has not been determined; however, the longest reported follow-up study of vaccine trial subjects indicated that efficacy continued for 5 years after vaccination. The manufacturer recommends revaccination with the entire 4-dose series every 5 years if continued or renewed exposure to S typhi is expected. This vaccine may be inactivated if given within 3 days of antibiotics.

Adverse effects are rare. They include abdominal discomfort, nausea, vomiting, fever, headache, and rash or urticaria.

The vaccine manufacturer of Ty21a recommends against use in children younger than 6 years. It should not be administered to immunocompromised persons; the parenteral vaccines present theoretically safer alternatives for this group.

A systemic review and meta-analysis of 4 randomized controlled trials on the efficacy and safety of Ty21a versus placebo or nontyphoid vaccine found a cumulative efficacy of 51% (95% CI, 36%-62%).

The efficacy of Ty21a has not been studied among persons from areas without endemic disease who travel to disease-endemic regions.

Acetone-inactivated parenteral vaccine

Acetone-inactivated parenteral vaccine is currently available only to members of the US Armed Forces. Efficacy rates for this vaccine range from 75%-94%. Booster doses should be administered every 3 years if continued or renewed exposure is expected.

The parenteral heat-phenol–inactivated vaccine (Wyeth-Ayerst) has been discontinued.

No information has been reported concerning the use of one vaccine as a booster after primary vaccination with a different vaccine. However, using either the series of 4 doses of Ty21a or 1 dose of ViCPS for persons previously vaccinated with parenteral vaccine is a reasonable alternative to administration of a booster dose of parenteral inactivated vaccine.

A more effective vaccine is on the horizon. Vi polysaccharide-tetanus typhoid conjugate vaccine (TCV) is a combination of the 1 polysaccharide antigen and tetanus toxoid. It appears to be more immunogenic and longer acting other typhoid vaccines. ^[60]

Targeted use of vaccines in areas of the world with high rates of typhoid fever and/or resistant Salmonella isolates makes economic sense in reducing the disease burden and associated costs. ^[61]

In the past 2 decades, reports from disease-endemic areas have documented a wide spectrum of neuropsychiatric manifestations of typhoid fever. Potential neuropsychiatric manifestations of typhoid fever include the following:

• A toxic confusional state, characterized by disorientation, delirium, and restlessness, is characteristic of late-stage typhoid fever. In some cases, these and other neuropsychiatric features dominate the clinical picture at an early stage.

• Facial twitching or convulsions may be the presenting feature. Meningismus is not uncommon, but frank meningitis is rare. Encephalomyelitis may develop, and the underlying pathology may be that of demyelinating leukoencephalopathy. In rare cases, transverse myelitis, polyneuropathy, or cranial mononeuropathy develops.

• Stupor, obtundation, or coma indicates severe disease.

• Focal intracranial infections are uncommon, but multiple brain abscesses have been reported. ^[62]

• Other less-common neuropsychiatric manifestations events have included spastic paraplegia, peripheral or cranial neuritis, Guillain-Barré syndrome, schizophrenialike illness, mania, and depression.

Respiratory complications may include the following:

• Cough

• Ulceration of posterior pharynx

• Occasional presentation as acute lobar pneumonia (pneumotyphoid)

Cardiovascular complications may include the following:

• Nonspecific electrocardiographic changes occur in 10%-15% of patients with typhoid fever.

• Toxic myocarditis occurs in 1%-5% of persons with typhoid fever and is a significant cause of death in endemic countries. Toxic myocarditis occurs in patients who are severely ill and toxemic and is characterized by tachycardia, weak pulse and heart sounds, hypotension, and electrocardiographic abnormalities.

• Pericarditis is rare, but peripheral vascular collapse without other cardiac findings is increasingly described. Pulmonary manifestations have also been reported in patients with typhoid fever. ^[63]

Hepatobiliary complications may include the following:

• Mild elevation of transaminases without symptoms is common in persons with typhoid fever.

• Jaundice may occur in persons with typhoid fever and may be due to hepatitis, cholangitis, cholecystitis, or hemolysis.

• Pancreatitis and accompanying acute renal failure and hepatitis with hepatomegaly have been reported. ^[64]

Intestinal manifestations may include the following:

• The 2 most common complications of typhoid fever include intestinal hemorrhage (12% in one British series) and perforation (3%-4.6% of hospitalized patients).

• From 1884-1909 (ie, preantibiotic era), the mortality rate in patients with intestinal perforation due to typhoid fever was 66%-90% but is now significantly lower. Approximately 75% of patients have guarding, rebound tenderness, and rigidity, particularly in the right lower quadrant.

• Diagnosis is particularly difficult in the approximately 25% of patients with perforation and peritonitis who do not have the classic physical findings. In many cases, the discovery of free intra-abdominal fluid is the only sign of perforation.

Genitourinary manifestations may include the following:

• Approximately 25% of patients with typhoid fever excrete S typhi in their urine at some point during their illness.

• Immune complex glomerulitis ^[65] and proteinuria have been reported, and IgM, C3 antigen, and S typhi antigen can be demonstrated in the glomerular capillary wall.

• Nephritic syndrome may complicate chronic S typhi bacteremia associated with urinary schistosomiasis.

• Nephrotic syndrome may occur transiently in patients with glucose-6-phosphate dehydrogenase deficiency.

• Cystitis: Typhoid cystitis is very rare. Retention of urine in the typhoid state may facilitate infection with coliforms or other contaminants.

Hematologic manifestations may include the following:

• Subclinical disseminated intravascular coagulation is common in persons with typhoid fever.

• Hemolytic-uremic syndrome is rare. ^[66]

• Hemolysis may also be associated with glucose-6-phosphate dehydrogenase deficiency.

Musculoskeletal and joint manifestations may include the following:

• Skeletal muscle characteristically shows Zenker degeneration, particularly affecting the abdominal wall and thigh muscles.

• Clinically evident polymyositis may occur. ^[67]

• Arthritis is very rare and most often affects the hip, knee, or ankle.

Late sequelae (rare in untreated patients and exceedingly rare in treated patients) may include the following:

• Neurologic - Polyneuritis, paranoid psychosis, or catatonia ^[68]

• Cardiovascular - Thrombophlebitis of lower-extremity veins

• Genitourinary -Orchitis

• Musculoskeletal - Periostitis, often abscesses of the tibia and ribs; spinal abscess (typhoid spine; very rare)

The prognosis among persons with typhoid fever depends primarily on the speed of diagnosis and initiation of correct treatment. Generally, untreated typhoid fever carries a mortality rate of 15%-30%. In properly treated disease, the mortality rate is less than 1%.

An unspecified number of patients experience long-term or permanent complications, including neuropsychiatric symptoms and high rates of gastrointestinal cancers. ^[69]

Because vigilant hand hygiene, vaccination, and the avoidance of risky foods and beverages are mainstays of prevention, educating travelers before they enter a disease-endemic region is important.

Because the protection offered by vaccination is at best partial, close attention to personal, food, and water hygiene should be maintained. The US Centers for Disease Control and Prevention dictum to "boil it, cook it, peel it, or forget it" is a good rule in any circumstance. If disease occurs while abroad despite these precautions, one can usually call the US consulate for a list of recommended doctors.

For excellent patient education resources, see eMedicineHealth's patient education article Foreign Travel

For the most up-to-date information, visit the Centers for Disease Control and Prevention Travelers' Health Typhoid resource (www.cdc.gov/travel) or call the Travelers' Health automated information line at 877-FYI-TRIP.