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Chronic carrier state

One to four percent of untreated patients become chronic carriers, defined as individuals who excrete Salmonella for more than 1 year. Some individuals may continue to excrete the bacterium for decades. Bladder infection with Schistosoma haematobium predisposes to urinary carriage. The parasite itself becomes a carrier. Stool carriage is more frequent in people with preexisting biliary abnormalities, perhaps because S enterica survives in gallstones, and these people have a greater incidence of cholecystitis. Chronic carriers have a greater risk for carcinoma of the gallbladder and other gastrointestinal malignancies; chronic carriers had a 6-fold increase in the risk of death due to hepatobiliary cancer. This may be due to chronic inflammation caused by the bacterium.

Causes: S typhi and S paratyphi cause typhoid fever.

	DIFFERENTIALS	Section 4 of 9
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Abdominal Abscess
Amebic Hepatic Abscesses
Brucellosis
Dengue Fever
Influenza
Leishmaniasis
Malaria
Toxoplasmosis
Tuberculosis
Tularemia
Typhus

Other Problems to be Considered:

Endocarditis
Connective tissue disease
Lymphoproliferative disorders

	WORKUP	Section 5 of 9
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Lab Studies:

• Typhoid fever causes various abnormalities in standard laboratory tests. Serological tests and cultures are the mainstay of diagnosis. DNA probes are used by researchers and are available to patients in well-funded facilities. The diagnosis is suggested by assays that identify Salmonella antibodies and antigens and is then confirmed by isolation of the organism.

• Standard laboratory tests: Most patients are moderately anemic, have an elevated erythrocyte sedimentation rate, thrombocytopenia, and relative lymphopenia. Most also have a slightly elevated prothrombin time (PT) and activated partial thromboplastin time, decreased fibrinogen levels, and levels of circulating fibrin degradation products that commonly rise to subclinical disseminated intravascular coagulation levels. Liver transaminase values and serum bilirubin levels are usually elevated to twice the reference range. Mild hyponatremia and hypokalemia are common.

• Specific serological tests
• Assays that identify Salmonella antibodies or antigens support the diagnosis but should be confirmed with cultures or DNA evidence.
• The Widal test is more than a century old and was the standard serologic test for typhoid fever diagnosis for decades. Now, it is mostly of historical interest. It produces false-negative results in a significant proportion of patients who do not mount a detectable antibody response. It is highly nonspecific, especially in endemic areas where cross-reacting antigens from similar organisms are common. The Widal test measures agglutinating antibodies against H and O antigens of S typhi.
• In acute infection, O antibody appears first, rising progressively, later falling, and often disappearing within a few months. H antibody appears slightly later but persists longer and can be used to distinguish between various types of enteric fever.
• Indirect hemagglutination, indirect fluorescent Vi antibody, and indirect enzyme-linked immunosorbent assay for immunoglobulin M (IgM) and IgG antibodies to S typhi polysaccharide are available. Monoclonal antibodies against S typhi flagellin are promising developments.

• Culture
• Definitive diagnosis of typhoid fever generally requires isolation of the organism from blood, bone marrow, vomitus, fresh stool, or urine. A bone marrow aspirate (BMA) culture is the most sensitive method of isolating S typhi. The sensitivity is 90% at any point in the disease course for as long as 5 days after the initiation of antibiotics. The test is extremely painful. Clinicians should try to establish the diagnosis with less traumatic means.
• If patients present within the first week of the disease, blood, intestinal secretions, and stool culture results are usually positive in approximately 85-90% of patients with typhoid fever. They decline to 20-30% later in the course of the disease. In particular, stool culture results may be positive for several days after S typhi ingestion. This is because of inflammation from the intraluminal dendritic cells. Later in the illness, bacteria shed through the gallbladder again cause positive stool culture results.
• Multiple positive blood culture results are 73-97% specific for typhoid fever. Large-volume blood culture and clot culture after serum removal increase sensitivity.
• Stool culture alone is less than 50% sensitive, and urine even less so. Cultures of punch biopsy samples of rose spots reportedly have a sensitivity of 63% and may show positive results even after antibiotics. A single rectal swab culture at hospital admission can be expected to detect S typhi in 30-40% of patients. S typhi has also been isolated from the cerebrospinal fluid, peritoneal fluid, mesenteric lymph nodes, resected intestine, pharynx, tonsils, abscess, bone, and urine, among others.
• After disease resolution, 3 stool cultures one month apart should be taken to rule out carrier state.
• BMA and blood are cultured in a selective medium, such as 10% aqueous oxgall, or a nutritious medium, such as tryptic soy broth, and are incubated at 37°C for at least 7 days. Subcultures are made daily to one selective medium, such as MacConkey agar, and one inhibitory medium, such as Salmonella-Shigella agar. These conventional culture techniques usually take 48-72 hours from acquisition until the organism is identified.

• DNA testing: Polymerase chain reaction assays for identifying S typhi are available in some areas. However, this is used mostly for research since the test is generally too expensive for patients in developing countries.

Imaging Studies:

• Radiography of the kidneys, ureters, and bladder (KUB) are useful if the clinician suspects bowel perforation. CT scanning or MRI may be warranted to investigate abscesses that may occur in, among other sites, the liver or bones.

Procedures:

• The most sensitive method of isolating S typhi is obtaining a BMA culture (see Lab Studies).

Histologic Findings: The hallmark histologic finding in typhoid fever is infiltration of tissues by macrophages (typhoid cells) that contain bacteria, erythrocytes, and degenerated lymphocytes. Aggregates of these macrophages are called typhoid nodules, which are found most commonly in the intestine, mesenteric lymph nodes, spleen, liver, and bone marrow but may be found in the kidneys, testes, and parotid glands. In the intestines, 4 classic pathologic stages occur in the course of infection: (1) hyperplastic changes, (2) necrosis of the intestinal mucosa, (3) sloughing of the mucosa, and (4) the development of ulcers. The ulcers may perforate into the peritoneal cavity.

In the mesenteric lymph nodes, the sinusoids are enlarged and distended by large collections of macrophages and reticuloendothelial cells. The spleen is enlarged, red, soft, and congested; its serosal surface may have a fibrinous exudate. Microscopically, the red pulp is congested and contains typhoid nodules. The gallbladder is hyperemic and may show evidence of cholecystitis. A liver biopsy specimen from a person with typhoid often shows cloudy swelling, balloon degeneration with vacuolation of hepatocytes, moderate fatty change, and focal typhoid nodules. Intact typhoid bacilli can be observed at these sites.

	TREATMENT	Section 6 of 9
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Medical Care: Health care workers caring for patients with typhoid fever should pay strict attention to adequate hand washing and safe disposal of feces and urine. Antibiotic therapy is essential and should begin empirically if the clinical evidence is strong. Patients must receive adequate fluids, electrolytes, and nutrition. Antimicrobials shorten the course, reduce the rate of complications if begun early, and drastically reduce the case-fatality rate.

Surgical Care: Surgery is usually indicated in cases of intestinal perforation. Most surgeons prefer simple closure of the perforation with drainage of the peritoneum. Small bowel resection is indicated for patients with multiple perforations.

If antibiotic treatment fails to eradicate the hepatobiliary carriage, the gallbladder should be resected. Cholecystectomy is not always successful in eradicating the carrier state because of persisting hepatic infection.

Consultations: Physicians should consult an infectious disease specialist. Consultation with a surgeon is indicated upon suspected gastrointestinal perforation, serious gastrointestinal hemorrhage, cholecystitis, or extraintestinal complications (arteritis, endocarditis, organ abscesses).

	MEDICATION	Section 7 of 9
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Antibiotics should be started empirically while the results of confirmatory tests are pending. The literature describes varying medication recommendations. The regional sensitivity profiles in the antibiotic sensitivity of typhoid vary; thus, the authors' opinion is that these should be taken into account in the initial choice of treatment. Final sensitivity results should be used to determine the definitive treatment.

In absolute numbers, most patients in the United States with typhoid fever were infected in Latin America. However, the greatest risk of infection is travel to India and Pakistan.

Because S typhi and S paratyphi rarely develop antibiotic resistance during treatment, patients who relapse may be given the same drug. However, relapse should dictate a search for anatomical, pathological, or genetic predispositions.

Drug Category: Antibiotics -- Chloramphenicol was introduced in 1948 and was once the mainstay of treatment. By the 1970s, widespread resistance to the drug developed. Ampicillin and co-trimoxazole became treatments of choice. However, in the late 1980s, some S typhi strains developed simultaneous plasmid-mediated resistance to all 3 drugs. Fluoroquinolones and third-generation cephalosporins have filled the breach, but some resistance exists to both.

Resistance to ciprofloxacin is increasing. Up to 50% of the isolates from Finns with typhoid fever returning from Southeast Asia had reduced susceptibility to ciprofloxacin, with a minimum inhibitory concentration (MIC) of 0.125-0.250—a 9-fold increase. For therapeutic purposes, intermediate susceptibility should be regarded as full resistance. Ciprofloxacin is no longer a good first-line treatment for S typhi infection that arises in Southeast Asia. When last evaluated, the rate of intermediate sensitivity in strains was 3.7% in the Americas (P =.132), 4.7% (P =0.144) in Sub-Saharan Africa, and 10.8% (P =.706) in the Middle East.

Uncomplicated typhoid fever from the western hemisphere should be treated empirically with ciprofloxacin for 7 days. The treatment for cases from Southeast Asia is controversial. Some authorities recommend high-dose ciprofloxacin in patients from areas with typhoid fever that is resistant to nalidixic acid. (Nalidixic acid is not used clinically but as an in vitro stand-in for measuring fluoroquinolone resistance.) The authors consider this inadequate, as reports of treatment failure under those conditions have increased. The authors recommend empiric first-line therapy with trimethoprim/sulfamethoxazole and second-line therapy with ampicillin or chloramphenicol. Resistance to these agents in Southeast Asia has declined to 5-10%.

Resistance to ceftriaxone is only sporadic in Southeast Asia and elsewhere. Ceftriaxone should be the first-line empiric treatment for severe typhoid fever, and the course should last 10-14 days.

Clinicians should consider a 48-hour course of dexamethasone if the patient has shock or altered mental status. This may reduce the mortality risk from 56% to 10%. Corticosteroids are reserved for the only the most ill patients because they may increase the risk of relapse.

Drug Category: Corticosteroids -- These agents reduce mortality in severely ill patients with depressed levels of consciousness or shock.

	FOLLOW-UP	Section 8 of 9
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Further Outpatient Care:

• Management of long-term carriers: Prolonged courses of amoxicillin or co-trimoxazole may be effective, but the failure rate is high if the patient has chronic gallbladder disease. Ciprofloxacin (750 mg bid) and norfloxacin (400 mg bid) have been much more effective, with cure rates of 78% and 83%, respectively.

Deterrence/Prevention:

• Travelers to endemic countries should avoid raw unpeeled fruits or vegetables since they may have been prepared with contaminated water; 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. In the absence of such a strategy, mass immunization with typhoid vaccines at regular intervals also considerably reduces the incidence of infections.

• Routine typhoid vaccination is not recommended in the United States. Vaccination is indicated for travelers to endemic areas, persons with intimate exposure (eg, household contact) to a documented S typhi carrier, and microbiology laboratory personnel who frequently work with S typhi.
• Travelers should be vaccinated at least 1 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.
• The only absolute contraindication to vaccination is a history of severe local or systemic reactions following a previous dose. No data have been reported on pregnant women who receive any of the typhoid vaccines available in the United States.
• The following 3 typhoid vaccines are used:

• Vi capsular polysaccharide (ViCPS) antigen vaccine (Typhim Vi, Pasteur Merieux) is composed of purified Vi antigen, the capsular polysaccharide elaborated by S typhi isolated from blood cultures. In recent studies, one 25-mg injection of purified ViCPS produced seroconversion (ie, at least a 4-fold rise in antibody titers) in 93% of healthy US adults. Similar results were observed in Europe. Two field trials in disease-endemic areas showed overall protection rates of 72% in Nepal and 50-64% in South Africa.
• 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.
• Primary vaccination with ViCPS consists of a single parenteral dose of 0.5 mL (25 mg 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, or induration greater than or equal to 1 cm. In a study conducted in Nepal, the ViCPS vaccine produced fewer local and systemic reactions than the control (the 23-valent pneumococcal vaccine). Among school children in South Africa, ViCPS produced less erythema and induration than the control bivalent vaccine.

• Ty21a (Vivotif Berna, Swiss Serum and Vaccine Institute) 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.
• No prospective randomized trials have been performed in the United States. Several field trials were conducted among school children in Chile. Using 3 doses on alternate days, investigators produced a 66% protection rate that lasted for 5 years (95% CI, 50-77%). In another trial in Chile, the incidence of clinical typhoid fever significantly decreased among persons who received 4 doses of vaccine compared with persons who received 2 doses (P <.001) or 3 doses (P =.002). However, an efficacy rate of only 42% was recorded in Indonesia, suggesting that the vaccine may not be effective in areas where exposure is intense. The efficacy of vaccination with Ty21a has not been studied among persons from areas without endemic disease who travel to disease-endemic regions.
• 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.
• Adverse effects are rare. They include abdominal discomfort, nausea, vomiting, fever, headache, and rash or urticaria.
• The vaccine manufacturer recommends that Ty21a not be administered to children younger than 6 years. It should not be used among immunocompromised persons. The parenteral vaccines present theoretically safer alternatives for this group.

• 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.

• Of note, 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.

Complications:

• Intestinal manifestations
• The 2 most common complications of enteric fever are 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 in typhoid fever was 66-90% but now is 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. Often, the discovery of free intra-abdominal fluid may be the only sign of perforation.

• Hepatobiliary manifestations
• Mild elevation of transaminases without symptoms is common in persons with typhoid fever.
• Jaundice may occur in persons with enteric fever and may be due to hepatitis, cholangitis, cholecystitis, or hemolysis.
• Pancreatitis and simultaneous acute renal failure and hepatitis with hepatomegaly have been reported.

• Cardiopulmonary manifestations
• Nonspecific electrocardiographic changes occur in 10-15% of patients with typhoid. Toxic myocarditis occurs in 1-5% of persons with typhoid and is a significant cause of death in disease-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 rarely occurs, but peripheral vascular collapse without other cardiac findings is increasingly described. Pulmonary manifestations have also been reported in patients with typhoid fever.

• Neuropsychiatric manifestations
• In the past 2 decades, reports from the disease-endemic areas have documented a wide spectrum of neuropsychiatric manifestations of typhoid fever.
• A toxic confusional state, characterized by disorientation, delirium, and restlessness, is characteristic of late-stage typhoid. Occasionally, these and other neuropsychiatric features may dominate the clinical picture at an early stage.
• Facial twitching or convulsions may be the presenting feature; sometimes, paranoid psychosis or catatonia may develop during convalescence. Meningismus is not uncommon, but frank meningitis is rare. Encephalomyelitis may develop, and the underlying pathology may be that of demyelinating leukoencephalopathy. Rarely, transverse myelitis, polyneuropathy, or cranial mononeuropathy may develop.
• Other less commonly reported events are spastic paraplegia, peripheral or cranial neuritis, Guillain-Barré syndrome, schizophrenialike illness, mania, and depression.

• Hematologic manifestations
• Subclinical disseminated intravascular coagulation occurs commonly in persons with typhoid fever.
• Hemolytic-uremic syndrome is rare.
• Hemolysis may also be associated with glucose-6-phosphate dehydrogenase deficiency.

• Genitourinary manifestations
• Approximately 25% of patients excrete S typhi in their urine at some point during their illness.
• Immune complex glomerulitis 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.

• Musculoskeletal manifestations

• Skeletal muscle characteristically shows Zenker degeneration, particularly affecting the abdominal wall and thigh muscles.
• Clinically evident polymyositis may occur.

• CNS manifestations

• Focal intracranial infections are uncommon.
• Recently, multiple brain abscesses have been reported.

Prognosis:

• The prognosis depends on the geographical area and its demographics. Generally, the mortality rate in untreated disease is 10-20%. In properly treated disease, it is less than 1%.

• Between 10% and 20% of patients treated with antibiotics have a relapse after initial recovery. A relapse typically occurs approximately 1 week after therapy is discontinued, but relapse after 70 days has been reported. The blood culture results are again positive, and high serum levels of H, O, and Vi antibodies and rose spots may reappear. A relapse generally is milder and shorter than the initial illness. Rarely, second or even third relapses may occur. Notably, the relapse rate is much lower following treatment with the new quinolone drugs, which have effective intracellular penetration.

Patient Education:

• Because the avoidance of risky foods and beverages and vaccination 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, visit eMedicine's Public Health Center. Also, see eMedicine's patient education article Foreign Travel.

• Case study
• A wealthy middle-aged man presented to his physician a few days after the onset of flulike symptoms, including fever, myalgias, chills, severe abdominal pain, and a cough, in addition to severe abdominal pain. Over the next 2 weeks, he lost a great deal of weight. He had intermittent but ever-increasing fevers. About 3 weeks after the onset of symptoms, he developed a few pale, salmon-colored macules on his trunk. His cough became much more frequent and severe. He became delirious, listlessly wandering around the house fiddling with doorknobs. During the fourth week of his illness, he rapidly declined with increasing somnolence. After nearly 4 weeks of illness, he died surrounded by his loving family.
• The patient was Prince Albert, the Consort to Queen Victoria. He was diagnosed with typhoid fever. His personal physician, Sir William Jenner, a leading expert on the disease, made the diagnosis of typhoid fever. Prince Albert received the best therapy of the day.

• For the most up-to-date information, visit the Centers for Disease Control and Prevention Travelers' Health Typhoid resource or call the Travelers' Health automated information line at 877-FYI-TRIP.
• Culture-confirmed typhoid fever should be reported to the state health department.