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Risk factors

Salmonella has mechanisms against acidic environments, but a pH level of 1.5 or less kills most of the bacilli. People who continually ingest antacids, histamine-2 receptor antagonists (H2 blockers), or proton pump inhibitors; who have undergone gastrectomy; or who have achlorhydria due to aging or other factors require fewer bacilli to produce clinical disease. Acquired immune deficiencies or hereditary deficiencies in immune modulars such as IL-12 and IL-23 increase risk for infection, complications, and death.

Frequency:

• In the US: From 1900-1960, the incidence of typhoid fever declined steadily and has remained low in the United States. Improved sanitation and successful antibiotic treatment led to this decline. An average of 245 cases have been reported annually, with an incidence of 0.2 per 100,000 population since 1985 compared with 35,994 reported cases in 1920. More than 70% of cases occurred within 30 days of returning from international travel, mostly to the Indian subcontinent and Latin America. The rare outbreaks of typhoid fever due to transmission within the United States are generally traceable to imported food or a food handler from an endemic region.

• Internationally: S typhi and S paratyphi infections occur worldwide but primarily in developing nations where sanitary conditions are poor. Typhoid and paratyphoid fevers are endemic in Asia, Africa, Latin America, the Caribbean, and Oceania. Typhoid fever affects 13-17 million people yearly and kills an estimated 600,000.

Mortality/Morbidity: Early antibiotic therapy has transformed a previously life-threatening illness of several weeks' duration with an overall mortality rate approaching 20% into a short-term febrile illness with negligible mortality. Case fatality rates of 10-50% have been reported from endemic countries when diagnosis is delayed.

Race: No racial predilection exists.

Sex: No sex-related predilection exists.

Age: In endemic areas, children aged 1-5 years are at the highest risk of infection, morbidity, and mortality because of waning passively acquired maternal antibody and a lack of acquired immunity. In young children, the clinical syndrome is often a nonspecific febrile illness that is not recognized as typhoid fever. In more recent years, prospective studies have shown that, although the incidence of classic typhoid fever in patients is highest in adolescents and young adults, the overall incidence of blood culture–confirmed disease is generally highest in children aged 3-9 years and declines significantly in late adolescence.

	CLINICAL	Section 3 of 9
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Bibliography

History: Untreated typhoid fever lasts at least 4 weeks. Most of the classic signs and symptoms of typhoid fever are prevented with prompt treatment. Clinical response begins about 2 days after starting antibiotics, and the patient's condition markedly improves within 4-5 days.

The incubation period of typhoid fever varies with the size of the infecting dose and averages 7-14 (range, 3-60) days. In paratyphoid infection, the incubation period ranges from 1-10 days. During the incubation period, 10-20% of patients have transient diarrhea (enterocolitis) that usually resolves before the onset of the full-fledged disease.

As bacteremia develops, the incubation period ends. Patients often experience chills, diaphoresis, anorexia, dry cough, a dull frontal headache, and myalgias before the onset of a high fever. About 20-40% of patients present with abdominal pain. In immunocompetent adults, constipation is common and is most likely due to hypertrophy of Peyer patches. Young children and individuals with AIDS are more likely to have diarrhea that is probably due to blunted secondary immunity. The incidence of constipation versus diarrhea varies geographically, perhaps because of local differences in diet or S typhi strains or genetic variation.

Unusual modes of onset include isolated severe headaches that may mimic meningitis. S typhi infection may cause an acute lobar pneumonia. In the early stages of the disease, rigors are rare unless the person also has malaria. This is not an unusual pairing of diseases. Patients may present with arthritis only, urinary symptoms, severe jaundice, or fever. Some patients, especially in India and Africa, may present with confusion and delirium or report parkinsonian symptoms or spastic rigidity. This regional variety in neuropsychiatric presentation may be due to the same factors that cause the variation in gastrointestinal symptoms.

Physical: The classic signs of enteric fever include fever, toxemia, delirium, abdominal pain, constipation, and hepatosplenomegaly.

Fever occurs in 75-85% of patients in the first week and is often initially remittent but becomes steady. The individual's temperature often rises to as high as 103-104°F (39-40°C) by the beginning of week 2. Constipation often develops early and is likely due to obstruction at the ileocecal valve by swollen Peyer patches. It may last for the entire duration of illness.

At approximately the end of the first week of illness, about a third of patients develop bacterial emboli to the skin known as rose spots. These are considered a classic symptom in typhoid fever, but they occasionally appear in shigellosis and nontyphoidal salmonellosis. Rose spots constitute a subtle, extremely sparse (often < 5 spots), salmon-colored, blanching, truncal, maculopapular rash with 1- to 4-cm lesions that generally resolve within 2-5 days. Relative bradycardia and a dicrotic pulse are also common during this stage of illness.

During the second week of illness, the patient is toxic-appearing and apathetic with sustained fever. The abdomen is slightly distended, and soft splenomegaly is common.

In the third week, the patient grows more toxic and anorexic with significant weight loss. The patient may have a thready pulse, tachypnea, conjunctivitis, and crackles over the lung bases. Pyrexia persists. The patient may enter into a typhoid state of apathy, confusion, and even psychosis. Patients may develop polyneuropathy. Abnormal cerebrospinal fluid should prompt a search for a different cause.

Meanwhile, the patient commonly has pronounced abdominal distension. Some individuals may produce liquid, foul, green-yellow diarrhea (pea soup diarrhea). At this stage, the patient may die from overwhelming toxemia, myocarditis, intestinal hemorrhage, or perforation due to necrotic Peyer patches. Rare complications of enteric fever include pancreatitis, meningitis, orchitis, and osteomyelitis.

During the fourth week, the fever, mental state, and abdominal distension slowly improve over a few days, but intestinal complications may still occur in surviving untreated individuals. Weight loss and debilitating weakness last months. Relapses occur in 10% of patients, mostly during the first 2-3 weeks of convalescence.