Typhoid Fever

AUTHOR: Glenn G. Fort, MD, MPH

Definition

Typhoid fever is a systemic infection caused by Salmonella typhi and Salmonella paratyphi (A, B, and C).

Synonyms

Typhoid

Enteric fever

ICD-10CM CODES
A01.00		Typhoid fever, unspecified
A01.02		Typhoid fever with heart involvement
A01.09		Typhoid fever with other complications

Epidemiology & Demographics

Incidence (In U.S.)

Approximately 400 cases of S. typhi infections are reported annually in the U.S. (Fig. E1). Over three quarters of the cases reported in the U.S. are now associated with foreign travel (most from Asia, Africa, and Central America).

Figure E1 Typhoid fever.

Number of reported cases by year, U.S., 1980 to 2010.

From Centers for Disease Control and Prevention: Summary of notifiable diseases-United States, 2010, MMWR Morb Mortal Wkly Rep 59[53]:1-111, 2012.

Physical Findings & Clinical Presentation

(Table E1)

Incubation period is 8 to 16 days.
Usual manifestations:
1. Prolonged fever (enteric fever). Temperature increases progressively and can remain elevated daily for 4 to 8 wk
2. Myalgias
3. Headache
4. Cough
5. Sore throat
6. Malaise
7. Anorexia, at times with abdominal pain and hepatosplenomegaly
8. Diarrhea or constipation may occur early in the course of illness. One fifth of patients have constipation at diagnosis
9. Rose spots, which are faint, maculopapular, blanching lesions, may sometimes be seen on the chest or abdomen
Relative bradycardia (despite high fever) may occur.
Moderate hepatosplenomegaly may be present.
In an untreated patient, fever may last 1 to 2 mo. The main complication of untreated disease is GI bleeding as a result of perforation from ulceration of Peyer patches in the ileum. Mental status changes and shock are rare complications. The relapse rate is ∼10%.

TABLE E1 Clinical Features of Typhoid and Paratyphoid Fever

	Clinical Feature	Approximate Frequency (%)∗
Flulike symptoms	Fever	>95
	Headache	80
	Chills	40
	Cough	30
	Myalgia	20
	Arthralgia	<5
Abdominal symptoms	Anorexia	50
	Abdominal pain	30
	Diarrhea	20
	Constipation	20
Physical findings	Coated tongue	50
	Hepatomegaly	10
	Splenomegaly	10
	Abdominal tenderness	5
	Rash	<5
	Generalized adenopathy	<5

^∗The proportion of patients demonstrating these clinical features of enteric fever varies depending on the time, region, and type of clinical population (hospitalized or ambulatory) assessed. Estimates are drawn from recent case series in an endemic area, with patients presenting for ambulatory or inpatient care.

From Bennett JE et al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Saunders.

Etiology

S. typhi or S. paratyphi found only in humans
Acquisition of disease by ingestion of food or water contaminated by human feces
In the U.S., most cases are acquired either during foreign travel or by ingestion of food prepared by chronic carriers, many of whom acquired the organism outside of the U.S., most common in the Indian subcontinent (South, East, and Southeast Asia) and portions of sub-Saharan Africa

Diagnosis ⬆ ⬇

Differential Diagnosis

Malaria
Tuberculosis
Brucellosis
Amebic liver abscess
Table E2 summarizes differential diagnoses of infectious diseases to consider in patients with possible typhoid or enteric fever

TABLE E2 Differential Diagnoses of Infectious Diseases to Consider in Patients With Possible Typhoid or Enteric Fever

Common Infectious Causes of Nonspecific Acute Febrile Illness in Resource-Limited Areas
Salmonella bacteremia (typhoidal and nontyphoidal serotypes) Malaria Dengue and other arboviral fevers Leptospirosis Influenza Rickettsioses Bartonelloses
Infectious Causes of Typhoidal Illnesses, Including Prolonged Nonlocalizing Febrile Illnesses
Persistent nontyphoidal bacteremia or abscess formation Typhus (rickettsiosis) Brucellosis Typhoidal tularemia Q fever Bartonellosis (including trench fever) Melioidosis Rat-bite fever, Haverhill fever (Streptobacillus moniliformis) Relapsing fever (borreliosis) Infective endocarditis Malaria Babesiosis Visceral leishmaniasis West African trypanosomiasis Tuberculosis Endemic mycoses (histoplasmosis)

From Bennett JE et al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Saunders.

Workup

Diagnosis is made by isolating S. typhi from blood, stool, urine, or bone marrow.
Blood, stool, and urine cultures are helpful.
Cultures should be repeated if results are initially negative.
Blood cultures are more likely to be positive early in the course of illness.
Stool and urine cultures are more commonly positive in the second and third week of illness.
Bone marrow biopsy cultures are 90% positive, although this procedure is usually not necessary.
Rapid serologic tests can distinguish Salmonella enterica serotype typhi antibodies.

Laboratory Tests

Neutropenia is common. Anemia and thrombocytopenia may be present.
Transaminitis is possible.
Culture:
1. Blood
2. Body fluids
3. Biopsy specimens

Diagnostic Imaging

Chest x-ray may reveal pulmonary infiltrates.

Treatment ⬆ ⬇

Acute General Rx

Multidrug-resistant strains (MDR) are now common worldwide with resistance to ampicillin, trimethoprim-sulfamethoxazole (TMP-SMX; Bactrim), and chloramphenicol. Resistance to quinolones is increasing, especially in Southeast Asia
If not acquired in Asia: Ciprofloxacin 400 mg orally/intravenous (PO/IV) q12h or levofloxacin 750 mg PO/IV q24h for 7 to 10 days
If acquired in Asia: Ceftriaxone 2 g/day IV for 7 to 14 days
An alternative agent for treatment remains azithromycin: Adults: 1 g PO on day 1, then 500 mg/day PO for 5 to 7 days. Children: 20 mg/kg PO on day 1, then 10 to 20 mg/kg (maximum 100 mg/day) for 5 to 7 days
Dexamethasone, 3 mg/kg IV initially, followed by 1 mg/kg IV q6h for 8 doses for patients with septic shock or typhoid meningitis with antibiotic therapy
Table E3 summarizes antibiotics commonly used in treating patients with enteric fever
In vitro susceptibility testing should be done due to increasing antibiotic resistance

TABLE E3 Antibiotics Commonly Used in Treating Patients With Enteric Fever

	Antibiotic	Route	Typical Pediatric Dosage ∗	Adult Dosage	Typical Duration	Comments
Original first-line agents	Chloramphenicol	PO/IV	12.5-25 mg/kg qid	2-3 g/day (divided qid)	14-21 days	These agents are effective for susceptible strains; however, multidrug resistance to all of these agents is common in many areas.
	Amoxicillin	PO	25-35 mg/kg tid	1 g tid	14 days
	Ampicillin	IV	25-50 mg/kg q6h	2 g q6h	14 days
	TMP-SMX	PO/IV	8-12 mg/kg daily (TMP) 40-60 mg/kg daily (SMX) (divided qid)	160 mg/800 mg qid	14 days
Fluoroquinolones	Ofloxacin	PO/IV	15 mg/kg bid	400 mg PO bid	5-14 days	Ofloxacin and ciprofloxacin are effective for nalidixic acid-susceptible strains. Short courses of 5-7 days are acceptable in uncomplicated cases. Courses of 10-14 days are recommended in patients requiring hospitalization or parenteral therapy. Gatifloxacin appears effective for uncomplicated cases caused by NaR strains.
	Ciprofloxacin	PO/IV	15 mg/kg bid	500 mg PO bid	5-14 days
	Gatifloxacin	PO	10 mg/kg daily	10 mg/kg daily	7 days
Third-generation cephalosporins	Ceftriaxone	IV	50-100 mg/kg daily	1-2 g IV daily	10-14 days ^†	These are an alternative to fluoroquinolones for NaR strains, and for empirical therapy in areas where NaR is common.
Third-generation cephalosporins	Cefixime	PO	10 mg/kg bid	200 mg PO bid	7-14 days
Macrolides	Azithromycin	PO	20 mg/kg daily	500-1000 mg/day PO	7 days	These are an alternative for uncomplicated infections caused by NaR strains and for empirical therapy where multidrug resistance and NaR are common.
Eradication of carriage	Ciprofloxacin	PO	-	500-750 mg bid	28 days	If eradication is indicated for public health reasons, a trial of medical therapy is justified, even in patients with evidence of cholelithiasis. Cholecystectomy may be considered.

NaR, Nalidixic acid resistant (see text); TMP-SMX, trimethoprim-sulfamethoxazole.

^∗Weight-based pediatric dosage should not exceed adult maximum.

^†Recommended that treatment continue for at least 7 days postdefervescence to minimize relapse.

From Bennett JE et al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Saunders.

Chronic Rx

Carrier states possible
More common in age >60 yr and in people with gallstones
Usual site of colonization: Gallbladder
Treatment in those with persistently positive stool cultures and in food handlers
Suggested regimens for eradication of carrier state:
1. Ciprofloxacin 500 mg PO bid for 4 wk
2. TMP-SMX 1 to 2 tabs PO bid for 6 wk (if susceptible)
3. Amoxicillin 2 g PO q8h for 6 wk (if susceptible)
Cholecystectomy possibly required in carriers with gallstones who fail medical therapy

Disposition

Treated patients usually respond to therapy, with a small percentage becoming chronic carriers.
The relapse rate is ∼10%.
Untreated patients may have serious complications.
Complications of typhoid and paratyphoid fever are summarized in Table E4.

TABLE E4 Complications of Typhoid and Paratyphoid Fever

System	Complication	Notes
Gastrointestinal	Hemorrhage	10%-15% in hospitalized patients
Gastrointestinal	Perforation	3% in hospitalized patients
Hepatobiliary	Jaundice	1%-3% in hospitalized patients
	Hepatitis	Usually subclinical (↑ ALT/AST)
	Acute cholecystitis	Rare; gallbladder may perforate
Neurologic	Mild encephalopathy	Confusion or apathy common
	Severe encephalopathy	Delirium, stupor, or coma
	Seizures	Common in children ≤5 yr
	Meningitis	Rare, primarily infants
	Guillain-Barré syndrome	Reported
Respiratory	Bronchitis	Dry cough is common
	Pneumonia	May be other concomitant bacterial infection (e.g., Streptococcus pneumoniae)
	Empyema	Rare reports
Cardiovascular	Myocarditis	Usually subclinical (ECG changes)
	Endocarditis	Rare reports
Hematologic	Anemia	Usually subclinical
	Disseminated intravascular coagulation	Usually subclinical (↑ PT/PTT)
Other	Musculoskeletal pyogenic infections	Osteomyelitis (particularly vertebral), psoas abscess and others reported
	Hemolytic-uremic syndrome	Reported
	Miscarriage	Reported

ALT, Alanine aminotransferase; AST, aspartate aminotransferase; ECG, electrocardiogram; PT, prothrombin time; PTT, partial thromboplastin time.

From Bennett JE et al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Saunders.

Referral

Failure of therapy
Chronic carrier

Pearls & Considerations ⬆ ⬇

Comments

Live attenuated PO and intramuscular (IM) parenteral vaccines are available for travelers to areas of high risk (Table E5).
PO vaccines are about 70% effective and last up to 5 yr. It is a series of four capsules taken on alternate days for persons ≥6 yr of age.
The IM vaccine is over 75% effective but lasts only 2 yr; it can be given to persons ≥2 yr of age.
Infection with antimicrobial-resistant S. typhi strains among U.S. patients with typhoid fever is associated with travel to the Indian subcontinent, and an increasing proportion of these infections are caused by S. typhi strains with decreased susceptibility to fluoroquinolones and beta-lactam antibiotics.
In 2017 in the U.S., there was an outbreak in 32 states of over 250 cases, including two deaths, with a strain of Salmonella resistant to Cipro and azithromycin whose source is contaminated beef from the U.S. and soft Mexican cheese.
In 2019 a large outbreak of salmonella occurred with cases in 49 states involving contact with backyard poultry. There were 1134 cases; 30% required hospitalization; there were two deaths, and 21% were children younger than 5 yr.

TABLE E5 Typhoid Fever Vaccines Commercially Available Internationally

Vaccine	Type	Route	Dose and Interval	Minimum Age (yr)	Protection Against S. typhi	Boosting Interval in Travelers
Ty21a	Live attenuated	Oral	Four doses (in U.S.) Administer one dose every other day until complete	5 ∗	50%-80%^†	Every 5 yr
Vi capsule antigen	Polysaccharide	Intramuscular	1	2	50%-80%	Every 2 yr

^∗5 yr and older per World Health Organization; 6 yr and older per U.S. Advisory Committee on Immunization Practices.

^†Has some efficacy against S. paratyphi B (see text). Additional vaccines are in development, including conjugate vaccines.

From Bennett JE et al: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Saunders.

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Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

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