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Typhoid Fever
Douglas W. MacPherson, MD, MSc-CTM, FRCPC
image BASICS
  • A common enteric bacterial disease transmitted by ingestion of contaminated food or water
  • Most cases in the United States are imported from endemic areas of South or Southeast Asia and Latin America.
DESCRIPTION
  • Typhoid fever is an acute systemic illness in humans caused by Salmonella typhi.
    • Classic example of enteric fever caused by Salmonella bacterium
  • Enteric fevers due to Salmonella paratyphi can present in a manner similar to classic typhoid fever.
  • Typhoid is endemic in developing nations with poor sanitation. Most cases in North America and other developed nations are acquired after travel to disease-endemic areas.
  • Travelers visiting family or friends may be at greater risk of typhoid.
  • Mode of transmission is fecal-oral through ingestion of contaminated food (commonly poultry or milk) or water.
  • Incubation period varies from 7 to 21 days.
  • System(s) affected: gastrointestinal; pulmonary; skin/exocrine
  • Synonym(s): typhoid; typhus abdominalis; enteric fever; nervous fever; slow fever
Geriatric Considerations
Disease is more serious in the elderly.
Pediatric Considerations
Disease is more serious in infants but may be milder in children.
EPIDEMIOLOGY
Although typhoid outbreaks have been described in the United States, most cases are reported in international travelers returning from endemic transmission areas.
  • Predominant age: all ages
  • Predominant sex: male = female
Incidence
In the United States, 300 to 500 new cases per year
ETIOLOGY AND PATHOPHYSIOLOGY
  • Historically, typhoid fever (untreated) occurs in several week-long stages.
  • The initial infection is transmitted via the fecal-oral route, with resultant bacteremia and sepsis. Involvement of the bowel wall (Peyer patch) rarely may be associated with bleeding from the bowel or bowel perforation.
  • The first stage involves fluctuations in temperature with relative bradycardia (Faget sign). Other symptoms include headache, cough, malaise, epistaxis, and abdominal pain.
  • The second stage involves higher fever (with persistent relative bradycardia). Mental status changes are possible (agitation—“nervous fever”). Rose spots appear on the chest and abdomen. In some patients, abdominal pain is common as is constipation or diarrhea (with characteristic malodorous “pea soup” appearance).
  • The third week is when most complications occur due to intestinal hemorrhage or encephalitis.
  • The final week is characterized by defervescence and recovery.
  • A chronic carrier state may occur with S. typhi shedding in the stools. Potential person-to-person transmission may occur. In a chronic carrier state, S. typhi resides in the biliary tract and gallbladder. Chronic suppressive antimicrobials may clear the carrier state. In extreme cases, cholecystectomy has been performed as an attempt to clear carriage of S. typhi.
RISK FACTORS
Consider in patients presenting with fever after tropical travel or exposure to a chronic carrier.
GENERAL PREVENTION
  • Food and water precautions help prevent all enteric infections, including typhoid fever.
  • Avoid tap water, salad/raw vegetables, unpeeled fruits, and dairy products in tropical travel.
  • Avoid undercooked poultry or poultry products left unrefrigerated for prolonged periods.
  • Wash hands before and after food preparation.
  • For high-risk travel to an endemic area, consider vaccination against typhoid (1)[A].
    • Parenteral ViCPS or capsular polysaccharide typhoid vaccine (Typhim Vi) or
    • Ty21a or live oral typhoid vaccine (Vivotif Berna), particularly if traveler will be at prolonged risk (>4 weeks)
  • Consider vaccination for workers exposed to S. typhi or those with household or intimate exposure to a carrier of S. typhi.
  • Occupational health and safety precautions, including screening of domestic and commercial food handlers, may be considered in some situations.
image DIAGNOSIS
Assess the clinical presentation and exposure history, including travel and known exposures to chronic S. typhi carriers.
PHYSICAL EXAM
  • Fever
  • Relative bradycardia
  • Cervical adenopathy
  • Conjunctivitis
  • Rose spot (transient erythematous maculopapular rash in anterior thorax or upper abdomen)
  • Splenomegaly
  • Hepatomegaly
DIFFERENTIAL DIAGNOSIS
  • Malaria
  • “Enteric fever-like” syndrome caused by Yersinia enterocolitica, pseudotuberculosis, and Campylobacter spp.
  • Enteric fever caused by nontyphoid Salmonella spp.
  • Infectious hepatitis
  • Dengue
  • Atypical pneumonia
  • Infectious mononucleosis
  • Subacute bacterial endocarditis
  • Tuberculosis
  • Brucellosis
  • Q fever
  • Toxoplasmosis
  • Typhus
  • Viral infections: Epstein-Barr virus (EBV), cytomegalovirus (CMV), viral hemorrhagic agents
DIAGNOSTIC TESTS & INTERPRETATION
Due to the rarity of enteric fevers/typhoid syndromes in the United States, a high level of clinical suspicion is required.
  • Definitive diagnosis is by culture of S. typhi from blood or other sterile body fluid.
  • Isolation of S. typhi in sputum, urine, or stool leads to a presumptive diagnosis.
  • Serology is nonspecific and typically not useful.
  • If there are multiple negative blood cultures or in patients with prior antibiotic therapy, diagnostic yield is better with bone marrow culture.
  • Anemia, leukopenia (neutropenia), thrombocytopenia, or evidence of disseminated intravascular coagulopathy. Elevated liver enzymes are common.
  • Have a high clinical suspicion for intestinal perforation, or consider serial plain abdominal films looking for evidence of perforation in ill patients complaining of persistent abdominal tenderness.
Diagnostic Procedures/Other
  • Bone marrow aspirate for culture of S. typhi is more sensitive than blood cultures but rarely indicated as a primary investigation.
  • Bone marrow aspiration may be done for evaluation of a fever of unknown origin.
Test Interpretation
Classically, pathology of the bowel shows mononuclear proliferation involving lymphoid tissue of intestinal tract, especially Peyer patches of the terminal ileum.
image TREATMENT
  • Treatment of typhoid disease and chronic carrier states must be determined on an individual basis. Factors to be considered include age, public health and occupational health risk (e.g., food handler, chronic care facilities, medical personnel), intolerance to antibiotics, and evidence of biliary tract disease.
  • Awareness of emerging drug-resistant S. typhi strains and the epidemiology of the patient's exposure help direct primary therapy. Knowledge of local resistance patterns for presumptive treatment or laboratory sensitivity also guide therapy. Fluoroquinolone-resistant S. typhi is common in Asia.
P.1073

GENERAL MEASURES
  • Fluid and electrolyte support
  • Strict isolation of patient's linen, stool, and urine
  • Consider serial plain abdominal films for evidence of perforation, usually in the 3rd to 4th week of illness.
  • For hemorrhage: blood transfusion and management of shock
MEDICATION
First Line
  • Chloramphenicol: pediatric 50 mg/kg/day PO QID for 2 weeks; adult dose 2 to 3 g per day PO divided q6h for 2 weeks or
  • Ampicillin: pediatric 100 mg/kg/day (max 2 g) QID PO for 2 weeks; adults 500 mg q6h for 2 weeks or
  • Ciprofloxacin: 500 mg PO BID for 2 weeks, indicated in multiple-drug-resistant typhoid
    • Has been used safely in children; WHO recommends as first line in areas with drug resistance to older first-line antibiotics.
    • Fluoroquinolones may prevent clinical relapse better than chloramphenicol (2)[A].
  • Ceftriaxone: pediatric 100 mg/kg/day for 2 weeks; adult dose: 1 to 2 g IV once daily for 2 weeks or
  • Azithromycin: pediatric 10 to 20 mg/kg (max 1 g) PO daily for 5 to 7 days; adult dose: 1 g PO once followed by 500 mg PO daily for 5 to 7 days
  • Chronic carrier state
    • Ampicillin: 4 to 5 g/day plus probenecid 2 g/day QID for 6 weeks (for patients with normal gallbladder function and no evidence of cholelithiasis)
    • Ciprofloxacin: 500 mg PO BID for 4 to 6 weeks is also efficacious. Chloramphenicol resistance has been reported in Mexico, South America, Central America, Southeast Asia, India, Pakistan, Middle East, and Africa.
  • Contraindications: Refer to manufacturer's profile.
  • Precautions: Rarely, Jarisch-Herxheimer reaction appears after antimicrobial therapy.
  • Significant possible interactions: Refer to manufacturer's profile for each drug.
Second Line
  • Trimethoprim-sulfamethoxazole one doublestrength tablet twice a day for 10 days (Note: Drug resistance is common, local resistance patterns and expert knowledge should guide choice of treatment agent.)
  • Furazolidone: 7.5 mg/kg/day PO for 10 days; in uncomplicated multidrug-resistant typhoid; safe in children; efficacy >85% cure
Pregnancy Considerations
Ciprofloxacin therapy is relatively contraindicated in children and in pregnant patients.
ISSUES FOR REFERRAL
Complications of sepsis, bowel perforation
SURGERY/OTHER PROCEDURES
  • Complications: bowel perforation
  • Cholecystectomy may be warranted in carriers with cholelithiasis, relapse after therapy, or intolerance to antimicrobial therapy.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Inpatient if acutely ill
  • Outpatient for less ill patient or for carrier
Nursing
Observe enteric precautions.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Bed rest initially, then activity as tolerated
Patient Monitoring
See “General Measures.”
DIET
NPO if abdominal symptoms are severe. With improvement, begin normal low-residue diet, with high-calorie supplementation if malnourished.
PATIENT EDUCATION
  • Discuss chronic carrier state and its complications.
  • For family members, travelers, or workers at risk, educate about food/water hygiene and provide vaccination.
  • Educate patients that the typhoid vaccines do not protect against S. paratyphi infection.
  • Typhoid vaccines protect 50-80% of recipients (not 100%) with diminishing effectiveness over 2 to 4 years.
  • CDC patient handout: http://www.cdc.gov/vaccines/hcp/vis/vis-statements/typhoid.html
PROGNOSIS
Overall prognosis is good with therapy, <2% mortality rate, 15% relapse rate with some antibiotic treatments, and 3% bowel perforation.
REFERENCES
1. Roggelin L, Vinnemeier CD, Fischer-Herr J, et al. Serological response following re-vaccination with Salmonella typhi Vi-capsular polysaccharide vaccines in healthy adult travellers. Vaccine. 2015;33(33):4141-4145.
2. Thaver D, Zaidi AK, Critchley J, et al. A comparison of fluoroquinolones versus other antibiotics for treating enteric fever: meta-analysis. BMJ. 2009; 338:b1865.
Additional Reading
&NA;
  • Basnyat B. Typhoid fever in the United States and antibiotic choice. JAMA. 2010;303(1):34; author reply 34-35.
  • Butler T. Treatment of typhoid fever in the 21st century: promises and shortcomings. Clin Microbiol Infect. 2011;17(7):959-963.
  • Centers for Disease Control and Prevention. National Center for Emerging and Zoonotic Infectious Diseases. Typhoid fever. http://www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever/. Accessed October 11, 2015.
  • Chalya PL, Mabula JB, Koy M, et al. Typhoid intestinal perforations at a University teaching hospital in Northwestern Tanzania: a surgical experience of 104 cases in a resource-limited setting. World J Emerg Surg. 2012;7:4.
  • Clark TW, Daneshvar C, Pareek M, et al. Enteric fever in a UK regional infectious diseases unit: a 10 year retrospective review. J Infect. 2010;60(2):91-98.
  • Crump JA, Mintz ED. Global trends in typhoid and paratyphoid fever. Clin Infect Dis. 2010;50(2): 241-246.
  • Date KA, Bentsi-Enchill A, Marks F, et al. Typhoid fever vaccination strategies. Vaccine. 2015;33 (Suppl 3):C55-C61.
  • Effa EE, Lassi ZS, Critchley JA, et al. Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). Cochrane Database Syst Rev. 2011;(10):CD004530.
  • Kaurthe J. Increasing antimicrobial resistance and narrowing therapeutics in typhoidal salmonellae. J Clin Diagn Res. 2013;7(3):576-579.
  • Newton AE, Routh JA, Mahon BE. Chapter 3. Infectious diseases related to travel. Typhoid and paratyphoid fever. http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-relatedto-travel/typhoid-paratyphoid-fever. Accessed October 11, 2015.
  • Sánchez-Vargas FM, Abu-El-Haija MA, Gómez-Duarte OG. Salmonella infections: an update on epidemiology, management, and prevention. Travel Med Infect Dis. 2011;9(6):263-277.
Codes
&NA;
ICD10
  • A01.00 Typhoid fever, unspecified
  • Z22.0 Carrier of typhoid
  • A01.03 Typhoid pneumonia
Clinical Pearls
&NA;
  • Consider typhoid (along with malaria, dengue, and other travel-associated infections) in febrile travelers returning from endemic areas such as Latin America, sub-Saharan Africa, or South Asia.
  • Routine blood cultures detect S. typhi but may be negative if antibiotics are administered prior to testing.
  • A history or documentation of vaccination against S. typhi does not exclude the diagnosis of typhoid fever.