Typhoid Fever

  • Author: John L Brusch, MD, FACP; Chief Editor: Michael Stuart Bronze, MD  more...
Updated: Feb 16, 2016


Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illness caused primarily by Salmonella enterica, subspecies enterica serovar typhi and, to a lesser extent, related serovars paratyphi A, B, and C.

The protean manifestations of typhoid fever make this disease a true diagnostic challenge. The classic presentation includes fever, malaise, diffuse abdominal pain, and constipation. Untreated, typhoid fever is a grueling illness that may progress to delirium, obtundation, intestinal hemorrhage, bowel perforation, and death within 1 month of onset. Survivors may be left with long-term or permanent neuropsychiatric complications.

S typhi has been a major human pathogen for thousands of years, thriving in conditions of poor sanitation, crowding, and social chaos. It may have responsible for the Great Plague of Athens at the end of the Pelopennesian War.[1] The name S typhi is derived from the ancient Greek typhos, an ethereal smoke or cloud that was believed to cause disease and madness. In the advanced stages of typhoid fever, the patient's level of consciousness is truly clouded. Although antibiotics have markedly reduced the frequency of typhoid fever in the developed world, it remains endemic in developing countries.[2]

S paratyphi causes the same syndrome but appears to be a relative newcomer. It may be taking over the typhi niche, in part, because of immunological naivete among the population and incomplete coverage by vaccines that target typhi.

Note that some writers refer to the typhoid and paratyphoid fever as distinct syndromes caused by the typhi versus paratyphi serovars, while others use the term typhoid fever for a disease caused by either one. We use the latter terminology. We refer to these serovars collectively as typhoidal salmonella.



All pathogenic Salmonella species, when present in the gut are engulfed by phagocytic cells, which then pass them through the mucosa and present them to the macrophages in the lamina propria. Nontyphoidal salmonellae are phagocytized throughout the distal ileum and colon. With toll-like receptor (TLR)–5 and TLR-4/MD2/CD-14 complex, macrophages recognize pathogen-associated molecular patterns (PAMPs) such as flagella and lipopolysaccharides. Macrophages and intestinal epithelial cells then attract T cells and neutrophils with interleukin 8 (IL-8), causing inflammation and suppressing the infection.[3, 4]

In contrast to the nontyphoidal salmonellae, S typhi and paratyphi enter the host's system primarily through the distal ileum. They have specialized fimbriae that adhere to the epithelium over clusters of lymphoid tissue in the ileum (Peyer patches), the main relay point for macrophages traveling from the gut into the lymphatic system. The bacteria then induce their host macrophages to attract more macrophages.[3]

S typhi has a Vi capsular antigen that masks PAMPs, avoiding neutrophil-based inflammation, while the most common paratyphi serovar, paratyphi A, does not. This may explain the greater infectivity of typhi compared with most of its cousins.[5]

Typhoidal salmonella co-opt the macrophages' cellular machinery for their own reproduction[6] as they are carried through the mesenteric lymph nodes to the thoracic duct and the lymphatics and then through to the reticuloendothelial tissues of the liver, spleen, bone marrow, and lymph nodes. Once there, they pause and continue to multiply until some critical density is reached. Afterward, the bacteria induce macrophage apoptosis, breaking out into the bloodstream to invade the rest of the body.[4]

The bacteria then infect the gallbladder via either bacteremia or direct extension of infected bile. The result is that the organism re-enters the gastrointestinal tract in the bile and reinfects Peyer patches. Bacteria that do not reinfect the host are typically shed in the stool and are then available to infect other hosts.[2, 4] See the image below.

Life cycle of Salmonella typhi. Life cycle of Salmonella typhi.

Chronic carriers are responsible for much of the transmission of the organism. While asymptomatic, they may continue to shed bacteria in their stool for decades. The organisms sequester themselves either as a biofilm on gallstones or gallbladder epithelium or, perhaps, intracellularly, within the epithelium itself.[7] The bacteria excreted by a single carrier may have multiple genotypes, making it difficult to trace an outbreak to its origin.[8]

Risk factors

Typhoidal salmonella have no nonhuman vectors. An inoculum as small as 100,000 organisms of typhi causes infection in more than 50% of healthy volunteers.[9] Paratyphi requires a much higher inoculum to infect, and it is less endemic in rural areas. Hence, the patterns of transmission are slightly different.

The following are modes of transmission of typhoidal salmonella:

  • Oral transmission via food or beverages handled by an often asymptomatic individual—a carrier—who chronically sheds the bacteria through stool or, less commonly, urine
  • Hand-to-mouth transmission after using a contaminated toilet and neglecting hand hygiene
  • Oral transmission via sewage-contaminated water or shellfish (especially in the developing world). [10, 11, 12]

Paratyphi is more commonly transmitted in food from street vendors. It is believed that some such foods provide a friendly environment for the microbe.

Paratyphi is more common among newcomers to urban areas, probably because they tend to be immunologically naïve to it. Also, travellers get little or no protection against paratyphi from the current typhoid vaccines, all of which target typhi.[13, 14]

Typhoidal salmonella are able to survive a stomach pH as low as 1.5. Antacids, histamine-2 receptor antagonists (H2 blockers), proton pump inhibitors, gastrectomy, and achlorhydria decrease stomach acidity and facilitate S typhi infection.[4]

HIV/AIDS is clearly associated with an increased risk of nontyphoidal Salmonella infection; however, the data and opinions in the literature as to whether this is true for S typhi or paratyphi infection are conflicting. If an association exists, it is probably minor.[15, 16, 17, 18]

Other risk factors for typhoid fever include various genetic polymorphisms. These risk factors often also predispose to other intracellular pathogens. For instance, PARK2 and PACGR code for a protein aggregate that is essential for breaking down the bacterial signaling molecules that dampen the macrophage response. Polymorphisms in their shared regulatory region are found disproportionately in persons infected with Mycobacterium leprae and S typhi.[11]

On the other hand, protective host mutations also exist. The fimbriae of S typhi bind in vitro to cystic fibrosis transmembrane conductance receptor (CFTR), which is expressed on the gut membrane. Two to 5% of white persons are heterozygous for the CFTR mutation F508del, which is associated with a decreased susceptibility to typhoid fever, as well as to cholera and tuberculosis. The homozygous F508del mutation in CFTR is associated with cystic fibrosis. Thus, typhoid fever may contribute to evolutionary pressure that maintains a steady occurrence of cystic fibrosis, just as malaria maintains sickle cell disease in Africa.[19, 20]

As the middle class in south Asia grows, some hospitals there are seeing a large number of typhoid fever cases among relatively well-off university students who live in group households with poor hygiene.[21] American clinicians should keep this in mind, as members of this cohort often come to the United States for advanced degrees.




United States

Since 1900, improved sanitation and successful antibiotic treatment have steadily decreased the incidence of typhoid fever in the United States. In 1920, 35,994 cases of typhoid fever were reported. In 2006, there were 314.

Between 1999 and 2006, 79% of typhoid fever cases occurred in patients who had been outside of the country within the preceding 30 days. Two thirds of these individuals had just journeyed from the Indian subcontinent. The 3 known outbreaks of typhoid fever within the United States were traced to imported food or to a food handler from an endemic region. Remarkably, only 17% of cases acquired domestically were traced to a carrier.[22]


Typhoid fever occurs worldwide, primarily in developing nations whose sanitary conditions are poor. Typhoid fever is endemic in Asia, Africa, Latin America, the Caribbean, and Oceania, but 80% of cases come from Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, or Vietnam.[23] Within those countries, typhoid fever is most common in underdeveloped areas. Typhoid fever infects roughly 21.6 million people (incidence of 3.6 per 1,000 population) and kills an estimated 200,000 people every year.[24]

In the United States, most cases of typhoid fever arise in international travelers. The average yearly incidence of typhoid fever per million travelers from 1999-2006 by county or region of departure was as follows:[22]

  • Canada - 0
  • Western Hemisphere outside Canada/United States - 1.3
  • Africa - 7.6
  • Asia - 10.5
  • India - 89 (122 in 2006)
  • Total (for all countries except Canada/United States) - 2.2


With prompt and appropriate antibiotic therapy, typhoid fever is typically a short-term febrile illness requiring a median of 6 days of hospitalization. Treated, it has few long-term sequelae and a 0.2% risk of mortality.[22] Untreated typhoid fever is a life-threatening illness of several weeks' duration with long-term morbidity often involving the central nervous system. The case fatality rate in the United States in the pre-antibiotic era was 9%-13%.[25]


Typhoid fever has no racial predilection.


Fifty-four percent of typhoid fever cases in the United States reported between 1999 and 2006 involved males.[22]


Most documented typhoid fever cases involve school-aged children and young adults. However, the true incidence among very young children and infants is thought to be higher. The presentations in these age groups may be atypical, ranging from a mild febrile illness to severe convulsions, and the S typhi infection may go unrecognized. This may account for conflicting reports in the literature that this group has either a very high or a very low rate of morbidity and mortality.[21, 26]

Contributor Information and Disclosures

John L Brusch, MD, FACP Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance

John L Brusch, MD, FACP is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.


Roberto Corales, DO, AAHIVS Senior Director, HIV Medicine and Clinical Research, Trillium Health

Roberto Corales, DO, AAHIVS is a member of the following medical societies: American Medical Association, International AIDS Society, American Osteopathic Association

Disclosure: Nothing to disclose.

Steven K Schmitt, MD Staff Physician, Department of Infectious Disease, Cleveland Clinic

Steven K Schmitt, MD is a member of the following medical societies: Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Thomas Garvey, MD, JD Primary Care Physician, Burlington Medical Associates; Co-chair, Medical Advisory Committee for the Elimination of Tuberculosis

Thomas Garvey, MD, JD is a member of the following medical societies: American College of Legal Medicine, American College of Physicians, American Society of Law, Medicine & Ethics

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Richard B Brown, MD, FACP Chief, Division of Infectious Diseases, Baystate Medical Center; Professor, Department of Internal Medicine, Tufts University School of Medicine

Richard B Brown, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Chest Physicians, American College of Physicians, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, Massachusetts Medical Society

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, Oklahoma State Medical Association, Southern Society for Clinical Investigation, Association of Professors of Medicine, American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

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Life cycle of Salmonella typhi.
Table 1. Incidence and Timing of Various Manifestations of Untreated Typhoid Fever [2, 31, 32, 33, 34, 35]
  Incubation Week 1 Week 2 Week 3 Week 4 Post
Systemic Recovery phase or death (15% of untreated cases) 10%-20% relapse; 3%-4% chronic carriers;

long-term neurologic sequelae (extremely rare);

gallbladder cancer (RR=167; carriers)

Stepladder fever pattern or insidious onset fever   Very commona Very common
Acute high fever   Very rareb    
Chills   Almost allc
Rigors   Uncommon
Anorexia   Almost all
Diaphoresis   Very common
Malaise   Almost all Almost all Typhoid state (common)
Insomnia     Very common
Confusion/delirium   Commond Very common
Psychosis   Very rare Common  
Catatonia   Very rare    
Frontal headache

(usually mild)

  Very common    
Meningeal signs   Raree Rare  
Parkinsonism   Very rare    
Ear, nose, and throat
Coated tongue   Very common    
Sore throatf        
Mild cough   Common    
Bronchitic cough   Common    
Rales   Common    
Pneumonia   Rare (lobar) Rare Common


Dicrotic pulse   Rare Common
Myocarditis   Rare    
Pericarditis   Extremely rareg    
Thrombophlebitis       Very rare
Constipation   Very common Common
Diarrhea   Rare Common (pea soup)
Bloating with tympany   Very common (84%)[35]    
Diffuse mild abdominal pain   Very common    
Sharp right lower quadrant pain   Rare    
Gastrointestinal hemorrhage   Very rare; usually trace Very common
intestinal perforation       Rare
Hepatosplenomegaly   Common
Jaundice   Common
Gallbladder pain   Very rare
Urinary retention   Common
Hematuria   Rare
Renal pain   Rare
Myalgias Very rare
Arthralgias Very rare
Arthritis (large joint) Extremely rare
Rose spots   Rare
Abscess (anywhere)   Extremely rare Extremely rare Extremely rare
a Very common: Symptoms occur in well over half of cases (approximately 65%-95%).

b Very rare: Symptoms occur in less than 5% of cases.

c Almost all: Symptoms occur in almost all cases.

d Common: Symptoms occur in 35%-65% of cases.

e Rare: Symptoms occur in 5%-35% of cases.

f Blank cells: No mention of the symptom at that phase was found in the literature.

g Extremely rare: Symptoms have been described in occasional case reports.

Table 2. Sensitivities of Cultures [2, 37, 38, 39]
  Incubation Week 1 Week 2 Week 3 Week 4
Bone marrow aspirate (0.5-1 mL)   90% (may decrease after 5 d of antibiotics)
Blood (10-30 mL), stool, or duodenal aspirate culture 40%-80% ~20% Variable (20%-60%)
Urine   25%-30%, timing unpredictable
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