Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.

com/article/231135-overview#a5

Typhoid Fever
Updated: May 18, 2017
Author: John L Brusch, MD, FACP; Chief Editor: Michael Stuart Bronze, MD more...

OVERVIEW

Background
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.

Pathophysiology
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]

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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.

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]

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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.

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Epidemiology
Frequency

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]

International

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

Mortality/Morbidity

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]

Race

Typhoid fever has no racial predilection.

Sex

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

Age

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]

Clinical Presentation

References

1. Papagrigorakis MJ, Synodinos PN, Yapijakis C. Ancient typhoid epidemic reveals possible
ancestral strain of Salmonella enterica serovar Typhi. Infect Genet Evol. 2007 Jan.
7(1):126-7. [Medline]. [Full Text].

2. Christie AB. Infectious Diseases: Epidemiology and Clinical Practice. 4th ed. Edinburgh,
Scotland: Churchill Livingstone; 1987.

3. Raffatellu M, Chessa D, Wilson RP, Tükel C, Akçelik M, Bäumler AJ. Capsule-mediated

immune evasion: a new hypothesis explaining aspects of typhoid fever pathogenesis. Infect
Immun. 2006 Jan. 74(1):19-27. [Medline].

4. Parry CM, Hien TT, Dougan G, et al. Typhoid fever. N Engl J Med. 2002 Nov 28.
347(22):1770-82. [Medline]. [Full Text].

5. de Jong HK, Parry CM, van der Poll T, Wiersinga WJ. Host-pathogen interaction in invasive
Salmonellosis. PLoS Pathog. 2012. 8(10):e1002933. [Medline]. [Full Text].

6. Ramsden AE, Mota LJ, Münter S, Shorte SL, Holden DW. The SPI-2 type III secretion system
restricts motility of Salmonella-containing vacuoles. Cell Microbiol. 2007 Oct. 9(10):2517-29.
[Medline].

7. Gonzalez-Escobedo G, Gunn JS. Gallbladder epithelium as a niche for chronic Salmonella

carriage. Infect Immun. 2013 Aug. 81(8):2920-30. [Medline]. [Full Text].

8. Chiou CS, Wei HL, Mu JJ, Liao YS, Liang SY, Liao CH, et al. Salmonella enterica serovar
Typhi variants in long-term carriers. J Clin Microbiol. 2013 Feb. 51(2):669-72. [Medline]. [Full
Text].

9. Levine MM, Tacket CO, Sztein MB. Host-Salmonella interaction: human trials. Microbes
Infect. 2001 Nov-Dec. 3(14-15):1271-9. [Medline].

10. Earampamoorthy S, Koff RS. Health hazards of bivalve-mollusk ingestion. Ann Intern Med.
1975 Jul. 83(1):107-10. [Medline]. [Full Text].

11. Ali S, Vollaard AM, Widjaja S, Surjadi C, van de Vosse E, van Dissel JT. PARK2/PACRG

5 of 25 7/11/17, 5:15 PM
Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

polymorphisms and susceptibility to typhoid and paratyphoid fever. Clin Exp Immunol. 2006
Jun. 144(3):425-31. [Medline].

12. Ram PK, Naheed A, Brooks WA, Hossain MA, Mintz ED, Breiman RF. Risk factors for typhoid
fever in a slum in Dhaka, Bangladesh. Epidemiol Infect. 2007 Apr. 135(3):458-65. [Medline].

13. Karkey A, Thompson CN, Tran Vu Thieu N, Dongol S, Le Thi Phuong T, Voong Vinh P, et al.
Differential epidemiology of Salmonella Typhi and Paratyphi A in Kathmandu, Nepal: a
matched case control investigation in a highly endemic enteric fever setting. PLoS Negl Trop
Dis. 2013. 7(8):e2391. [Medline]. [Full Text].

14. Vollaard AM, Ali S, van Asten HA, Widjaja S, Visser LG, Surjadi C, et al. Risk factors for
typhoid and paratyphoid fever in Jakarta, Indonesia. JAMA. 2004 Jun 2. 291(21):2607-15.
[Medline].

15. Gotuzzo E, Frisancho O, Sanchez J, Liendo G, Carrillo C, Black RE, et al. Association
between the acquired immunodeficiency syndrome and infection with Salmonella typhi or
Salmonella paratyphi in an endemic typhoid area. Arch Intern Med. 1991 Feb. 151(2):381-2.
[Medline].

16. Manfredi R, Chiodo F. Salmonella typhi disease in HIV-infected patients: case reports and
literature review. Infez Med. 1999. 7(1):49-53. [Medline].

17. Gordon MA, Graham SM, Walsh AL, Wilson L, Phiri A, Molyneux E, et al. Epidemics of
invasive Salmonella enterica serovar enteritidis and S. enterica Serovar typhimurium infection
associated with multidrug resistance among adults and children in Malawi. Clin Infect Dis.
2008 Apr 1. 46(7):963-9. [Medline].

18. Monack DM, Mueller A, Falkow S. Persistent bacterial infections: the interface of the
pathogen and the host immune system. Nat Rev Microbiol. 2004 Sep. 2(9):747-65. [Medline].

19. van de Vosse E, Ali S, de Visser AW, Surjadi C, Widjaja S, Vollaard AM, et al. Susceptibility
to typhoid fever is associated with a polymorphism in the cystic fibrosis transmembrane
conductance regulator (CFTR). Hum Genet. 2005 Oct. 118(1):138-40. [Medline].

20. Poolman EM, Galvani AP. Evaluating candidate agents of selective pressure for cystic
fibrosis. J R Soc Interface. 2007 Feb 22. 4(12):91-8. [Medline].

21. Dutta TK, Beeresha, Ghotekar LH. Atypical manifestations of typhoid fever. J Postgrad Med.
2001 Oct-Dec. 47(4):248-51. [Medline].

22. Lynch MF, Blanton EM, Bulens S, Polyak C, Vojdani J, Stevenson J. Typhoid fever in the
United States, 1999-2006. JAMA. 2009 Aug 26. 302(8):859-65. [Medline].

23. Chau TT, Campbell JI, Galindo CM, Van Minh Hoang N, Diep TS, Nga TT, et al. Antimicrobial
drug resistance of Salmonella enterica serovar typhi in asia and molecular mechanism of
reduced susceptibility to the fluoroquinolones. Antimicrob Agents Chemother. 2007 Dec.
51(12):4315-23. [Medline].

24. Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull World Health Organ.
2004 May. 82(5):346-53. [Medline].

6 of 25 7/11/17, 5:15 PM
Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

25. Crump JA, Ram PK, Gupta SK, Miller MA, Mintz ED. Part I. Analysis of data gaps pertaining
to Salmonella enterica serotype Typhi infections in low and medium human development
index countries, 1984-2005. Epidemiol Infect. 2008 Apr. 136(4):436-48. [Medline].

26. Mulligan TO. Typhoid fever in young children. Br Med J. 1971 Dec 11. 4(5788):665-7.
[Medline].

27. Rahaman MM, Jamiul AK. Rose spots in shigellosis caused by Shigella dysenteriae type 1
infection. Br Med J. 1977 Oct 29. 2(6095):1123-4. [Medline].

28. Cunha BA. Malaria or typhoid fever: a diagnostic dilemma?. Am J Med. 2005 Dec.
118(12):1442-3; author reply 1443-4. [Medline].

29. Woodward TE, Smadel JE. Management of typhoid fever and its complications. Ann Intern
Med. 1964 Jan. 60:144-57. [Medline].

30. Hermans P, Gerard M, van Laethem Y, et al. Pancreatic disturbances and typhoid fever.
Scand J Infect Dis. 1991. 23(2):201-5. [Medline].

31. Butler T, Islam A, Kabir I, et al. Patterns of morbidity and mortality in typhoid fever dependent
on age and gender: review of 552 hospitalized patients with diarrhea. Rev Infect Dis. 1991
Jan-Feb. 13(1):85-90. [Medline].

32. Butler T, Knight J, Nath SK, et al. Typhoid fever complicated by intestinal perforation: a
persisting fatal disease requiring surgical management. Rev Infect Dis. 1985 Mar-Apr.
7(2):244-56. [Medline].

33. Crum NF. Current trends in typhoid Fever. Curr Gastroenterol Rep. 2003 Aug. 5(4):279-86.
[Medline].

34. Huang DB, DuPont HL. Problem pathogens: extra-intestinal complications of Salmonella
enterica serotype Typhi infection. Lancet Infect Dis. 2005 Jun. 5(6):341-8. [Medline].

35. Abdel Wahab MF, el-Gindy IM, Sultan Y, el-Naby HM. Comparative study on different recent
diagnostic and therapeutic regimens in acute typhoid fever. J Egypt Public Health Assoc.
1999. 74(1-2):193-205. [Medline].

36. Wain J, Pham VB, Ha V, Nguyen NM, To SD, Walsh AL, et al. Quantitation of bacteria in
bone marrow from patients with typhoid fever: relationship between counts and clinical
features. J Clin Microbiol. 2001 Apr. 39(4):1571-6. [Medline].

37. Escamilla J, Florez-Ugarte H, Kilpatrick ME. Evaluation of blood clot cultures for isolation of
Salmonella typhi, Salmonella paratyphi-A, and Brucella melitensis. J Clin Microbiol. 1986
Sep. 24(3):388-90. [Medline].

38. Gilman RH, Terminel M, Levine MM, Hernandez-Mendoza P, Hornick RB. Relative efficacy of
blood, urine, rectal swab, bone-marrow, and rose-spot cultures for recovery of Salmonella
typhi in typhoid fever. Lancet. 1975 May 31. 1(7918):1211-3. [Medline].

39. Farooqui BJ, Khurshid M, Ashfaq MK, Khan MA. Comparative yield of Salmonella typhi from
blood and bone marrow cultures in patients with fever of unknown origin. J Clin Pathol. 1991
Mar. 44(3):258-9. [Medline].

7 of 25 7/11/17, 5:15 PM
Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

40. Ambati SR, Nath G, Das BK. Diagnosis of typhoid fever by polymerase chain reaction. Indian
J Pediatr. 2007 Oct. 74(10):909-13. [Medline].

41. Song JH, Cho H, Park MY, et al. Detection of Salmonella typhi in the blood of patients with
typhoid fever by polymerase chain reaction. J Clin Microbiol. 1993 Jun. 31(6):1439-43.
[Medline].

42. Sadallah F, Brighouse G, Del Giudice G, et al. Production of specific monoclonal antibodies
to Salmonella typhi flagellin and possible application to immunodiagnosis of typhoid fever. J
Infect Dis. 1990 Jan. 161(1):59-64. [Medline].

43. Balasubramanian S, Kaarthigeyan K, Srinivas S, Rajeswari R. Serum ALT: LDH Ratio in

Typhoid Fever and Acute Viral Hepatitis. Indian Pediatr. 2009 Jul 1. [Medline].

44. Capoor MR, Nair D, Deb M, Aggarwal P. Enteric fever perspective in India: emergence of
high-level ciprofloxacin resistance and rising MIC to cephalosporins. J Med Microbiol. 2007
Aug. 56:1131-2. [Medline].

45. Pai H, Byeon JH, Yu S, Lee BK, Kim S. Salmonella enterica serovar typhi strains isolated in
Korea containing a multidrug resistance class 1 integron. Antimicrob Agents Chemother.
2003 Jun. 47(6):2006-8. [Medline].

46. Mamun KZ, Tabassum S, Ashna SM, Hart CA. Molecular analysis of multi-drug resistant
Salmonella typhi from urban paediatric population of Bangladesh. Bangladesh Med Res
Counc Bull. 2004 Dec. 30(3):81-6. [Medline].

47. Ahmed D, D'Costa LT, Alam K, Nair GB, Hossain MA. Multidrug-resistant Salmonella enterica
serovar typhi isolates with high-level resistance to ciprofloxacin in Dhaka, Bangladesh.
Antimicrob Agents Chemother. 2006 Oct. 50(10):3516-7. [Medline].

48. Zhanel GG, Smith HJ. Flouroquinolone resistance-associated gene mutations in

Streptococcus pneumoniae. Fuchs J, Podda M, eds. Encyclopedia of Medical Genomics and
Proteomics. CRC Press; 2004. 497-8. [Full Text].

49. Turner AK, Nair S, Wain J. The acquisition of full fluoroquinolone resistance in Salmonella
Typhi by accumulation of point mutations in the topoisomerase targets. J Antimicrob
Chemother. 2006 Oct. 58(4):733-40. [Medline].

50. Effa EE, Lassi ZS, Critchley JA, et al. Fluoroquinolones for treating typhoid and paratyphoid
fever (enteric fever). Cochrane Database Syst Rev. 2011 Oct 5. CD004530. [Medline].

51. Arjyal A, Pandit A. Treatment of enteric fever. J Infect Dev Ctries. 2008 Dec 1. 2(6):426-30.
[Medline].

52. Kundu R, Ganguly N, Ghosh TK, et al. IAP Task Force Report: management of enteric fever
in children. Indian Pediatr. 2006 Oct. 43(10):884-7. [Medline].

53. Islam MN, Rahman ME, Rouf MA, Islam MN, Khaleque MA, Siddika M, et al. Efficacy of
azithromycin in the treatment of childhood typhoid Fever. Mymensingh Med J. 2007 Jul.
16(2):149-53. [Medline].

54. Acosta C et al. Background document: The diagnosis, treatment and prevention of typhoid

8 of 25 7/11/17, 5:15 PM
Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

fever. 07/2003. Available at www.who.int/vaccines-documents/.

55. National Antimicrobial Resistance Monitoring System 2012 Human Isolates Final Report.
Available at http://www.cdc.gov/narms/pdf/2012-annual-report-narms-508c.pdf.

56. Dutta S, Sur D, Manna B, Bhattacharya SK, Deen JL, Clemens JD. Rollback of Salmonella
enterica serotype Typhi resistance to chloramphenicol and other antimicrobials in Kolkata,
India. Antimicrob Agents Chemother. 2005 Apr. 49(4):1662-3. [Medline].

57. Vaccines and Biologicals. World Health Organization. May, 2003.

58. Cooke FJ, Wain J. The emergence of antibiotic resistance in typhoid fever. Travel Med Infect
Dis. 2004 May. 2(2):67-74. [Medline].

59. Trivedi NA, Shah PC. A meta-analysis comparing the safety and efficacy of azithromycin over
the alternate drugs used for treatment of uncomplicated enteric fever. J Postgrad Med. 2012
Apr. 58(2):112-8. [Medline].

60. Hoffman SL, Punjabi NH, Kumala S, et al. Reduction of mortality in chloramphenicol-treated
severe typhoid fever by high-dose dexamethasone. N Engl J Med. 1984 Jan 12. 310(2):82-8.
[Medline].

61. Bhutta ZA. Current concepts in the diagnosis and treatment of typhoid fever. BMJ. 2006 Jul
8. 333(7558):78-82. [Medline].

62. Rogerson SJ, Spooner VJ, Smith TA, et al. Hydrocortisone in chloramphenicol-treated severe
typhoid fever in Papua New Guinea. Trans R Soc Trop Med Hyg. 1991 Jan-Feb. 85(1):113-6.
[Medline].

63. Jackson BR, Iqbal S, Mahon B. Updated recommendations for the use of typhoid vaccine -
advisory committee on immunization practices, United States, 2015. MMWR Morb Mortal
Wkly Rep. 2015 Mar 27. 64(11):305-8. [Medline].

64. Schwartz E, Shlim DR, Eaton M, Jenks N, Houston R. The effect of oral and parenteral
typhoid vaccination on the rate of infection with Salmonella typhi and Salmonella paratyphi A
among foreigners in Nepal. Arch Intern Med. 1990 Feb. 150(2):349-51. [Medline].

65. Pakkanen SH, Kantele JM, Kantele A. Cross-reactive immune response induced by the vi
capsular polysaccharide typhoid vaccine against salmonella paratyphi strains. Scand J
Immunol. 2014 Mar. 79(3):222-9. [Medline].

66. Acharya IL, Lowe CU, Thapa R, et al. Prevention of typhoid fever in Nepal with the Vi
capsular polysaccharide of Salmonella typhi. A preliminary report. N Engl J Med. 1987 Oct
29. 317(18):1101-4. [Medline].

67. Sur D, Ochiai RL, Bhattacharya SK, Ganguly NK, Ali M, Manna B, et al. A cluster-
randomized effectiveness trial of Vi typhoid vaccine in India. N Engl J Med. 2009 Jul 23.
361(4):335-44. [Medline].

68. Hanel RA, Araujo JC, Antoniuk A, et al. Multiple brain abscesses caused by Salmonella
typhi: case report. Surg Neurol. 2000 Jan. 53(1):86-90. [Medline].

69. Koul PA, Wani JI, Wahid A, et al. Pulmonary manifestations of multidrug-resistant typhoid

9 of 25 7/11/17, 5:15 PM
Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

fever. Chest. 1993 Jul. 104(1):324-5. [Medline].

70. Khan M, Coovadia Y, Sturm AW. Typhoid fever complicated by acute renal failure and
hepatitis: case reports and review. Am J Gastroenterol. 1998 Jun. 93(6):1001-3. [Medline].

71. Sitprija V, Pipantanagul V, Boonpucknavig V, et al. Glomerulitis in typhoid fever. Ann Intern
Med. 1974 Aug. 81(2):210-3. [Medline].

72. Baker NM, Mills AE, Rachman I, et al. Haemolytic-uraemic syndrome in typhoid fever. Br Med
J. 1974 Apr 13. 2(5910):84-7. [Medline].

73. Naidoo PM, Yan CC. Typhoid polymyositis. S Afr Med J. 1975 Nov 8. 49(47):1975-6.
[Medline].

74. Breakey WR, Kala AK. Typhoid catatonia responsive to ECT. Br Med J. 1977 Aug 6.
2(6083):357-9. [Medline].

75. Ackers ML, Puhr ND, Tauxe RV, et al. Laboratory-based surveillance of Salmonella serotype
Typhi infections in the United States: antimicrobial resistance on the rise. JAMA. 2000 May
24-31. 283(20):2668-73. [Medline]. [Full Text].

76. Adam D. Use of quinolones in pediatric patients. Rev Infect Dis. 1989 Jul-Aug. 11 Suppl
5:S1113-6. [Medline].

77. Akalin HE. Quinolones in the treatment of typhoid fever. Drugs. 1999. 58 Suppl 2:52-4.
[Medline].

78. Ambrosch F, Fritzell B, Gregor J, et al. Combined vaccination against yellow fever and
typhoid fever: a comparative trial. Vaccine. 1994 May. 12(7):625-8. [Medline].

79. Anand AC, Kataria VK, Singh W, et al. Epidemic multiresistant enteric fever in eastern India.
Lancet. 1990 Feb 10. 335(8685):352. [Medline].

80. Angorn IB, Pillay SP, Hegarty M, et al. Typhoid perforation of the ileum: A therapeutic
dilemma. S Afr Med J. 1975 May 3. 49(19):781-4. [Medline].

81. Cunha BA. Antibiotic Essentials. 7th Ed. Royal Oak, MI: Physicians Press; 2008.

82. Archampong EQ. Operative treatment of typhoid perforation of the bowel. Br Med J. 1969
Aug 2. 3(5665):273-6. [Medline].

83. Ashcroft MT, Singh B, Nicholson CC, et al. A seven-year field trial of two typhoid vaccines in
Guyana. Lancet. 1967 Nov 18. 2(7525):1056-9. [Medline].

84. Bitar R, Tarpley J. Intestinal perforation in typhoid fever: a historical and state-of-the-art
review. Rev Infect Dis. 1985 Mar-Apr. 7(2):257-71. [Medline].

85. Blaser MJ, Hickman FW, Farmer JJ 3rd, et al. Salmonella typhi: the laboratory as a reservoir
of infection. J Infect Dis. 1980 Dec. 142(6):934-8. [Medline].

86. Blaser MJ, Newman LS. A review of human salmonellosis: I. Infective dose. Rev Infect Dis.
1982 Nov-Dec. 4(6):1096-106. [Medline].

10 of 25 7/11/17, 5:15 PM
Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

87. Bodhidatta L, Taylor DN, Thisyakorn U, et al. Control of typhoid fever in Bangkok, Thailand,
by annual immunization of schoolchildren with parenteral typhoid vaccine. Rev Infect Dis.
1987 Jul-Aug. 9(4):841-5. [Medline].

88. Brumell JH, Grinstein S. Salmonella redirects phagosomal maturation. Curr Opin Microbiol.
2004 Feb. 7(1):78-84. [Medline]. [Full Text].

89. Butler T, Rumans L, Arnold K. Response of typhoid fever caused by chloramphenicol-

susceptible and chloramphenicol-resistant strains of Salmonella typhi to treatment with
trimethoprim-sulfamethoxazole. Rev Infect Dis. 1982 Mar-Apr. 4(2):551-61. [Medline].

90. Calva JJ, Ruiz-Palacios GM. Salmonella hepatitis: detection of salmonella antigens in the
liver of patients with typhoid fever. J Infect Dis. 1986 Aug. 154(2):373-4. [Medline].

91. Cancellieri V, Fara GM. Demonstration of specific IgA in human feces after immunization with
live Ty21a Salmonella typhi vaccine. J Infect Dis. 1985 Mar. 151(3):482-4. [Medline].

92. Capoor MR, Rawat D, Nair D, Hasan AS, Deb M, Aggarwal P, et al. In vitro activity of
azithromycin, newer quinolones and cephalosporins in ciprofloxacin-resistant Salmonella
causing enteric fever. J Med Microbiol. 2007 Nov. 56:1490-4. [Medline].

93. Carcelen A, Chirinos J, Yi A. Furazolidone and chloramphenicol for treatment of typhoid

fever. Scand J Gastroenterol Suppl. 1989. 169:19-23. [Medline].

94. Centers for Disease Control and Prevention. CDC Typhoid Immunization Recommendations
of the Advisory Committee on Immunization Practices (ACIP). MMWR. 1994. 43(RR-14):1-7.

95. Coovadia YM, Gathiram V, Bhamjee A, et al. An outbreak of multiresistant Salmonella typhi
in South Africa. Q J Med. 1992 Feb. 82(298):91-100. [Medline].

96. Crosa JH, Brenner DJ, Ewing WH, et al. Molecular relationships among the Salmonelleae. J
Bacteriol. 1973 Jul. 115(1):307-15. [Medline].

97. Cryz SJ Jr. Post-marketing experience with live oral Ty21a vaccine. Lancet. 1993 Jan 2.
341(8836):49-50. [Medline].

98. Cumberland NS, St Clair Roberts J, Arnold WS, et al. Typhoid Vi: a less reactogenic vaccine.
J Int Med Res. 1992 Jun. 20(3):247-53. [Medline].

99. Cunha BA. Osler on typhoid fever: differentiating typhoid from typhus and malaria. Infect Dis
Clin North Am. 2004 Mar. 18(1):111-25. [Medline].

100. Cunha BA. Typhoid fever: the temporal relations of key clinical diagnostic points. Lancet
Infect Dis. 2006 Jun. 6(6):318-20; author reply 320-1. [Medline].

101. Dashti AA, Jadaon MM, Habeeb F, West PW, Panigrahi D, Amyes SG. Salmonella enterica
Serotype typhi in Kuwait and its reduced susceptibility to ciprofloxacin. J Chemother. 2008
Jun. 20(3):297-302. [Medline].

102. Djemgou PC, Gatsing D, Hegazy ME, El-Hamd Mohamed AH, Ngandeu F, Tane P, et al.
Turrealabdane, turreanone and an antisalmonellal agent from Turraeanthus africanus.
Planta Med. 2010 Feb. 76(2):165-71. [Medline].

11 of 25 7/11/17, 5:15 PM
Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

103. Dong B, Galindo CM, Shin E, Acosta CJ, Page AL, Wang M, et al. Optimizing typhoid fever
case definitions by combining serological tests in a large population study in Hechi City,
China. Epidemiol Infect. 2007 Aug. 135(6):1014-20. [Medline].

104. Duggan MB, Beyer L. Enteric fever in young Yoruba children. Arch Dis Child. 1975 Jan.
50(1):67-71. [Medline].

105. Dunne EF, Fey PD, Kludt P, et al. Emergence of domestically acquired ceftriaxone-resistant
Salmonella infections associated with AmpC beta-lactamase. JAMA. 2000 Dec 27.
284(24):3151-6. [Medline].

106. Edelman R, Levine MM. Summary of an international workshop on typhoid fever. Rev Infect
Dis. 1986 May-Jun. 8(3):329-49. [Medline].

107. Effa EE, Bukirwa H. Azithromycin for treating uncomplicated typhoid and paratyphoid fever
(enteric fever). Cochrane Database Syst Rev. 2008 Oct 8. CD006083. [Medline].

108. Farid Z, Higashi GI, Bassily S, et al. Letter: Immune-complex disease in typhoid and
paratyphoid fevers. Ann Intern Med. 1975 Sep. 83(3):432. [Medline].

109. Farmer JJ. Enterobacteriaceae: introduction and identification. Murray PR, Baron EF, Pfaller
MA, eds. Manual of Clinical Microbiology. 6th ed. Washington, DC: American Society for
Microbiology; 1995. 438-49.

110. Ferreccio C, Levine MM, Manterola A, Rodriguez G, Rivara I, Prenzel I, et al. Benign
bacteremia caused by Salmonella typhi and paratyphi in children younger than 2 years. J
Pediatr. 1984 Jun. 104(6):899-901. [Medline].

111. Ferreccio C, Levine MM, Rodriguez H, et al. Comparative efficacy of two, three, or four doses
of TY21a live oral typhoid vaccine in enteric-coated capsules: a field trial in an endemic area.
J Infect Dis. 1989 Apr. 159(4):766-9. [Medline].

112. Ferreccio C, Morris JG, Valdivieso C, et al. Efficacy of ciprofloxacin in the treatment of chronic
typhoid carriers. J Infect Dis. 1988 Jun. 157(6):1235-9. [Medline].

113. Frenck RW Jr, Nakhla I, Sultan Y, Bassily SB, Girgis YF, David J, et al. Azithromycin versus
ceftriaxone for the treatment of uncomplicated typhoid fever in children. Clin Infect Dis. 2000
Nov. 31(5):1134-8. [Medline].

114. Frenck RW, Nakhla I, Sultan Y, et al. Azithromycin versus ceftriaxone for the treatment of
uncomplicated typhoid fever in children. Clin Infect Dis. 2000. 31:134-1138. [Medline].

115. Ghosh SK. Typhoid fever in present-day Britain. Public Health. 1974 Jan. 88(2):71-8.
[Medline].

116. Gilman RH, Hornick RB, Woodard WE, et al. Evaluation of a UDP-glucose-4-epimeraseless
mutant of Salmonella typhi as a liver oral vaccine. J Infect Dis. 1977 Dec. 136(6):717-23.
[Medline].

117. Gilman RH, Terminel M, Levine MM, et al. Relative efficacy of blood, urine, rectal swab,
bone-marrow, and rose- spot cultures for recovery of Salmonella typhi in typhoid fever.
Lancet. 1975 May 31. 1(7918):1211-3. [Medline].

12 of 25 7/11/17, 5:15 PM
Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

118. Gorden J, Small PL. Acid resistance in enteric bacteria. Infect Immun. 1993 Jan. 61(1):364-7.
[Medline].

119. Gordon MA. Salmonella infections in immunocompromised adults. J Infect. 2008 Jun.
56(6):413-22. [Medline].

120. Gotuzzo E, Frisancho O, Sanchez J, Liendo G, Carrillo C, Black RE, et al. Association
between the acquired immunodeficiency syndrome and infection with Salmonella typhi or
Salmonella paratyphi in an endemic typhoid area. Arch Intern Med. 1991 Feb. 151(2):381-2.
[Medline].

121. Gotuzzo E, Guerra JG, Benavente L, et al. Use of norfloxacin to treat chronic typhoid
carriers. J Infect Dis. 1988 Jun. 157(6):1221-5. [Medline].

122. Gray LD. Escherichia, Salmonella, Shigella, and Yersinia. Murray PR, Baron EJ, Pfaller MA,
eds. Manual of Clinical Microbiology. 6th ed. Washington, DC: American Society for
Microbiology; 1995. 450-6.

123. Greisman SE, Woodward TE, Hornick RB, Snyder MJ, Carozza FA Jr. Typhoid fever: a study
of pathogenesis and physiologic abnormalities. Trans Am Clin Climatol Assoc. 1961.
73:146-61. [Medline].

124. Gulati S, Marwaha RK, Prakash D, et al. Multi-drug-resistant Salmonella typhi--a need for
therapeutic reappraisal. Ann Trop Paediatr. 1992. 12(2):137-41. [Medline].

125. Gupta A. Multidrug-resistant typhoid fever in children: epidemiology and therapeutic

approach. Pediatr Infect Dis J. 1994 Feb. 13(2):134-40. [Medline].

126. Gupta SP, Gupta MS, Bhardwaj S, et al. Current clinical patterns of typhoid fever: a
prospective study. J Trop Med Hyg. 1985 Dec. 88(6):377-81. [Medline].

127. Hensel M. Salmonella pathogenicity island 2. Mol Microbiol. 2000 Jun. 36(5):1015-23.
[Medline].

128. Herzog C. Chemotherapy of typhoid fever: a review of literature. Infection. 1976. 4(3):166-73.
[Medline].

129. Herzog C. New trends in the chemotherapy of typhoid fever. Acta Trop. 1980 Sep.
37(3):275-80. [Medline].

130. Hoffman SL, Edman DC, Punjabi NH, et al. Bone marrow aspirate culture superior to
streptokinase clot culture and 8 ml 1:10 blood-to-broth ratio blood culture for diagnosis of
typhoid fever. Am J Trop Med Hyg. 1986 Jul. 35(4):836-9. [Medline].

131. Hoffman SL, Flanigan TP, Klaucke D, et al. The Widal slide agglutination test, a valuable
rapid diagnostic test in typhoid fever patients at the Infectious Diseases Hospital of Jakarta.
Am J Epidemiol. 1986 May. 123(5):869-75. [Medline].

132. Hoffman SL, Punjabi NH, Rockhill RC, et al. Duodenal string-capsule culture compared with
bone-marrow, blood, and rectal-swab cultures for diagnosing typhoid and paratyphoid fever.
J Infect Dis. 1984 Feb. 149(2):157-61. [Medline].

133. Hornick RB, DuPont HL, Levine MM, et al. Efficacy of a live oral typhoid vaccine in human

13 of 25 7/11/17, 5:15 PM
Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

volunteers. Dev Biol Stand. 1976. 33:89-92. [Medline].

134. Hornick RB, Greisman SE, Woodward TE, et al. Typhoid fever: pathogenesis and
immunologic control. N Engl J Med. 1970 Sep 24. 283(13):686-91. [Medline].

135. Hornick RB, Greisman SE, Woodward TE, et al. Typhoid fever: pathogenesis and
immunologic control. 2. N Engl J Med. 1970 Oct 1. 283(14):739-46. [Medline].

136. Hornick RB, Griesman S. On the pathogenesis of typhoid fever. Arch Intern Med. 1978 Mar.
138(3):357-9. [Medline].

137. Hornick RB, Woodward TE. Appraisal of typhoid vaccine in experimentally infected human
subjects. Trans Am Clin Climatol Assoc. 1967. 78:70-8. [Medline].

138. Huckstep RL. Recent advances in the surgery of typhoid fever. Ann R Coll Surg Engl. 1960
Apr. 26:207-30. [Medline].

139. Huckstep RL. Typhoid Fever and Other Salmonella Infections. Edinburgh, Scotland:
Churchill Livingstone; 1962.

140. Joshi N, Rajeshwari K, Dubey AP, Singh T, Kaur R. Clinical spectrum of fever of unknown
origin among Indian children. Ann Trop Paediatr. 2008 Dec. 28(4):261-6. [Medline].

141. Keitel WA, Bond NL, Zahradnik JM, et al. Clinical and serological responses following
primary and booster immunization with Salmonella typhi Vi capsular polysaccharide
vaccines. Vaccine. 1994. 12(3):195-9. [Medline].

142. Keusch GT. Antimicrobial therapy for enteric infections and typhoid fever: state of the art.
Rev Infect Dis. 1988 Jan-Feb. 10 Suppl 1:S199-205. [Medline].

143. Khosla SN. Changing patterns of typhoid (a reappraisal). Asian Med J. 1982. 25:185-98.

144. Khosla SN. Typhoid hepatitis. Postgrad Med J. 1990 Nov. 66(781):923-5. [Medline].

145. Kim JP, Oh SK, Jarrett F. Management of ileal perforation due to typhoid fever. Ann Surg.
1975 Jan. 181(1):88-91. [Medline].

146. Klotz SA, Jorgensen JH, Buckwold FJ, et al. Typhoid fever. An epidemic with remarkably few
clinical signs and symptoms. Arch Intern Med. 1984 Mar. 144(3):533-7. [Medline].

147. Klugman KP, Gilbertson IT, Koornhof HJ, et al. Protective activity of Vi capsular
polysaccharide vaccine against typhoid fever. Lancet. 1987 Nov 21. 2(8569):1165-9.
[Medline].

148. Klugman KP, Koornhof HJ, Robbins JB. Immunogenicity and protective efficacy of Vi vaccine
against typhoid fever three years after immunization (abstract). Second Asia-Pacific
Symposium on Typhoid Fever and Other Salmonellosis. Bangkok, Thailand: 1994.

149. Kohbata S, Yokoyama H, Yabuuchi E. Cytopathogenic effect of Salmonella typhi GIFU 10007
on M cells of murine ileal Peyer's patches in ligated ileal loops: an ultrastructural study.
Microbiol Immunol. 1986. 30(12):1225-37. [Medline].

150. Lesser, CF, Miller, SI. Salmonellosis. Harrison's Principles of Internal Medicine. 16th ed.

14 of 25 7/11/17, 5:15 PM
Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

2005. 1: 898-902.

151. Levine MM, Ferreccio C, Black RE, et al. Large-scale field trial of Ty21a live oral typhoid
vaccine in enteric-coated capsule formulation. Lancet. 1987 May 9. 1(8541):1049-52.
[Medline].

152. Levine MM, Taylor DN, Ferreccio C. Typhoid vaccines come of age. Pediatr Infect Dis J. 1989
Jun. 8(6):374-81. [Medline].

153. Luby, S, Mintz, E. Typhoid Fever. Health Information for International Travel (CDC).
2005-2006. Web link:[Full Text].

154. Ly KT, Casanova JE. Mechanisms of Salmonella entry into host cells. Cell Microbiol. 2007
Sep. 9(9):2103-11. [Medline].

155. Mandal BK. Salmonella infections. Manson-Bahr, PEC, Bell DR, Manson P, eds. Manson’s
Tropical Medicine. 20th ed. London, UK: Saunders; 1996. 849-63.

156. Mandal BK. Modern treatment of typhoid fever. J Infect. 1991 Jan. 22(1):1-4. [Medline].

157. Mani V, Brennand J, Mandal BK. Invasive illness with Salmonella virchow infection. Br Med J.
1974 Apr 20. 2(5911):143-4. [Medline].

158. Maskalyk J. Typhoid fever. CMAJ. 2003 Jul 22. 169(2):132. [Medline].

159. Meier DE, Imediegwu OO, Tarpley JL. Perforated typhoid enteritis: operative experience with
108 cases. Am J Surg. 1989 Apr. 157(4):423-7. [Medline].

160. Murphy JR, Baqar S, Munoz C, et al. Characteristics of humoral and cellular immunity to
Salmonella typhi in residents of typhoid-endemic and typhoid-free regions. J Infect Dis. 1987
Dec. 156(6):1005-9. [Medline].

161. Nardiello S, Pizzella T, Russo M, et al. Serodiagnosis of typhoid fever by enzyme-linked

immunosorbent assay determination of anti-Salmonella typhi lipopolysaccharide antibodies.
J Clin Microbiol. 1984 Oct. 20(4):718-21. [Medline].

162. Ochiai RL, Acosta CJ, Danovaro-Holliday MC, Baiqing D, Bhattacharya SK, Agtini MD, et al.
A study of typhoid fever in five Asian countries: disease burden and implications for controls.
Bull World Health Organ. 2008 Apr. 86(4):260-8. [Medline]. [Full Text].

163. Osuntokun BO, Bademosi O, Ogunremi K, et al. Neuropsychiatric manifestations of typhoid

fever in 959 patients. Arch Neurol. 1972 Jul. 27(1):7-13. [Medline].

164. Parker MT. Salmonella. Wilson G, Miles A, Parker MT, eds. Topley and Wilson’s Principles of
Bacteriology, Virology and Immunity. 7th ed. Baltimore, Md: Williams & Wilkins; 1983. 332-55.

165. Parry CM, Karunanayake L, Coulter JB, Beeching NJ. Test for quinolone resistance in
typhoid fever. BMJ. 2006 Jul 29. 333(7561):260-1. [Medline].

166. Parry CM, Threlfall EJ. Antimicrobial resistance in typhoidal and nontyphoidal salmonellae.
Curr Opin Infect Dis. 2008 Oct. 21(5):531-8. [Medline].

167. Parry, CM. Epidemiological and Clinical Aspects of Typhoid Fever. Mastroeni, P and Maskell,

15 of 25 7/11/17, 5:15 PM
Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

D. Salmonella InfectionsClinical, Immunological, and Molecular Aspects. 1st. Nw York, New

York: 2006. 1-24/1. [Full Text].

168. Pithie AD, Wood MJ. Treatment of typhoid fever and infectious diarrhoea with ciprofloxacin. J
Antimicrob Chemother. 1990 Dec. 26 Suppl F:47-53. [Medline].

169. Polish Typhoid Committee. Controlled field trials and laboratory studies on the effectiveness
of typhoid vaccines in Poland, 1961-64. Bull World Health Organ. 1966. 34(2):211-22.
[Medline].

170. Punjabi NH, Hoffman SL, Edman DC, et al. Treatment of severe typhoid fever in children with
high dose dexamethasone. Pediatr Infect Dis J. 1988 Aug. 7(8):598-600. [Medline].

171. Punjabi NH, Hoffman SL, Edman DC, Sukri N, Laughlin LW, Pulungsih SP, et al. Treatment
of severe typhoid fever in children with high dose dexamethasone. Pediatr Infect Dis J. 1988
Aug. 7(8):598-600. [Medline].

172. Raffatellu M, Chessa D, Wilson RP, Dusold R, Rubino S, Bäumler AJ. The Vi capsular
antigen of Salmonella enterica serotype Typhi reduces Toll-like receptor-dependent
interleukin-8 expression in the intestinal mucosa. Infect Immun. 2005 Jun. 73(6):3367-74.
[Medline].

173. Ramachandran S, Wickremesinghe HR, Perera MV. Acute disseminated encephalomyelitis in

typhoid fever. Br Med J. 1975 Mar 1. 1(5956):494-5. [Medline].

174. Robbins JD, Robbins JB. Reexamination of the protective role of the capsular polysaccharide
(Vi antigen) of Salmonella typhi. J Infect Dis. 1984 Sep. 150(3):436-49. [Medline].

175. Rowland HA. The complications of typhoid fever. J Trop Med Hyg. 1961 Jun. 64:143-52.
[Medline].

176. Rowland HA. The treatment of typhoid fever. J Trop Med Hyg. 1961 May. 64:101-10.
[Medline].

177. Rubin FA, Kopecko DJ, Sack RB, et al. Evaluation of a DNA probe for identifying Salmonella
typhi in Peruvian and Indonesian bacterial isolates. J Infect Dis. 1988 May. 157(5):1051-3.
[Medline].

178. Rubin FA, McWhirter PD, Punjabi NH, et al. Use of a DNA probe to detect Salmonella typhi
in the blood of patients with typhoid fever. J Clin Microbiol. 1989 May. 27(5):1112-4.
[Medline].

179. Rubin RH, Weinstein L. Salmonellosis: Microbiologic, Pathologic, and Clinical Features. New
York, NY: Stratton Intercontinental; 1977.

180. Ryan CA, Hargrett-Bean NT, Blake PA. Salmonella typhi infections in the United States,
1975-1984: increasing role of foreign travel. Rev Infect Dis. 1989 Jan-Feb. 11(1):1-8.
[Medline].

181. Salerno-Goncalves R, Pasetti MF, Sztein MB. Characterization of CD8(+) effector T cell
responses in volunteers immunized with Salmonella enterica serovar Typhi strain Ty21a
typhoid vaccine. J Immunol. 2002 Aug 15. 169(4):2196-203. [Medline].

16 of 25 7/11/17, 5:15 PM
Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

182. Salerno-Gonçalves R, Wyant TL, Pasetti MF, Fernandez-Viña M, Tacket CO, Levine MM, et
al. Concomitant induction of CD4+ and CD8+ T cell responses in volunteers immunized with
Salmonella enterica serovar typhi strain CVD 908-htrA. J Immunol. 2003 Mar 1.
170(5):2734-41. [Medline].

183. Scottish Home and Health Department. The Aberdeen Typhoid Outbreak. Edinburgh:.
HMSO. 1964.

184. Scragg JN, Rubidge CJ. Amoxycillin in the treatment of typhoid fever in children. Am J Trop
Med Hyg. 1975 Sep. 24(5):860-5. [Medline].

185. Scully BE, Nakatomi M, Ores C, et al. Ciprofloxacin therapy in cystic fibrosis. Am J Med.
1987 Apr 27. 82(4A):196-201. [Medline].

186. Simanjuntak CH, Paleologo FP, Punjabi NH, et al. Oral immunisation against typhoid fever in
Indonesia with Ty21a vaccine. Lancet. 1991 Oct 26. 338(8774):1055-9. [Medline].

187. Smith T. The hog-cholera group of bacteria. US Bur Anim Ind Bull. 1894. 6:6-40.

188. Soe GB, Overturf GD. Treatment of typhoid fever and other systemic salmonelloses with
cefotaxime, ceftriaxone, cefoperazone, and other newer cephalosporins. Rev Infect Dis. 1987
Jul-Aug. 9(4):719-36. [Medline].

189. Spanò S, Ugalde JE, Galán JE. Delivery of a Salmonella Typhi exotoxin from a host
intracellular compartment. Cell Host Microbe. 2008 Jan 17. 3(1):30-8. [Medline].

190. Spreng S, Dietrich G, Weidinger G. Rational design of Salmonella-based vaccination

strategies. Methods. 2006 Feb. 38(2):133-43. [Medline].

191. Stanley PJ, Flegg PJ, Mandal BK, et al. Open study of ciprofloxacin in enteric fever. J
Antimicrob Chemother. 1989 May. 23(5):789-91. [Medline].

192. Steinberg EB, Bishop R, Haber P, Dempsey AF, Hoekstra RM, Nelson JM, et al. Typhoid
fever in travelers: who should be targeted for prevention?. Clin Infect Dis. 2004 Jul 15.
39(2):186-91. [Medline].

193. Stoleru GH, Le Minor L, Lheritier AM. Polynucleotide sequence divergence among strains of
Salmonella sub-genus IV and closely related organisms. Ann Microbiol (Paris). 1976 May-
Jun. 127(4):477-86. [Medline].

194. Stuart BM, Pullen RL. Typhoid: clinical analysis of three hundred and sixty cases. Arch Intern
Med. 1946. 78:629-61.

195. Thaver D, Zaidi AK, Critchley J, Azmatullah A, Madni SA, Bhutta ZA. A comparison of
fluoroquinolones versus other antibiotics for treating enteric fever: meta-analysis. BMJ. 2009
Jun 3. 338:b1865. [Medline]. [Full Text].

196. Thaver D, Zaidi AK, Critchley JA, Azmatullah A, Madni SA, Bhutta ZA. Fluoroquinolones for
treating typhoid and paratyphoid fever (enteric fever). Cochrane Database Syst Rev. 2008
Oct 8. CD004530. [Medline].

197. Thielman, NM, Guerrant, RL. Enteric Fever and Other Causes of Abdominal Symptoms with

17 of 25 7/11/17, 5:15 PM
Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

Fever. Principles and Practice of Infectious Diseases. 6th ed. 2005. 1273-86.

198. Tran TH, Bethell DB, Nguyen TT, et al. Short course of ofloxacin for treatment of multidrug-
resistant typhoid. Clin Infect Dis. 1995 Apr. 20(4):917-23. [Medline].

199. Uneke CJ. Concurrent malaria and typhoid fever in the tropics: the diagnostic challenges
and public health implications. J Vector Borne Dis. 2008 Jun. 45(2):133-42. [Medline].

200. Vollaard AM, Ali S, van Asten HA, Widjaja S, Visser LG, Surjadi C, et al. Risk factors for
typhoid and paratyphoid fever in Jakarta, Indonesia. JAMA. 2004 Jun 2. 291(21):2607-15.
[Medline].

201. Walker DH, Le TP, Hoffman S, et al. Typhoid fever. Tropical Infectious Diseases: Principles,
Pathogens, and Practice. New York, NY: Churchill Livingstone; 1999.

202. Woodward TE, Hall HE, Dias-Rivera R, et al. Treatment of typhoid fever. II. Control of clinical
manifestations with cortisone. Ann Intern Med. 1951 Jan. 34(1):10-9. [Medline].

203. Yanagi D, de Vries GC, Rahardjo D, Alimsardjono L, Wasito EB, De I, et al. Emergence of
fluoroquinolone-resistant strains of Salmonella enterica in Surabaya, Indonesia. Diagn
Microbiol Infect Dis. 2009 Aug. 64(4):422-6. [Medline].

204. Yugoslav Typhoid Commission. A controlled field trial of the effectiveness of acetone-dried
and inactivated and heat-phenol-inactivated typhoid vaccines in Yugoslavia. Bull WHO.
1964. 30:623-30.

205. Zinder ND, Lederberg J. Genetic exchange in Salmonella. J Bacteriol. 1952 Nov.
64(5):679-99. [Medline].

Media Gallery

Life cycle of Salmonella typhi.

of 1

Tables

Table 1. Incidence and Timing of Various Manifestations of Untreated Typhoid Fever [2, 31,
32, 33, 34, 35]
Table 2. Sensitivities of Cultures [2, 37, 38, 39]

Table 1. Incidence and Timing of Various Manifestations of Untreated Typhoid Fever [2, 31, 32, 33, 34,
35]

Week
Incubation Week 1 Week 2 Week 3 Post
4

Recovery 10%-20%
Systemic phase or relapse;
death (15% 3%-4%

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chronic
carriers;

long-term
neurologic
sequelae
(extremely
of
rare);
untreated
cases)

gallbladder
cancer
(RR=167;
carriers)

Stepladder fever Very Very

pattern or insidious
onset fever common a common

Acute high fever Very rareb

Chills Almost allc

Rigors Uncommon

Anorexia Almost all

Very
Diaphoresis
common

Neurologic

Typhoid
Malaise Almost all Almost all state
(common)

Very
Insomnia
common

Very
Confusion/delirium Common d common

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Psychosis Very rare Common

Catatonia Very rare

Frontal headache

Very
(usually mild) common

Meningeal signs Raree Rare

Parkinsonism Very rare

Ear, nose, and

throat

Very
Coated tongue
common

Sore throatf

Pulmonary

Mild cough Common

Bronchitic cough Common

Rales Common

Common

Rare
Pneumonia Rare
(lobar) (basal)

Cardiovascular

Dicrotic pulse Rare Common

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Myocarditis Rare

Extremely
Pericarditis
rareg

Thrombophlebitis Very rare

Gastrointestinal

Very
Constipation Common
common

Common
Diarrhea Rare (pea
soup)

Very
Bloating with common
tympany
(84%) [35]

Diffuse mild Very

abdominal pain common

Sharp right lower

Rare
quadrant pain

Very rare;
Gastrointestinal Very
usually
hemorrhage common
trace

intestinal perforation Rare

Hepatosplenomegaly Common

Jaundice Common

Gallbladder pain Very rare

Urogenital

Urinary retention Common

Hematuria Rare

Renal pain Rare

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Musculoskeletal

Myalgias Very rare

Arthralgias Very rare

Rheumatologic

Extremely
Arthritis (large joint)
rare

Dermatologic

Rose spots Rare

Miscellaneous

Extremely Extremely Extremely

Abscess (anywhere)
rare rare rare

aVery 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.

dCommon:
Symptoms occur in
35%-65% of cases.

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eRare: Symptoms
occur in 5%-35% of
cases.

fBlank 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]

Week Week
Incubation Week 1 Week 2
3 4

90% (may decrease

Bone marrow
after 5 d of
aspirate (0.5-1 mL)
antibiotics)

Blood (10-30 mL),

Variable
stool, or duodenal 40%-80% ~20%
(20%-60%)
aspirate culture

25%-30%, timing
Urine
unpredictable

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Contributor Information and Disclosures

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Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

Author

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.

Coauthor(s)

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.

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.

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.

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Typhoid Fever: Background, Pathophysiology, Epidemiology http://emedicine.medscape.com/article/231135-overview#a5

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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