Typhoid Fever

*** For full access to the review article, please sign up for the Surgery in Africa Reviews by contacting Dr. Brian Ostrow or ptolemy.info@utoronto.ca or see the sign up information at the bottom of this page***


Introduction  
History
Epidemiology
Genetics
Pathogenesis
Prevention
  Food and water sanitation
  Vaccine
Clinical Spectrum
Diagnosis
Treatment
Complications
  Perforation
  Other complications
Conclusions
 Recommendations
Clinical Photos

Introduction
Typhoid or enteric fever is an ancient disease, which has afflicted mankind since human populations grew large enough to contaminate their water and food supplies. It is caused by Salmonella enterica serovar typhi (previously known as salmonella typhi), a pathogen specific only to humans, as well as by certain non-typhoid salmonella (NTS), particularly Paratyphoid strains A, B, C. These waterborne gram negative aerobes are associated with poor sanitation and fecal contamination of water and food supplies. The syndrome needs to be distinguished from that caused by many other organisms. Today there are as many as 16-30 million cases per year, almost exclusively in the developing world, with a mortality rate of 10%. Recent developments in the mapping of the Salmonella genome have provided insights into its pathogenicity and how antibiotic resistance and human immunity develop. Typhoid fever is important surgically because abdominal complications such as intestinal perforation, bleeding, cholecystitis and pancreatitis represent the most serious complications of the illness. Typhoid perforation of the ileum is one of the most common causes of bowel perforation in the developing world. (1) Excellent reviews are available for both adult (2-6) as well as pediatric disease. (7) This Review will focus on recent developments in our understanding of this disease.

History
Typhoid fever was not well understood in the ancient world, probably because its symptoms are not primarily diarrheal, but rather systemic and non-specific. It was only in the mid-19th century that physicians began to distinguish it from typhus and malaria. (8) Sir William Osler’s clinical description remains unsurpassed. Typhoid fever was frequently associated with military campaigns and was a significant cause of death in the American Civil War and Boer War where deaths from typhoid exceeded those from combat. (9) With recognition that fecal contamination of food and water supplies was the main mode of transmission of the illness and measures taken to prevent these (10;11), typhoid fever has been restricted, in industrialized countries, to localized epidemics (12;13) and infections in travelers returning from endemic areas. (14)

Epidemiology
In contrast to that seen in the rich countries, typhoid fever remains an important cause of illness in the developing world where annual incidences in Papua New Guinea and Indonesia may reach 1200/100,000 population. A recent epidemiologic study showed that south-east and south-central Asia are the regions of highest endemicity with rates greater than 100/100,000 cases per year; the rest of Asia, Africa, Latin America, the Caribbean and Oceania (except Australia and New Zealand) are the next highest with incidence rates of 10-100/100,000 and Europe, North America and the rest of the developed world have low rates of disease. (15) Typhoid fever represents the 4th most common cause of death in Pakistan. (16)
The majority of patients, 60-90%, are treated as outpatients and, therefore, hospital based studies will underestimate true incidence. Two hospital based case-control studies from Vietnam found that risk of infection was related to recent contact with an infected person, lack of education and drinking untreated water. (17;18) S. paratyphi A, which normally causes about 15-20% of cases of typhoid fever in Asia, increasingly is becoming a pathogen in India (19) and China (20), possibly due to vaccination against S. typhi. Recent epidemiologic studies also show the rise of multi-drug resistant (MDR) organisms. (21) In a study of 1100 hospitalized children in Pakistan, the mortality rate of 1.6% was found to be related to younger age and MDR infection. (22)
Traditionally the age range considered to be at greatest risk was 5-25 years. However this has been questioned in a study from a private laboratory in Bangladesh, which found that the 57% of S. typhi isolates were in children less than 5 years of age and 27% less than 2 years. (23) This has significant implications for vaccination policies.

Genetics
In 2001 the entire genome of a MDR isolate of S. typhi was sequenced. (24) This showed that Salmonella share more than 70-80% of genes with other enteric bacteria, like E. coli. Another feature of S. typhi genome is the presence of over 200 inactivated genes which are felt to be related to the adaptation of the bacteria to the human host and possibly its ability to invade human tissue. Drug resistance is encoded in a transmissible plasmid. The development of additional horizontal genes in the salmonella pathogenicity islands (SPI) represented the separation of the E. Coli and Salmonella lineages and allows for the targeting of intestinal epithelial cells by Salmonella. (25)

Pathogenesis
Much of the genetic and cellular studies on the pathophysiology of invasive Salmonella infection have been carried out in the murine model using S. typhimurium, which causes invasive disease in mice but not in humans. As opposed to the Salmonella spp. associated with human diarrheal illness, S. typhi and those strains that cause typhoid fever are able to achieve cellular invasion.
The pathophysiology of typhoid fever is a complex process which proceeds through several stages. (24;26;27) The disease begins with an asymptomatic incubation period of 7-14 days, (inversely related to the size of the infecting dose), during which bacteria invade macrophages and spread throughout the reticuloendothelial system. The first week of symptomatic disease is characterized by progressive elevation of the temperature followed by bacteremia. The second week begins with the development of rose spots, abdominal pain and splenomegaly. The third week is marked by a more intense intestinal inflammatory response particularly in the Peyer’s patches with associated necrosis which can result in perforation and hemorrhage. These clinical stages are associated with complex cellular events just now being understood.
First, ingested bacteria must survive the acidic environment of the stomach. The known increased risk of typhoid fever with concomitant Helicobacter pylori infection (28) may express itself via the hypochlorhydria associated with chronic H.pylori infection. (29) Invading organisms pass through the intestinal epithelial cells and come into contact with phagocytic cells in the Peyer’s patches of the intestinal wall. However the macrophages do not kill the bacteria. Thence, bacterial replication is primarily intracellular. Salmonella avoids encapsulation in lysosomes by diverting normal cellular mechanisms. (30) Bacteria inject effector proteins into the cells of the innate immune system (macrophages and natural killer cells) though a type III protein secretion system (TTSS) which stimulate both pro and anti-inflammatory responses. (31)
Over the asymptomatic incubation period of 7-14 days the bacteria proliferate and spread through the blood stream to other cells in the reticuloendothelial system in the liver, spleen, bone marrow and gall bladder. As replication inside phagocytic cells continues, bacteria are shed into the blood stream in sustained but low concentrations and the clinical syndrome of fever, headache and abdominal pain begins. The gallbladder is felt to be a significant site (32) for ongoing exposure of intestinal epithelial cells to the pathogen. The inflammatory response to this process of repeated exposure is felt to give rise to the necrosis which is a prominent feature of the disease. (33) This occurs in areas of greatest macrophage concentration such as the Peyer’s patches and explains why intestinal bleeding and perforation are the most frequent complications. Elsewhere typhoid nodules, foci of macrophages and lymphocytes proliferate. As the infection progresses the typical changes of sepsis accumulate in the heart, brain and kidneys. If not interrupted this process may lead to circulatory failure and death from overwhelming sepsis.

Prevention
Infected or asymptomatic carrier humans represent the reservoir for S. typhi. Therefore identification and treatment of these individuals represents one strategy for interruption of transmission.
Food and water sanitation
There is no doubt that lack of clean drinking water and unsanitary conditions for the production and preparation of food represent the main reasons for the ongoing endemicity of typhoid fever in the developing world. Poor water quality, sanitation and hygiene account for some 1.7 million deaths a year world-wide (3.1% of all deaths and 3.7% of all DALY's), mainly through infectious diarrhea. Nine out of 10 such deaths are in children. (34) Poverty, uncontrolled urbanization and inadequate infrastructure all contribute to the contamination of water supplies. (35) Filtration and chlorination together are effective methods of interrupting the transmission of water-borne diseases. (36;37)
Vaccine
The other approach to the control and eradication of typhoid fever has been through vaccination. Acquired immunity to S. typhi infection is both humoral and cellular but is incomplete, allowing for subsequent infections and restricting the efficacy of vaccines. (38;39) Older, parenteral whole-cell vaccines resulted in significant local and systemic reactions. (40) Two new vaccines are in current use: a parenteral capsule polysaccharide vaccine based on the Vi antigen and an oral live attenuated vaccine containing strain Ty21a. The first, while resulting in local pain in 86% of children, requires 1 injection with a booster in 3 years and confers protection within 7-10 days of inoculation. On the other hand the Ty21a vaccine requires several doses, is only moderately immunogenic and its efficacy is reduced by simultaneous anti-malarial therapy, (although a report from Gabon showed that simultaneous anti-malarial prophylaxis with atovaquone/proguanil does not have this effect (41)). A systematic review for the Cochrane Database showed these two vaccines had significantly reduced efficacy (efficacy rates approx.50%) in comparison to the older whole-cell vaccines, but fewer side effects.(42) Current vaccines do not afford protection against Paratyphoid strains. The search for better vaccines continues. (43)
The use of vaccines for travelers to endemic areas has been recommended for some time; (44) even if the travel is for short periods. (45) Malaria remains the most common febrile disease of returning travelers to Italy requiring hospital admission. (46)
Mass vaccination campaigns have been used to lower the risk of disease in India and Thailand, but their use in the rest of the developing world is otherwise limited. A report from the ongoing epidemic in Tajikistan advocated mass vaccination. (47) A recent report from an urban slum community in Delhi, India showed the high costs of typhoid fever and recommended more widespread vaccination. (48) The current Vi and Ty21a vaccines are not licensed for use in children less than 2 years, in whom its efficacy is unproven, and therefore are deemed unsuitable for expanded immunization programs which target infants in their first year of life. (49) They are also costly. All these factors have restricted mass vaccination for typhoid in endemic countries.
The World Health Organization appears to advocate mass vaccination in endemic areas. (50;51) However this is seldom implemented. The Diseases of the Most Impoverished (DOMI) project is undertaking a randomized cluster vaccination program in Asia which should help to clarify the effects of mass typhoid vaccination. (52)

Clinical Spectrum
Traditionally the age range considered at greatest risk is 5-25 years of age, although young children and infants may also be infected. In these the disease may present as a non-specific febrile illness until diagnostic tests are positive. Akpede from Nigeria provides an excellent review of the management of these cases, including those with HIV. (53)
After the initial 7-14 day asymptomatic phase, the clinical features of typhoid fever begin with the onset of a remitting diurnal fever, anorexia, headache, lethargy, confusion, cough and abdominal pain. (54) Constipation is considered a feature, although diarrhea and vomiting is recognized, particularly with young children and those infected with HIV. Relative bradycardia is said to be a feature; increased heart rate is correlated with later stages and with mortality. (55) The clinical signs are few: rose spots (pink macules which blanch on pressure, are present on the thorax and abdomen of 60% of light-skinned patients but are considerably more difficult to detect in dark-skinned patients); abdominal tenderness (acute abdomen if perforation); splenomegaly more common than hepatomegaly; rales (with a normal chest xray); conjunctivitis and apathy. Assessment of hemodynamic and mental status is important and correlates with severity of illness. In contrast to other investigators Haq et al. found clinical factors strongly correlated with diagnostic accuracy. (56)
Thielman gives a very good differential diagnosis of other infectious which may mimic typhoid fever. (3) In Africa, malaria is probably the most important disease from which typhoid must be distinguished. (57;58)
Non resolution gives rise to complications which are discussed below. Typhoid fever patients suffer a relapse rate of 5-10% and 1-3% will become asymptomatic carriers, potentially infecting others. Relapses take the form of a milder disease and are less common after quinolone therapy. Carriers excrete S. typhi in the stool more than 3 months after treatment. In Egypt, carrier state is associated with urinary pathology such as Schistosomiasis and may be evidenced by urinary excretion. (6) Carriers require treatment with high dose quinolones (ciprofloxacin 750mg q12h) for 4 weeks. Carrier state associated with cholelithiasis is a risk for gall bladder cancer and requires cholecystectomy. (59)

Diagnosis
The lack of specificity of the clinical spectrum, added to the difficulty of achieving a definitive bacteriologic or serologic diagnosis, frustrates clinicians managing typhoid fever.(60;61) Laboratory tests are non-specific but haemoglobin, white cell and platelet counts are usually reduced. Liver function tests are mildly elevated.
Culture of the infectious agent may be obtained from stool, urine, blood, bone marrow or bile. Bone marrow is the most sensitive source (80-95%) and positive blood cultures (60-80%) are facilitated by increasing the volume sampled. (62) Detection of S. typhi DNA by polymerase chain reaction (PCR) has recently been shown to be a very sensitive index of infection. (63)
Serologic tests have a long but limited history of use in typhoid fever. The Widal test, useful only for infection with S. typhi, detects O (surface) and H (flagellar) antigens. However, baseline titers in the general population must be determined for each geographic region. (64-66) When used as a single test in endemic areas, it lacks sensitivity and specificity. (67) A 4 fold rise in O, H or Vi titers provides support for the diagnosis of typhoid fever, but is not useful in the acute situation. As a result, numerous other serologic tests are being developed (2): ELISA; (68-70) salivary IgA;(71) a modified Widal test to detect IgM; (72) and dipstick assay.(73)

Treatment
It is recommended that treatment of typhoid fever begin on the basis of clinical findings prior to definitive diagnosis. Sadly in endemic regions, facilities for definitive diagnosis, based on blood or bone marrow culture or serologic tests may be entirely lacking. Supportive measures such as oral or intravenous rehydration, antipyretics, appropriate nutrition and blood transfusion are important.
Mortality from typhoid fever showed a marked decline from 20% to 1% after the introduction of chloramphenicol in 1948. (74) Chloramphenicol however does not prevent relapse unless given for 2-3 weeks; the carrier state is not eradicated; nor is it useful against MDR strains. (75) Ampicillin and sulfonamides, co-trimazole, became the next antibiotics to be used, but multi-drug resistant MDR organisms developed.(76-78) In some regions with high MDR prevalence, sensitivity to chloramphenicol has re-emerged. (79) MDR strains are noted to be more virulent and associated with increased mortality and complications.
The flouroquinolones - ofloxacin and ciprofloxacin, the third generation cephalosporins -ceftriazone and cefixime, and azithromycin, a macrolide antibiotic, are the drugs of choice for MDR typhoid fever. Flouroquinolones achieve excellent penetration in macrophages and bile, important sites of infection. In the developed countries they have been used infrequently in patients less than 18 years of age, because of potential arthropathy. However there is increased evidence for their safety in this population. However, resistance to flouroquinolones has also developed and represents a significant threat to the treatment of typhoid fever. (80) The presence of nalidixic acid resistance is a marker for decreased susceptibility to flouroquinolones and should be tested for when dealing with MDR strains.(81-83) Nalidixic acid resistant strains may show a slower response to flouroquinolones and require higher doses (ciprofloxacin 1500mg/d instead of 1000mg/d). Switching to ceftriaxone or azithromycin may be preferable in these patients. (84) These agents should be given for at least 7 days.
The standard duration of treatment has been for 10-14 days, but uncomplicated typhoid fever has been shown to respond to shorter courses of flouroquinolones, ie. 2-3 days of treatment.(85) Thaver (75), in a systematic review for the Cochrane database comparing flouroquinolones with other antibiotics, concluded that the scientific data derived from RCTs was poor, and that there was little to recommend flouroquinolones over 1st line drugs, (chloramphenicol, ampicillin and co-trimazole). Flouroquinolones reduced failure rates when compared to third generation cephalosporins. The study recommended large multi-center outpatient trials comparing flouroquinolones and 1st line therapy in children to settle this question. Thaver et al admit their conclusions differ from those of Parry (5) and standard textbooks which recommend flouroquinolones as modern 1st line therapy. (3;4)
Since there is great regional variability with regard to antibiotic sensitivity and the presence of MDR strains and because misuse of antibiotics is a potent cause of the development of MDR strains (86), it is essential that physicians working in regions where typhoid fever is endemic, ascertain the nature and prevalence of the different strains and base appropriate recommendations for first and second line therapy on this information.
The WHO recommends the following regimes for uncomplicated typhoid fever.

Table 1 page 20 (2)


In severe disease the following regimes are recommended. Table 2 page 23 (2)

Complications
Complications occur in 10-15% of patients, particularly those who have been ill for more than 2 weeks. Gastrointestinal hemorrhage, perforation and encephalopathy are the most important. GI hemorrhage is most common but usually resolves without surgery. Severe typhoid may be defined as occurring in those patients with hypotension despite rehydration and mental confusion or altered state of consciousness. These patients may benefit from high dose dexamethasone therapy (3mg/kg followed by 8 doses of 1mg/kg q6h) with a marked reduction in mortality. (87) This is one of the few instances where high dose steroids are of value in sepsis. (88)
Perforation
The surgeon is typically consulted in typhoid fever when perforation is suspected. It may present suddenly as an acute abdomen or more commonly as worsening in an already sick patient with increasing abdominal signs, rising pulse and falling blood pressure. (89) The presence of free air on abdominal xrays is pathognomonic.
These are very sick patients who require vigorous resuscitation and the addition of metronidazole to combat gram-negative anaerobes and gentamycin for aerobes. Conservative therapy has been abandoned with improved mortality rates. (90) Mortality increased when time to presentation is delayed and also with delayed time to surgery after perforation. (91) Mortality rates vary from 14% in Nigeria (89) to 34% in Cote d’Ivoire. (92) Single perforations are most common (70%) and in the terminal ileum, but multiple perforations may occur.(93)
At operation the entire small bowel and proximal colon should be carefully examined for perforation. Debate exists as to the various methods of closure from simple suture, to wedge resection and closure to segmental resection and primary anastomosis. (94;95) It is not clear to me that any conclusion can be drawn from the evidence. Obviously multiple perforations lend themselves to segmental resection.
Other complications
Numerous other complications are seen with typhoid fever. (4) see Table 163-1 The most important surgical ones being: hepatic or splenic abscess(96), splenic rupture (97) and pancreatitis. Encephalomyelitis (98), osteomyelitis (99), glomerulonephritis and renal failure (100) may all occur. Myocarditis is a common cause of circulatory collapse.

Conclusions
Despite intensive scrutiny and major advances in genetic research and understanding the details of cellular inflammation, typhoid fever remains a major cause of death and disease in the developing world. Its eradication awaits the provision of sanitary water supplies and proper disposal of human sewage. Its eradication would probably be accelerated by programs of mass vaccination in endemic regions. Appropriate antibiotic therapy may postpone the further development of MDR strains. In the meantime, surgeons will continue to be asked to care for desperately sick typhoid patients with intestinal perforations and other complications.

Recommendations

  1. Typhoid fever should be suspected in young children and infants with fevers of unknown origins in endemic regions.
  2. Filtration and chlorination are the two important steps in ensuring a safe water supply. In urban areas safe drinking water should be made available though piped systems or trucked tankers.
  3. Appropriate food handling is essential: washing hands with soap before preparing and handling food; eating only cooked or still hot food; avoiding raw food, shellfish, ice.
  4. Appropriate systems for human waste disposal must be available for the entire community.
  5. Countries with high rates of typhoid fever should consider mass immunization programs using new Vi and Ty21a vaccines for those more than 2 years of age.
  6. In hospitals where microbiological facilities are available for the culture of salmonella spp., bone marrow samples, as well as blood and stool should be obtained in patients when typhoid fever is suspected.
  7. Testing should include stools of recovering patients at 3 months or urine in regions where schistosomiasis is common, to detect the carrier state.
  8. The Widal test cannot be used in the diagnosis without assessing background antibody levels in the population. Better serologic tests should be available soon.
  9. Antibiotic therapy should be based on the sensitivity spectrum of local S. typhi strains. Chloramphenicol, ampicillin or co-trimazole may be adequate agents if strains are susceptible.
  10. In regions where MDR strains are known to exist, fluroquinolones are the agents of choice.
  11. In regions where MDR strains exist and where quinolone use has been extensive, testing for relative flouroquinolone resistance with nalidixic acid discs should be undertaken.
  12. Patients, with “severe typhoid” manifested by hypotension and/or altered state of consciousness, should receive short term high dose steroid therapy.
  13. The treatment of typhoid perforation is aggressive resuscitation using broad spectrum antibiotics against enteric organisms, prompt surgery with examination of the entire small bowel and right colon with resection (local or segmental) of all full thickness ulcers and perforations.

Brian Ostrow MD, FRCS(C)
Guelph, Ontario, Canada

Save review as .PDF
Clinical Photos

Click here to join the Surgery in Africa Discussion Group


Reference List

  1. McConkey SJ, McConkey SJ. Case series of acute abdominal surgery in rural Sierra Leone. World Journal of Surgery 2002; 26(4):509-513.
  2. anon. Background document: the diagnosis, treatment and prevention of typhoid fever. 2003. Geneva, World Health Organization.
    Ref Type: Pamphlet
  3. Thielman NM&GRL. Enteric Fever. In: Mandell GLBJE&DR, editor. Mandell, Bennett & Dolin: Principles and Practice of Infectious Diseases. Philadelphia: Churchill Livingstone, 2005: 1273-1279.
  4. Richens J. Typhoid Fever. In: Cohen J&PWG, editor. Cohen & Powderly: Infectious Diseases. Edinburgh: Mosby Inc., 2004: 1561-1565.
  5. Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ, Parry CM et al. Typhoid fever. New England Journal of Medicine 2002; 347(22):1770-1782.
  6. Kamel R&WM. Salmonellosis. In: Kamel R&LJ, editor. Textbook of Tropical Surgery. London: Westminster Publishing Ltd., 2004: 908-912.
  7. Graham SM, Graham SM. Salmonellosis in children in developing and developed countries and populations. Current Opinion in Infectious Diseases 2002; 15(5):507-512.
  8. Cunha BA, Cunha BA. Osler on typhoid fever: differentiating typhoid from typhus and malaria. Infectious Disease Clinics of North America 2004; 18(1):111-125.
  9. Lim ML, Wallace MR, Lim ML, Wallace MR. Infectious diarrhea in history. Infectious Disease Clinics of North America 2004; 18(2):261-274.
  10. Casner N, Casner N. "Do It Now!" Yakima, Wash, and the campaign against rural typhoid. American Journal of Public Health 2001; 91(11):1768-1775.
  11. Scuderi G, Scuderi G. A review of the Salmonellosis surveillance systems in Italy: evolution during the course of time within the international framework.[erratum appears in Eur J Epidemiol 2000;16(12):1187 Note: Gabriella S [corrected to Scuderi G]]. European Journal of Epidemiology 2000; 16(9):861-868.
  12. Yoon J, Segal-Maurer S, Rahal JJ, Yoon J, Segal-Maurer S, Rahal JJ. An outbreak of domestically acquired typhoid fever in Queens, NY. Archives of Internal Medicine 2004; 164(5):565-567.
  13. Katz DJ, Cruz MA, Trepka MJ, Suarez JA, Fiorella PD, Hammond RM et al. An outbreak of typhoid Fever in Florida associated with an imported frozen fruit. Journal of Infectious Diseases 2002; 186(2):234-239.
  14. Mermin JH, Townes JM, Gerber M, Dolan N, Mintz ED, Tauxe RV et al. Typhoid fever in the United States, 1985-1994: changing risks of international travel and increasing antimicrobial resistance. Archives of Internal Medicine 1998; 158(6):633-638.
  15. Crump JA, Luby S, Mintz E. The global burden of typhoid disease. Bulletin of the World Health Organization 2004; 82:346-353.
  16. World Health Organization. 6th International Conference on Typhoid Feve and other Salmonelloses. 2006. Geneva, WHO.
    Ref Type: Pamphlet
  17. Tran HH, Bjune G, Nguyen BM, Rottingen JA, Grais RF, Guerin PJ et al. Risk factors associated with typhoid fever in Son La province, northern Vietnam. Transactions of the Royal Society of Tropical Medicine & Hygiene 2005; 99(11):819-826.
  18. Luxemburger C, Chau MC, Mai NL, Wain J, Tran TH, Simpson JA et al. Risk factors for typhoid fever in the Mekong delta, southern Viet Nam: a case-control study. Transactions of the Royal Society of Tropical Medicine & Hygiene 2001; 95(1):19-23.
  19. Tankhiwale SS, Agrawal G, Jalgaonkar SV, Tankhiwale SS, Agrawal G, Jalgaonkar SV. An unusually high occurrence of Salmonella enterica serotype paratyphi A in patients with enteric fever. Indian Journal of Medical Research 2003; 117:10-12.
  20. Ochiai RL, Wang X, von Seidlein L, Yang J, Bhutta ZA, Bhattacharya SK et al. Salmonella paratyphi A rates, Asia. Emerging Infectious Diseases 2005; 11(11):1764-1766.
  21. Walia M, Gaind R, Mehta R, Paul P, Aggarwal P, Kalaivani M et al. Current perspectives of enteric fever: a hospital-based study from India. Annals of Tropical Paediatrics 2005; 25(3):161-174.
  22. Bhutta ZA, Bhutta ZA. Impact of age and drug resistance on mortality in typhoid fever. Archives of Disease in Childhood 1996; 75(3):214-217.
  23. Saha SK, Baqui AH, Hanif M, Darmstadt GL, Ruhulamin M, Nagatake T et al. Typhoid fever in Bangladesh: implications for vaccination policy. Pediatric Infectious Disease Journal 2001; 20(5):521-524.
  24. Wain J, House D, Parkhill J, Parry C, Dougan G, Wain J et al. Unlocking the genome of the human typhoid bacillus. The Lancet Infectious Diseases 2002; 2(3):163-170.
  25. Fierer J, Guiney DG, Fierer J, Guiney DG. Diverse virulence traits underlying different clinical outcomes of Salmonella infection. Journal of Clinical Investigation 2001; 107(7):775-780.
  26. de Andrade DR, Andrade Junior DR, de Andrade DR, de Andrade Junior DR. Typhoid fever as cellular microbiological model. Revista do Instituto de Medicina Tropical de Sao Paulo 2003; 45(4):185-191.
  27. House D, Bishop A, Parry C, Dougan G, Wain J, House D et al. Typhoid fever: pathogenesis and disease. Current Opinion in Infectious Diseases 2001; 14(5):573-578.
  28. Bhan MK, Bahl R, Sazawal S, Sinha A, Kumar R, Mahalanabis D et al. Association between Helicobacter pylori infection and increased risk of typhoid fever. Journal of Infectious Diseases 2002; 186(12):1857-1860.
  29. Frenck RW, Jr., Clemens J, Frenck RWJ, Clemens J. Helicobacter in the developing world. Microbes & Infection 2003; 5(8):705-713.
  30. Patel JC, Rossanese OW, Galan JE, Patel JC, Rossanese OW, Galan JE. The functional interface between Salmonella and its host cell: opportunities for therapeutic intervention. Trends in Pharmacological Sciences 2005; 26(11):564-570.
  31. Hensel M, Hensel M. Salmonella pathogenicity island 2. Molecular Microbiology 2000; 36(5):1015-1023.
  32. Shetty PB, Broome DR, Shetty PB, Broome DR. Sonographic analysis of gallbladder findings in Salmonella enteric fever. Journal of Ultrasound in Medicine 1998; 17(4):231-237.
  33. Everest P, Wain J, Roberts M, Rook G, Dougan G, Everest P et al. The molecular mechanisms of severe typhoid fever. Trends in Microbiology 2001; 9(7):316-320.
  34. Ashbolt NJ, Ashbolt NJ. Microbial contamination of drinking water and disease outcomes in developing regions. Toxicology 2004; 198(1-3):229-238.
  35. Kumar KS, Harada H, Kumar Karn S, Harada H. Field survey on water supply, sanitation and associated health impacts in urban poor communities--a case from Mumbai City, India. Water Science & Technology 2002; 46(11-12):269-275.
  36. Schoenen D, Schoenen D. Role of disinfection in suppressing the spread of pathogens with drinking water: possibilities and limitations. Water Research 2002; 36(15):3874-3888.
  37. Tulchinsky TH, Burla E, Clayman M, Sadik C, Brown A, Goldberger S et al. Safety of community drinking-water and outbreaks of waterborne enteric disease: Israel, 1976-97. Bulletin of the World Health Organization 2000; 78(12):1466-1473.
  38. Levine MM, Tacket CO, Sztein MB, Levine MM, Tacket CO, Sztein MB. Host-Salmonella interaction: human trials. Microbes & Infection 2001; 3(14-15):1271-1279.
  39. Mastroeni P, Menager N, Mastroeni P, Menager N. Development of acquired immunity to Salmonella. Journal of Medical Microbiology 2003; 52(Pt 6):453-459.
  40. Garmory HS, Brown KA, Titball RW, Garmory HS, Brown KA, Titball RW. Salmonella vaccines for use in humans: present and future perspectives. FEMS Microbiology Reviews 2002; 26(4):339-353.
  41. Faucher JF, Binder R, Missinou MA, Matsiegui PB, Gruss H, Neubauer R et al. Efficacy of atovaquone/proguanil for malaria prophylaxis in children and its effect on the immunogenicity of live oral typhoid and cholera vaccines. Clinical Infectious Diseases 2002; 35(10):1147-1154.
  42. Engels EA, Lau J, Engels EA, Lau J. Vaccines for preventing typhoid fever. Cochrane Database of Systematic Reviews 2000;(2):CD001261.
  43. Kirkpatrick BD, Tenney KM, Larsson CJ, O'Neill JP, Ventrone C, Bentley M et al. The novel oral typhoid vaccine M01ZH09 is well tolerated and highly immunogenic in 2 vaccine presentations. Journal of Infectious Diseases 2005; 192(3):360-366.
  44. Connor BA, Schwartz E, Connor BA, Schwartz E. Typhoid and paratyphoid fever in travellers. The Lancet Infectious Diseases 2005; 5(10):623-628.
  45. Steinberg EB, Bishop R, Haber P, Dempsey AF, Hoekstra RM, Nelson JM et al. Typhoid fever in travelers: who should be targeted for prevention? Clinical Infectious Diseases 2004; 39(2):186-191.
  46. Antinori S, Galimberti L, Gianelli E, Calattini S, Piazza M, Morelli P et al. Prospective observational study of fever in hospitalized returning travelers and migrants from tropical areas, 1997-2001. Journal of Travel Medicine 2004; 11(3):135-142.
  47. Tarr PE, Kuppens L, Jones TC, Ivanoff B, Aparin PG, Heymann DL et al. Considerations regarding mass vaccination against typhoid fever as an adjunct to sanitation and public health measures: potential use in an epidemic in Tajikistan. American Journal of Tropical Medicine & Hygiene 1999; 61(1):163-170.
  48. Bahl R, Sinha A, Poulos C, Whittington D, Sazawal S, Kumar R et al. Costs of illness due to typhoid fever in an Indian urban slum community: implications for vaccination policy. Journal of Health, Population & Nutrition 2004; 22(3):304-310.
  49. Levine MM, Levine MM. Immunization against bacterial diseases of the intestine. Journal of Pediatric Gastroenterology & Nutrition 2000; 31(4):336-355.
  50. anon. Joint WHO/Unicef Statement for Typhoid Vaccine use in Tsunami-Affected areas. 2006. World Health Organization.
    Ref Type: Report
  51. anon. Typhoid Vaccine. 2003. Geneva, World Health Organization. Immunization, Vaccines and Biologicals.
    Ref Type: Report
  52. Acosta CJ, Galindo CM, Ali M, Elyazeed RA, Ochiai RL, Danovaro-Holliday MC et al. A multi-country cluster randomized controlled effectiveness evaluation to accelerate the introduction of Vi polysaccharide typhoid vaccine in developing countries in Asia: rationale and design. Tropical Medicine & International Health 2005; 10(12):1219-1228.
  53. Akpede GO, Akenzua GI, Akpede GO, Akenzua GI. Management of children with prolonged fever of unknown origin and difficulties in the management of fever of unknown origin in children in developing countries. Paediatric Drugs 2001; 3(4):247-262.
  54. Caumes E, Ehya N, Nguyen J, Bricaire F, Caumes E, Ehya N et al. Typhoid and paratyphoid fever: a 10-year retrospective study of 41 cases in a Parisian hospital. Journal of Travel Medicine 2001; 8(6):293-297.
  55. Otegbayo JA, Daramola OO, Onyegbutulem HC, Balogun WF, Oguntoye OO, Otegbayo JA et al. Retrospective analysis of typhoid fever in a tropical tertiary health facility.[erratum appears in Trop Gastroenterol. 2002 Apr-Jun;23(2):p3 Note: Daramola, O O O [corrected to Daramola, O O M]]. Tropical Gastroenterology 2002; 23(1):9-12.
  56. Haq SA, Alam MN, Hossain SM, Ahmed T, Tahir M, Haq SA et al. Value of clinical features in the diagnosis of enteric fever. Bangladesh Medical Research Council Bulletin 1997; 23(2):42-46.
  57. Cunha BA, Cunha BA. Typhoid fever: the temporal relations of key clinical diagnostic points. The Lancet Infectious Diseases 2006; 6(6):318-320.
  58. Nsutebu EF, Martins P, Adiogo D, Nsutebu EF, Martins P, Adiogo D. Prevalence of typhoid fever in febrile patients with symptoms clinically compatible with typhoid fever in Cameroon. Tropical Medicine & International Health 2003; 8(6):575-578.
  59. Dutta U, Garg PK, Kumar R, Tandon RK, Dutta U, Garg PK et al. Typhoid carriers among patients with gallstones are at increased risk for carcinoma of the gallbladder. American Journal of Gastroenterology 2000; 95(3):784-787.
  60. Vollaard AM, Ali S, Widjaja S, Asten HA, Visser LG, Surjadi C et al. Identification of typhoid fever and paratyphoid fever cases at presentation in outpatient clinics in Jakarta, Indonesia. Transactions of the Royal Society of Tropical Medicine & Hygiene 2005; 99(6):440-450.
  61. Ngwu BA, Agbo JA, Ngwu BA, Agbo JA. Typhoid fever: clinical diagnosis versus laboratory confirmation. Nigerian Journal of Medicine: Journal of the National Association of Resident Doctors of Nigeria 2003; 12(4):187-192.
  62. 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. Journal of Clinical Microbiology 2001; 39(4):1571-1576.
  63. Massi MN, Shirakawa T, Gotoh A, Bishnu A, Hatta M, Kawabata M et al. Rapid diagnosis of typhoid fever by PCR assay using one pair of primers from flagellin gene of Salmonella typhi. Journal of Infection & Chemotherapy 2003; 9(3):233-237.
  64. Shukla S, Patel B, Chitnis DS, Shukla S, Patel B, Chitnis DS. 100 years of Widal test & its reappraisal in an endemic area. Indian Journal of Medical Research 1997; 105:53-57.
  65. Ibadin MO, Ogbimi AO, Ibadin MO, Ogbimi AO. Anti-typhoid agglutinins in school aged African children. East African Medical Journal 2002; 79(2):92-95.
  66. Frimpong EH, Feglo P, Essel-Ahun M, Addy PA, Frimpong EH, Feglo P et al. Determination of diagnostic Widal titres in Kumasi, Ghana. West African Journal of Medicine 2000; 19(1):34-38.
  67. Parry CM, Hoa NT, Diep TS, Wain J, Chinh NT, Vinh H et al. Value of a single-tube widal test in diagnosis of typhoid fever in Vietnam. Journal of Clinical Microbiology 1999; 37(9):2882-2886.
  68. House D, Chinh NT, Diep TS, Parry CM, Wain J, Dougan G et al. Use of paired serum samples for serodiagnosis of typhoid fever. Journal of Clinical Microbiology 2005; 43(9):4889-4890.
  69. Jesudason MV, Sridharan G, Arulselvan R, Babu PG, John TJ, Jesudason MV et al. Diagnosis of typhoid fever by the detection of anti-LPS & anti-flagellin antibodies by ELISA. Indian Journal of Medical Research 1998; 107:204-207.
  70. Nguyen NQ, Tapchaisri P, Chongsa-nguan M, Cao VV, Doan TT, Sakolvaree Y et al. Diagnosis of enteric fever caused by Salmonella spp. in Vietnam by a monoclonal antibody-based dot-blot ELISA. Asian Pacific Journal of Allergy & Immunology 1997; 15(4):205-212.
  71. Herath HM, Herath HMTU. Early diagnosis of typhoid fever by the detection of salivary IgA. Journal of Clinical Pathology 2003; 56(9):694-698.
  72. Pai AP, Koppikar GV, Deshpande S, Pai AP, Koppikar GV, Deshpande S. Role of modified Widal test in the diagnosis of enteric fever. Journal of the Association of Physicians of India 2003; 51:9-11.
  73. Hatta M, Goris MG, Heerkens E, Gooskens J, Smits HL, Hatta M et al. Simple dipstick assay for the detection of Salmonella typhi-specific IgM antibodies and the evolution of the immune response in patients with typhoid fever. American Journal of Tropical Medicine & Hygiene 2002; 66(4):416-421.
  74. Lakshmi V, Ashok R, Susmita J, Shailaja VV, Lakshmi V, Ashok R et al. Changing trends in the antibiograms of Salmonella isolates at a tertiary care hospital in Hyderabad. Indian Journal of Medical Microbiology 2006; 24(1):45-48.
  75. Thaver Deal. Fluoroquinolones for treating typhoid and paratyphoid fevers (enteric fevers). Cochrane Database of Systematic Reviews 2006; 1.
  76. Wain J, Kidgell C, Wain J, Kidgell C. The emergence of multidrug resistance to antimicrobial agents for the treatment of typhoid fever. Transactions of the Royal Society of Tropical Medicine & Hygiene 2004; 98(7):423-430.
  77. Kariuki S, Revathi G, Muyodi J, Mwituria J, Munyalo A, Mirza S et al. Characterization of multidrug-resistant typhoid outbreaks in Kenya. Journal of Clinical Microbiology 2004; 42(4):1477-1482.
  78. Mills-Robertson F, Addy ME, Mensah P, Crupper SS, Mills-Robertson F, Addy ME et al. Molecular characterization of antibiotic resistance in clinical Salmonella typhi isolated in Ghana. FEMS Microbiology Letters 2002; 215(2):249-253.
  79. Wasfy MO, Frenck R, Ismail TF, Mansour H, Malone JL, Mahoney FJ et al. Trends of multiple-drug resistance among Salmonella serotype Typhi isolates during a 14-year period in Egypt. Clinical Infectious Diseases 2002; 35(10):1265-1268.
  80. Renuka K, Kapil A, Kabra SK, Wig N, Das BK, Prasad VV et al. Reduced susceptibility to ciprofloxacin and gyra gene mutation in North Indian strains of Salmonella enterica serotype Typhi and serotype Paratyphi A. Microbial Drug Resistance-Mechanisms Epidemiology & Disease 2004; 10(2):146-153.
  81. Parry CM, Parry CM. The treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever in Viet Nam. Transactions of the Royal Society of Tropical Medicine & Hygiene 2004; 98(7):413-422.
  82. Slinger R, Desjardins M, McCarthy AE, Ramotar K, Jessamine P, Guibord C et al. Suboptimal clinical response to ciprofloxacin in patients with enteric fever due to Salmonella spp. with reduced fluoroquinolone susceptibility: a case series. BMC Infectious Diseases 2004; 4:36.
  83. Crump JA, Barrett TJ, Nelson JT, Angulo FJ, Crump JA, Barrett TJ et al. Reevaluating fluoroquinolone breakpoints for Salmonella enterica serotype Typhi and for non-Typhi salmonellae. Clinical Infectious Diseases 2003; 37(1):75-81.
  84. Chinh NT PCLNHHTMDTW. A randomized controlled comparison of azithromycin and ofloxacin for treatment of multidrug-resistant or nalidixic acid-resistant enteric fever. Antimicrobial agents and chemotherapy 2000; 44(7):1855-1859.
  85. Vinh H, Duong NM, Phuong lT, Truong NT, Bay PV, Wain J et al. Comparative trial of short-course ofloxacin for uncomplicated typhoid fever in Vietnamese children. Annals of Tropical Paediatrics 2005; 25(1):17-22.
  86. Hart CA, Kariuki S, Hart CA, Kariuki S. Antimicrobial resistance in developing countries. BMJ 1998; 317(7159):647-650.
  87. Ajao OG AA. Methylprednisolone sodium succinate (Solu-Medrol) in the treatment of typhoid perforation (a preliminary report). Transactions of the Royal Society of Tropical Medicine and Hygiene 1984; 78(5):573-576.
  88. Annane D, Annane D. Glucocorticoids in the treatment of severe sepsis and septic shock. Current Opinion in Critical Care 2005; 11(5):449-453.
  89. Ugwu BT, Yiltok SJ, Kidmas AT, Opaluwa AS, Ugwu BT, Yiltok SJ et al. Typhoid intestinal perforation in north central Nigeria. West African Journal of Medicine 2005; 24(1):1-6.
  90. Chatterjee H, Jagdish S, Pai D, Satish N, Jayadev D, Reddy PS et al. Changing trends in outcome of typhoid ileal perforations over three decades in Pondicherry. Tropical Gastroenterology 2001; 22(3):155-158.
  91. Aziz M, Qadir A, Aziz M, Faizullah., Aziz M, Qadir A et al. Prognostic factors in typhoid perforation. Jcpsp, Journal of the College of Physicians & Surgeons - Pakistan 2005; 15(11):704-707.
  92. Kouame J, Kouadio L, Turquin HT, Kouame J, Kouadio L, Turquin HT. Typhoid ileal perforation: surgical experience of 64 cases. Acta Chirurgica Belgica 2004; 104(4):445-447.
  93. Agbakwuru EA, Adesunkanmi AR, Fadiora SO, Olayinka OS, Aderonmu AO, Ogundoyin OO et al. A review of typhoid perforation in a rural African hospital. West African Journal of Medicine 2003; 22(1):22-25.
  94. Ameh EA, Dogo PM, Attah MM, Nmadu PT, Ameh EA, Dogo PM et al. Comparison of three operations for typhoid perforation. British Journal of Surgery 1997; 84(4):558-559.
  95. Pal DK, Pal DK. Evaluation of best surgical procedures in typhoid perforation--an experience of 60 cases. Tropical Doctor 1998; 28(1):16-18.
  96. Chaudhry R, Mahajan RK, Diwan A, Khan S, Singhal R, Chandel DS et al. Unusual presentation of enteric fever: three cases of splenic and liver abscesses due to Salmonella typhi and Salmonella paratyphi A. Tropical Gastroenterology 2003; 24(4):198-199.
  97. Julia J, Canet JJ, Lacasa XM, Gonzalez G, Garau J, Julia J et al. Spontaneous spleen rupture during typhoid fever. International Journal of Infectious Diseases 2000; 4(2):108-109.
  98. Krishna KK, Mitra DK, Diwan AG, Bamnikar AA, Krishna KK, Mitra DK et al. Acute disseminated encehalomyelitis with typhoid fever. Journal of the Association of Physicians of India 1999; 47(10):1017-1019.
  99. Laloum E, Zeller V, Graff W, Aerts J, Chazerain P, Mamoudy P et al. Salmonella typhi osteitis can mimic tuberculosis. A report of three cases. Joint, Bone, Spine: Revue du Rhumatisme 2005; 72(2):171-174.
  100. Khan M, Coovadia Y, Sturm AW, Khan M, Coovadia Y, Sturm AW. Typhoid fever complicated by acute renal failure and hepatitis: case reports and review. American Journal of Gastroenterology 1998; 93(6):1001-10.
    Questions

      Click here to join the Surgery in Africa Discussion Group

    (Back to Top)