Synonyms: enteric fever

Epidemiology

Typhoid fever is caused by a Gram negative organism Salmonella enterica, either serovar Typhi (S. typhi) or serovar Paratyphi (S. paratyphi). The latter (paratyphoid) is divided into 3 subtypes (A, B and C) and is generally similar but usually less severe.^1,2,3

It affects only humans (who are the reservoir) and is spread through consumption of contaminated food and drink handled by people who shed the organism from stool or, less commonly urine or water contaminated with sewage. Shellfish from water polluted by raw sewage and canned meat production with poor technique have caused outbreaks.
Typhoid fever has virtually disappeared in the developed world, but is still endemic in developing countries.
Approximately 21.6 million cases occur per year worldwide (2004), mostly in Asia, Africa, and Latin America (200,000 deaths). In global hot spots, (e.g. Indonesia and Papua New Guinea) 91% of typhoid fever occur in children aged 3-19 years in whom it is a common cause of death. The highest risk of complications and death occurs in children in the first year of life, and in older adults.⁴

The majority of new cases here in the UK are believed to be related to foreign travel. There were around 230 cases of each S.typhi and S.paratyphi reported in England and Wales in 2005;¹ and the HPA are interested in more information about each new case (enhanced surveillance).¹
See related article Salmonella Gastroenteritis. Food is generally heavily contaminated - approximately 10⁵ to 10⁹ cells may be required to cause illness.¹

Incubation period

This depends on the size of the infecting dose - is usually 10 to 20 days for S. typhi (but may be as short as 3 days). During this phase 10 to 20% of patients have transient diarrhoea. For paratyphoid the incubation period is shorter: 1 to 10 days.⁵

Presentation

Typhoid is one of the most common febrile illnesses seen by practitioners in the developing world.

Symptoms

• Initially there may be intermittent diarrhoea.⁵
• Fever which develops in steps over 2 or 3 days with temperatures up to 39°C or 40°C during the bacteraemic phase (early antibiotics may modify the presentation).⁶
• Headaches, non productive cough and constipation may also occur.

In this bacteraemic phase it is possible to find bacteria in the reticuloendothelial tissues of the liver, spleen, bone marrow, gallbladder and Peyer's patches in the terminal ileum. The gallbladder is infected via the liver and infected bile gives positive stool cultures. Gallstones predispose to chronic biliary infection and long-term faecal carriage.

Signs

• Rose spots - caused by bacterial emboli - are crops of macules 2 to 4mm in diameter that blanch on pressure.
• Relative bradycardia - the pulse is slower than would be expected from the degree of temperature.
• Eye complications may occur (usually only with associated systemic illness) which include corneal ulcers, uveitis, abscesses (eyelid or orbit), vitreous or retinal haemorrhage, retinal detachment, optic neuritis, extraocular muscle palsies, orbital thromboses.

Subsequent course

• During the 2nd week the patient has a toxic appearance with apathy and sustained pyrexia. The abdomen is distended slightly and splenomegaly is common.⁵
• By the 3rd week there is considerable weight loss. Pyrexia persists and a delirious state may occur. Marked abdominal distension develops and liquid, foul, green-yellow "pea soup diarrhoea" is common.
• The patient is weak with a weak pulse, raised respiratory rate and crackles may develop over the lung bases. Death can occur at this stage from overwhelming toxaemia, myocarditis, intestinal haemorrhage, or perforation of the gut, usually at Peyer's patches.
• In the untreated patient the 4th week sees the fever, mental state and abdominal distension slowly improve over a few days, but intestinal complications may still occur. Convalescence is prolonged, and most relapses occur at this stage.

Differential diagnosis

• Amoebiasis
• Influenza
• Malaria
• Tuberculosis
• Typhus

Remember to consider co-existent malaria or schistosomiasis.

Investigations

• Culture Diagnosis is by culturing the organism. It may be obtained from stool or other sources. Blood cultures are only positive in 40-60% of cases.⁸The most sensitive source with around 90% isolation rate is bone marrow aspiration. Isolation of Salmonella typhi is highest in the 1st week and becomes more difficult as time passes.
• Serology The traditional serological test is the Widal test. It measures agglutinating antibodies against flagellar (H) and somatic (O) antigens of S typhi. In acute infection the O antibody appears first, rising progressively, falls later, and often disappearing within a few months. H antibody appears slightly later but persists longer. High or rising O antibody titres generally indicate acute infection, whereas H antibody is used to identify the type of infection. The test is positive on admission in between 40 and 60% of patients but the test has enormous variation between laboratories in terms of sensitivity, specificity and predictive value. Indirect agglutination tests are available and PCR tests are being developed.⁹

Management

• Supportive - Adequate rest, rehydration and correction of electrolyte disturbances³
• Antipyretic therapy as required.
• Hygiene - Carers must be meticulous with hand washing and the disposal of faeces and urine.
• Early diagnosis and rapid commencement of treatment is important.
• Antibiotics shorten the course, reduce the rate of complications if begun early and reduce mortality. Discuss with microbiologist.
  Drug resistance is a problem, even in the UK.¹⁰ Ciprofloxacin has been the drug of choice for the last decade since the emergence of strains resistant to chloramphenicol, ampicillin, and trimethoprim. Unfortunately in 2006 a large number of cultures have shown reduced susceptibility to this antibiotic.³ In adults, fluoroquinolones may be better for reducing clinical relapse rates compared to chloramphenicol.¹¹

  Recommended antibiotic treatment for typhoid fever8
  Uncomplicated typhoid fever	Fully sensitive - Fluoroquinolone (eg ofloxacin or ciprofloxacin) for 5-7 days Multiple resistant - Fluoroquinolone (for 5-7 days), or Cefixime (7-14 days) Quinolone resistant - Azithromycin (7 days) or Ceftriaxone (10-14 days)
  Severe typhoid fever requiring parenteral treatment	Fully sensitive - Fluoroquinolone (such as ofloxacin) for 10-14 days Multiple resistant - Fluoroquinolone (such as ofloxacin) for 10-14 days Quinolone resistant - Ceftriaxone or Cefotaxime (10-14 days)

  Steroids have occasionally been used in severe cases - but may induce relapse so not generally recommended.

• Surgical - If perforation of the bowel occurs it will require closure. Treatment with antibiotics alone was once favoured but simple closure and drainage is required.¹²

Chronic carrier state

• Ciprofloxacin 750 mg b.d. and norfloxacin 400 mg b.d. have both been effective in the past. Norfloxacin has a cure rate of 78%. - discuss with microbiologist.
• Bacteriological surveillance after recovery should continue until 6 consecutive negative results are obtained on faecal and urine cultures. Long-term urinary carriers should be assessed for urinary tract abnormalities, including schistosomiasis.
• In long term faecal carriage, cholecystectomy is not very effective as the liver is a reservoir.

Complications

• The 2 commonest complications are haemorrhage (including DIC) and perforation of the bowel. Before antibiotics perforation had a mortality of around 75%.
• Jaundice may be due to hepatitis, cholangitis, cholecystitis, or haemolysis.
• Pancreatitis with acute renal failure and hepatitis with hepatomegaly are rare.
• Toxic myocarditis occurs in 1 to 5% of patients (ECG changes may be present). It is a significant cause of death in endemic areas.
• Toxic confusional states and other neurological and psychiatric disturbances have been reported.

Prognosis

In the days before antibiotics mortality was 20%. Between 10% and 20% of patients treated with antibiotics have a relapse, usually a week after stopping the antibiotic but it can be much later. The relapse rate is lower with quinolones as they penetrate the cells (but see discussion about antibiotic resistance).
A study of 552 patients in Bangladesh¹³ showed that seizures occurred more frequently in children under 10 years of age (5%-11%) and pneumonia more frequently in children under 5 years (8%-15%). Intestinal perforation occurred more frequently in patients over 11 years old (5%-25%). The case-fatality rate was 4.3% overall, with the highest rates for children under 1 year of age (11%) and adults over 31 year (10%). Death was independently associated with seizures, intestinal perforation, pneumonia, and delirium or coma.

Prevention

• In countries in which typhoid is endemic the most important action is attention to safe drinking water and disposal of sewage.
• Mass vaccination with typhoid vaccine is also effective.
• Travellers to endemic areas should also take precautions with regard to hygiene but they must receive vaccination too (there is no vaccine for S. paratyphi A).

Document references

1. Typhoid, Health Protection Agency
2. Bhan MK, Bahl R, Bhatnagar S; Typhoid and paratyphoid fever. Lancet. 2005 Aug 27-Sep 2;366(9487):749-62. [abstract]
3. Bhutta ZA, Current concepts in the diagnosis and treatment of typhoid fever BMJ 2006;333:78-82
4. Curtis T, Wheeler DT; Typhoid Fever. eMedicine, 2006.
5. Brusch JL, Garvey T, Corales R, Schmitt SK; Typhoid Fever. eMedicine, July 2006.
6. Siddiqui FJ, Rabbani F, Hasan R, et al; Typhoid fever in children: some epidemiological considerations from Karachi, Pakistan.; Int J Infect Dis. 2006 May;10(3):215-22. Epub 2006 Jan 23. [abstract]
7. Bhutta ZA; Impact of age and drug resistance on mortality in typhoid fever.; Arch Dis Child. 1996 Sep;75(3):214-7. [abstract]
8. Background document: the diagnosis, prevention and treatment of typhoid fever, World Health Organization
9. Tam FC, Wang M, Dong B, et al; New rapid test for paratyphoid a fever: usefulness, cross-detection, and solution. Diagn Microbiol Infect Dis. 2008 Oct;62(2):142-50. Epub 2008 Aug 20. [abstract]
10. Threlfall EJ, Day M, de Pinna E, et al; Drug-resistant enteric fever in the UK.; Lancet. 2006 May 13;367(9522):1576.
11. Thaver D, Zaidi AK, Critchley JA, et al; Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). Cochrane Database Syst Rev. 2008 Oct 8;(4):CD004530. [abstract]
12. 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. [abstract]
13. 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. [abstract]

Internet and further reading

• Typhoid fever, Medine Plus Medical Encyclopedia
• Tam FC, Wang M, Dong B, et al; New rapid test for paratyphoid a fever: usefulness, cross-detection, and solution. Diagn Microbiol Infect Dis. 2008 Oct;62(2):142-50. Epub 2008 Aug 20. [abstract]

Acknowledgements