oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
Synonyms: enteric fever
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 three subtypes (A, B and C) and is generally similar but usually less severe.
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. Food is generally heavily contaminated - approximately 105 to 109 cells may be required to cause illness.
Typhoid fever has virtually disappeared in the developed world, but is still endemic in developing countries, and its treatment is becoming increasingly costly in the UK. Precise incidences are difficult to obtain due to the lack of accurate diagnostic and epidemiological data in endemic countries. In 2004 it was estimated that there were 21.6 million cases, and 200,000 deaths per year worldwide due to enteric fever. Most occur in Asia and Africa. In Latin America, despite there being evidence that the incidence has decreased in parallel with economic transition and with water and sanitation measures, it remains a public health problem there. In global hot spots (eg Indonesia and Papua New Guinea) 91% of typhoid fever occurs 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.
In the UK, an average of almost 500 cases were reported per year between 2006 and 2010. This is a 25% increase on the previous five years. Over half of these cases were in London. Between 2007 and 2010, the demographics of typhoid and paratyphoid disease were scrutinised by the Health Protection Agency by enhanced surveillance. 1,673 surveillance questionnaires were received. They showed that 73% of cases were of Indian, Pakistani or Bangladeshi ethnicity, that 96% of cases were acquired abroad and that the bulk of travel was to India, Pakistan or Bangladesh. 84% of those who had travelled were visiting friends and relatives. Interestingly, 7% of those who completed questionnaires had no travel history, and for most of these, there was no identifiable source of infection. 40% of non- travel cases were from London.
This depends on the size of the infecting dose - is usually 10-20 days for S. typhi (but may be as short as 3 days). During this phase, 10-20% of patients have transient diarrhoea. The incubation period for paratyphoid had previously been reported to be shorter: 1-10 days. However the surveillance data for England, Wales and Northern Ireland 2007-2010 did not show any significant differences between typhoid and paratyphoid in time of onset of symptoms on arrival to the UK.
- 98% of cases with a documented travel history had an onset date within 35 days of return from travel.
- Of these, 91% had an onset date within 21 days.
- 5% had an onset date between 22-28 days.
- 2% had an onset date between 29-35 days.
Typhoid is one of the most common febrile illnesses seen by practitioners in the developing world.
- Initially there may be intermittent diarrhoea.
- 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).
- 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.
- Rose spots - caused by bacterial emboli - are crops of macules 2-4 mm 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, and orbital thromboses.
- During the second week the patient has a toxic appearance with apathy and sustained pyrexia. The abdomen is distended slightly and splenomegaly is common.
- By the third 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 and 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 fourth 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.
|Typhoid Features (in hospitalised cases)|
Remember to consider co-existent malaria or schistosomiasis.
- 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. However, this may be enhanced to above 80% using two sets of blood cultures and modern methods. The most sensitive source with around 90% isolation rate is bone marrow aspiration. Isolation of S. typhi is highest in the first week and becomes more difficult as time passes.
- Serology. The traditional serological test is Widal's 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 disappears 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. The validity of rapid diagnostic tests for typhoid and paratyphoid has been submitted for Cochrane review.
In non-endemic countries, patients presenting with symptoms suggestive of typhoid or paratyphoid are initially assessed in hospital where a firm diagnosis by blood culture or bone marrow culture can be made, and antibiotic sensitivities determined. Empiric antibiotic treatment is commenced depending on the likely source of the infection (country travelled to). Clinically unstable patients are admitted to hospital for IV treatment while those who are stable may be treated as outpatients.
- Supportive - adequate rest, rehydration and correction of electrolyte disturbances.
- 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 are important.
- Antibiotics - shorten the course, reduce the rate of complications if begun early and reduce mortality. Drug resistance is a problem.
- Ciprofloxacin had been the drug of choice for the decade following the emergence of strains resistant to chloramphenicol, ampicillin, and trimethoprim (multidrug-resistant typhoid). However, over 80% of S. typhi and over 70% of S. paratyphi infections imported to the UK from Asia have been found to have reduced susceptibility to fluoroquinolones.
- Patients who are clinically unstable are empirically treated with IV ceftriaxone if the infection is likely to have originated from Asia. If the infection is likely to be from Africa, South America or Central America, ciprofloxacin may still be used (fewer than 4% of infections imported to the UK from Africa are resistant to fluoroquinolones). The antibiotic is appropriately changed once sensitivities are available.
- Azithromycin and some of the newer fluoroquinolones such as gatifloxacin are suitable alternatives to ciprofloxacin in stable patients, and may be better for reducing clinical relapse rates compared to chloramphenicol. However, increasing resistance to azithromycin has been reported and local resistance patterns need to be considered when choosing the most appropriate antibiotic.
Recommended antibiotic treatment for typhoid fever Uncomplicated typhoid fever:
- Empirical treatment if infection is likely to have originated in Asia - azithromycin.
- 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:
- Empirical treatment if the origin of infection is likely to be Asia - ceftriaxone.
- 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. However, they may induce relapse, so are 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 are required.
- The two most common complications are haemorrhage (including disseminated intravascular coagulation) 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 1-5% 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.
Chronic carrier state
One week following treatment, a stool culture is taken from asymptomatic patients to check that these infections have cleared. If the sample is positive, strict hygiene procedures need to be continued, and retreatment may be necessary. If the patient is in a 'risk group' (see 'Risk groups', below) re-treatment, exclusion, redeployment and bacteriological surveillance are needed until there have been three negative clearance faecal samples taken at least 48 hours apart.
- Ciprofloxacin 750 mg bd and norfloxacin 400 mg bd have both been effective in the past. This may remain effective treatment in cases where Africa or South America was the source of infection. Where the source is Southeast Asia, however, newer quinolones such as gatifloxacin, ampicillin, amoxicillin with probenecid or co-trimoxazole have been used. (Discuss with microbiologist).
- 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.
Community containment and public health management
Close collaboration between the infectious disease consultant, microbiologist, public health physician and general practitioner helps to prevent the spread of S. typhi and S. paratyphi through the community. All patients, carriers, co-travellers and contacts should adhere to strict hygiene standards.
Exclusion or redeployment should be considered for those in risk groups who have had enteric fever for at least 48 hours after their symptoms subside. One week after completing their treatment, three samples taken 48 hours apart need to be negative before they are no-longer considered to be at risk of passing on the infection.
In the UK, public health management of S. typhi and S. paratyphi focuses on 'Risk Groups' which are defined as:
- Any person of doubtful personal hygiene or with unsatisfactory toilet, hand washing or hand drying facilities at home, work or school.
- All children aged five years old or under who attend school, preschool, nursery or other childcare or minding groups.
- People whose work involves preparing or serving unwrapped food to be served raw or not subjected to further heating.
- Clinical, social care or nursery staff who work with young children, the elderly, or other particularly vulnerable people, and whose activities increase the risk of transferring infection via the faeco-oral route, eg caring for a chronically sick relative.
Exclusion/redeployment are not required of those not in the above risk groups, but strict standards of hygiene should be adhered to.
Documented cases of S. typhi and S. paratyphi
In the UK, all cases of S. typhi and S. paratyphi - with a documented diagnosis based on a blood or faecal sample taken in the UK or abroad - should be notified to the Health Protection Unit (HPU). Those who are in 'risk groups', above, should be excluded while they are symptomatic and for at least 48 hours after the symptoms have subsided. The HPU will advise them of any necessary further action, and when they can return to work.
Non-documented cases of S. typhi and S. paratyphi
Some people may have received a diagnosis of typhoid fever and have been treated while abroad, without having a documented blood culture diagnosis. If they are asymptomatic at presentation, a stool specimen should be sent for screening to a local laboratory. They need not be excluded while they are waiting for the results unless they become symptomatic. If the result is positive, the HPU should be informed. If they are symptomatic at presentation, they should be treated appropriately, the HPU should be informed, and they should be excluded if they are in a 'risk group', above, until 48 hours after their symptoms have subsided.
Asymptomatic co-travelling contacts of known typhoid cases are likely to have been exposed to the same source of typhoid or paratyphoid as their companion. A stool specimen should be sent for culture as soon as possible. They should be given strict hygiene advice, informed of symptoms and signs of these infections, and advised to contact their GP, or the hospital if they become unwell. If they develop symptoms of typhoid or paratyphoid, they should be excluded, as above, and treated as necessary. If they remain asymptomatic, they need not be excluded while they are waiting for the results of their stool culture. If the stool culture is positive, the HPU should be notified. If they are in a high-risk group, they should be excluded until the HPU advises them that they can go back to work or school.
Household or sexual contacts of patients with enteric fever should be given hygiene advice and warned to contact their GP if they develop symptoms of the disease. They do not need a screening sample and do not need to be excluded unless they become unwell.
In the days before antibiotics, mortality was 20%. Between 10-20% of patients treated with antibiotics have a relapse, usually a week after stopping the antibiotic; however, it can be much later. The relapse rate is lower with quinolones, as they penetrate the cells (but see 'Antibiotics' (antibiotic resistance) under 'Management', above). A study of 552 patients in Bangladesh 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 aged under 1 year (11%) and adults over 31 years (10%). Death was independently associated with seizures, intestinal perforation, pneumonia, and delirium or coma.
- 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).
Further reading & references
- 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.
- Typhoid, Health Protection Agency
- Bhan MK, Bahl R, Bhatnagar S; Typhoid and paratyphoid fever. Lancet. 2005 Aug 27-Sep 2;366(9487):749-62.
- Bhutta ZA, Current concepts in the diagnosis and treatment of typhoid fever BMJ 2006;333:78-82
- Reddy S, Rangaiah J, Addiman S, et al; Epidemiology, antibiotic resistance trends and the cost of enteric fever in East Travel Med Infect Dis. 2011 Jul;9(4):206-12. Epub 2011 Jun 1.
- Crump JA, Luby SP, Mintz ED; The global burden of typhoid fever. Bull World Health Organ. 2004 May;82(5):346-53.
- Crump JA, Mintz ED; Global trends in typhoid and paratyphoid Fever. Clin Infect Dis. 2010 Jan 15;50(2):241-6.
- Brusch JL et al, Typhoid Fever, Medscape, Sep 2011
- Public Health Operational Guidelines for Typhoid and Paratyphoid (Enteric Fever), Health Protection Agency (Feb 2012)
- 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.
- Bhutta ZA; Impact of age and drug resistance on mortality in typhoid fever.; Arch Dis Child. 1996 Sep;75(3):214-7.
- Background document: the diagnosis, prevention and treatment of typhoid fever, World Health Organization (2003)
- Johnston V, Stockley JM, Dockrell D, et al; Fever in returned travellers presenting in the United Kingdom: recommendations J Infect. 2009 Jul;59(1):1-18. Epub 2009 May 27.
- 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.
- Threlfall EJ, Day M, de Pinna E, et al; Drug-resistant enteric fever in the UK.; Lancet. 2006 May 13;367(9522):1576.
- Pilot of Enhanced Surveillance of Enteric Fever in England, Wales and Northern Ireland 2006-2007, Health Protection Agency
- Sanchez-Vargas FM, Abu-El-Haija MA, Gomez-Duarte OG; Salmonella infections: an update on epidemiology, management, and prevention. Travel Med Infect Dis. 2011 Nov;9(6):263-77. Epub 2011 Nov 25.
- Cooke FJ, Day M, Wain J, et al; Cases of typhoid fever imported into England, Scotland and Wales (2000-2003). Trans R Soc Trop Med Hyg. 2007 Apr;101(4):398-404. Epub 2006 Oct 2.
- Effa EE, Lassi ZS, Critchley JA, et al; Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever). Cochrane Database Syst Rev. 2011 Oct 5;(10):CD004530.
- 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.
- 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.
- 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.
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Dr Huw Thomas
Dr Michelle Williams
Dr Helen Huins