Synonyms: enteric fever
Typhoid and paratyphoid fevers are caused by related but different strains of Salmonella spp. There is considerable overlap in symptoms, although typhoid is the more severe and long-lasting disease, and is the one more likely to result in death if prompt treatment is not given. The name typhoid means 'resembling typhus', and was chosen because of the occurrence of neuropsychiatric symptoms in all three diseases. However, although there can be some symptom overlap, typhus, and the related condition scrub typhus, are completely separate diseases.
- Is caused by a Gram-negative organism Salmonella enterica subspecies enterica serovar Typhi (Salmonella typhi).
- Is divided into three subtypes (A, B and C). Paratyphoid fever is caused by any of three serovars of Salmonella enterica subspecies enterica:
- S. paratyphi A.
- S. schottmuelleri (also called S. paratyphi B).
- S. hirschfeldii (also called S. paratyphi C).
- Type A is the most common worldwide, although B predominates in Europe. Type C is rare, and is seen only in the Far East[1, 2, 3].
- The overall ratio of disease caused by S. typhi to that caused by S. paratyphi is about 10 to 1.
Enteric fever 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. It may also be acquired from ingesting water contaminated with sewage. Shellfish from water polluted by raw sewage and canned meat production with poor technique have also caused outbreaks. Food needs to be heavily contaminated for infection to occur - approximately 105 to 109 cells may be required to cause illness.
Global trends in prevalence
Typhoid fever has virtually disappeared in the developed world, but is still endemic in many developing countries. Most cases now occur in Africa and Asia. In Latin America, incidence has decreased with water and sanitation measures, but it remains a public health concern[4, 5, 6].
- 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. Previous estimates had been much higher[4, 5, 7].
- In the tropics, enteric fever tends to be more common during the hot dry seasons when the concentration of bacteria in rivers and streams increases, or in the rainy season if flooding distributes sewage to drinking water sources.
- In some areas the incidence of typhoid may be as high as 1,000 cases per 100,000 population per year. In such areas typhoid is predominantly a disease of children, and stool excretion of S. typhi during and after infection is the main source of the infection. In such areas infections are commonly mild and self-limiting. Severe disease represents the 'tip of the iceberg'.
- In temperate countries, persistent carriers are a more important reservoir of infection.
- For travellers the highest attack rates are associated with visits to South Asia. Although Indonesia has a reported annual incidence up to 1%, the attack rate for travellers is low.
- In general, the mortality is low (<1%) where antibiotics are available, but in poorer areas, or in the context of natural disasters, war, migrations, large concentrated refugee populations, and other privations, the mortality may rise to 10-30%, despite antibiotic therapy.
- Typhoid tends to cluster in families, presumably reflecting a common source of the infection and is associated with poverty and poor housing.
- A complicating factor in assessing incidence is that the HIV and AIDS epidemic in Africa has been associated with a concomitant increase in community-acquired bacteraemia due to non-typhoidal Salmonella spp. such as S. typhimurium - an illness that may be clinically indistinguishable from typhoid.
Typhoid and paratyphoid fever in the UK
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 cases were in London. Between 2007 and 2010, 1,673 surveillance questionnaires were received by the Health Protection Agency. They showed that 73% of affected patients 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. 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.
Apart from exposure to the organism, a number of host factors increase the risk of infection with Salmonella spp. by reducing the necessary infectious organism load. These include:
- Disease-related or iatrogenic achlorhydria (antacids, H2-receptor antagonists, proton pump inhibitors), reduction in stomach acidity or gut pathology (surgery, inflammatory bowel disease, malignancy) and recent antibiotics increase the susceptibility to infection.
- Immunosuppression of any cause.
- Several other infections, notably schistosomiasis, malaria, histoplasmosis and bartonellosis, are associated with an increased risk of infection with Salmonella spp.
- Typhoid is more common, and more severe at the extremes of age. Neonatal typhoid, usually acquired from the mother, may follow a fulminant course often with meningitis.
- Patients with haemoglobinopathies, particularly sickle cell disease, are also at increased risk.
This depends on the infecting dose ingested - it is typically 10-20 days for S. typhi (but may be as short as three days). During this phase, 10-20% of patients have transient diarrhoea. The incubation period for paratyphoid has 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 had an onset date within 35 days of return from travel.
- 91% had an onset date within 21 days.
Typhoid is one of the most common febrile illnesses seen by practitioners in the developing world. Untreated, the illness usually lasts for three to four weeks, but may be longer. Symptoms vary from mild to severe and life-threatening.
The course of untreated typhoid fever is classically divided into four stages, each lasting about a week. This disease pattern is not commonly seen, with severe disease representing the 'tip of the iceberg' in typhoid, and with the advent of antibiotics altering the course of the disease. For descriptions of the untreated disease the literature relies on historical descriptive accounts by physicians such as Sir William Osler.
- Gradual rise in temperature, typically worse through the day, over the first 2-3 days, typically reaches 40°C (104°F).
- Dry cough.
- Relative bradycardia (Faget's sign): - the pulse is slower than would be expected from the degree of temperature.
- Epistaxis in around a third.
- Abdominal pain.
- Leukopenia with relative lymphocytosis.
- Blood cultures are positive for S. typhi (or S. paratyphi).
- Widal's test is usually negative.
- In this bacteraemic phase it is possible to find bacteria in the reticuloendothelial tissues of the liver, spleen, bone marrow, and gallbladder and Peyer's patches in the terminal ileum. The gallbladder is infected via the liver and infected bile gives positive stool cultures and re-infects the bowel. Gallstones predispose to chronic biliary infection and long-term faecal carriage.
- During the second week the patient has a toxic appearance with apathy and sustained pyrexia.
- High fever around 40°C (104°F), often swinging.
- Malaise and weakness.
- Relative bradycardia, with dicrotic pulse wave.
- Confusional state, which gave typhoid the name of 'nervous fever'.
- Rose spots on the lower chest and abdomen - seen in around one third of Caucasian patients; difficult to see in darker skin. Rose spots are caused by bacterial emboli. They are crops of macules 2-4 mm in diameter that blanch on pressure.
- Lung base rhonchi.
- Abdominal distension with right lower quadrant tenderness and increased borborygmi.
- Diarrhoea, typically green, with a characteristic foul smell, often compared to pea soup.
- Constipation may also occur.
- Hepatosplenomegaly is common.
- Elevated liver transaminases.
- Positive Widal's test.
- By the third week there is considerable weight loss.
- Pyrexia persists and a toxic confusional state may occur.
- Marked abdominal distension develops and liquid, foul, green-yellow diarrhoea is common.
- The patient is weak with a weak pulse and raised respiratory rate.
- 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.
- Complications which are most likely to develop at this stage include:
- Intestinal haemorrhage due to bleeding from congested Peyer's patches.
- Perforation of the distal ileum, frequently fatal. There may be little warning, and peritonitis is a common complication.
- Neuropsychiatric symptoms: muttering, picking at clothes, confusion.
- Metastatic abscesses.
- Dehydration is a significant risk.
- One third develop a macular truncal rash.
- Thrombocytopenia with risk of bleeding.
- Eye complications may occur (usually only with associated systemic illness) including corneal ulcers, uveitis, abscesses (eyelid or orbit), vitreous or retinal haemorrhage, retinal detachment, optic neuritis, extraocular muscle palsies, and orbital thromboses.
- 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.
2-3% of patients infected with typhoid fever may have a low-grade infection. They may not develop any significant symptoms, and then become carriers of the disease.
Symptoms of paratyphoid fever
- Vague chills, sweating, headache, weakness, dry cough, anorexia, sore throat, dizziness, and muscle pains are frequently present before the onset of fever.
- Rising then persistent fever.
- Abdominal pain (in about a third of patients).
- Relative bradycardia.
- Rose spots (in about a third of patients).
- Constipation (more common than diarrhoea).
- Very rarely, neuropsychiatric symptoms.
- Very rarely, epileptiform seizures.
The group of symptoms which most clearly suggests the diagnosis of typhoid fever is:
- Gradually increasing fever with evening exacerbation and morning remission.
- General malaise with headache.
- Furred tongue with red edges and tip.
- Relatively slow pulse (possibly dicrotic).
- Abdominal distension with increased bowel sounds.
- Tenderness in the right iliac fossa on firm pressure.
- A roseolar eruption confined principally to the abdomen and chest.
- Bronchial catarrh.
The differential diagnosis of this group of symptoms will depend on travel history and may include a wide variety of tropical and non-tropical causes of fever and rash. Always consider co-existent malaria or schistosomiasis.
In patients with appropriate travel history malaria remains the most likely cause of febrile illness, although this does not rule out the presence of additional disease. A list of diagnoses to consider in the returning traveller with febrile illness, abdominal pain, neurological symptoms and rashes should include:
- Viral haemorrhagic fever - eg, Ebola.
- Non-typhoid infection with Salmonella spp.
- Scrub typhus.
- Abdominal abscess.
- Yellow fever.
- African trypanosomiasis (sleeping sickness).
- Diagnosis is made by culturing the organism. This 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 (90% isolation rate) is bone marrow aspiration.
- Isolation of S. typhi is highest in the first week and becomes more difficult as time passes.
- The traditional serological test is Widal's test. It measures agglutinating antibodies against flagellar (H) and somatic (O) antigens of S. typhi.
- 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 40-60% 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 was submitted for Cochrane review in 2010.
In non-endemic countries, patients presenting with symptoms suggestive of typhoid or paratyphoid fever 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.
- Rapid diagnosis and institution of appropriate antibiotic treatment.
- Adequate nutrition - a soft, easily digestible diet should be continued unless the patient has abdominal distension or ileus
- 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.
- Close attention to hand washing and limitation of close contact with susceptible individuals during the acute phase of infection.
- Regular follow-up and monitoring for complications and clinical relapse (this may include confirmation of stool clearance in non-endemic areas or in high-risk groups such as food handlers.
- Antibiotics (see below) - shorten the course, reduce the rate of complications if begun early and reduce mortality.
- 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.
- Ideal antibiotic treatment is safe and available in short courses of five days, causes resolution of fever within one week, renders blood and stool cultures sterile, and prevents relapse.
- Azithromycin has been found to meet these criteria better than other drugs, although localised areas of resistance to azithromycin have been reported.
- Ciprofloxacin was the drug of choice for ten years following the emergence of resistance 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 reduced susceptibility to fluoroquinolones.
- Among fluoroquinolones, which are more effective than cephalosporins, gatifloxacin appears more effective than ciprofloxacin and ofloxacin for bacteria showing decreased ciprofloxacin sensitivity.
- Ceftriaxone is a useful second-line drug.
- Chloramphenicol, despite its toxicity for bone marrow and history of plasmid-mediated resistance, is used in developing countries where the organism is sensitive to it.
- The antibiotic is appropriately changed once sensitivities are available.
Uncomplicated typhoid fever
- Empirical treatment if infection is likely to have originated in Asia - azithromycin.
- Multiple-resistant - fluoroquinolone (5-7 days), or cefixime (7-14 days).
- Quinolone-resistant - azithromycin (7 days) or ceftriaxone (10-14 days).
- If the infection is likely to be from Africa, South America or Central America, fluoroquinolones (eg, ciprofloxacin) may still be used (5-7 days). Fewer than 4% of infections imported to the UK from Africa are resistant to fluoroquinolones.
Severe typhoid fever requiring parenteral treatment
- If the origin of infection is likely to be Asia - IV 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 for 10-14 days.
- 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 kidney injury 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 carriers of typhoid
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.
The story of 'Typhoid Mary'
The woman known to history as 'Typhoid Mary' was an Irish immigrant to the USA who worked as a private cook to a series of families in New York. She left behind her a trail of cases of typhoid, some fatal, moving on without leaving a forwarding address when her clients fell ill.
Although pursued by the authorities from 1907 (who wanted to remove her gallbladder as a possible cure for her chronic enteric secretion) she never accepted that she was an infection source, finding the idea that an apparently healthy individual could pose a health risk very difficult to accept.
She is believed to have, eventually, infected over fifty people, of whom three certainly died of the disease. She spent the last few decades of her life in isolation, having refused to voluntarily give up working as a cook.
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 5 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 fever 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 fever, 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 (although it can be much later). This relapse rate is lower with quinolones.
Today mortality is low (<1%); however, in the context of natural and man-made disasters and catastrophes, outbreak mortality rises back to 10-30%, despite antibiotic therapy.
A study of 581 patients hospitalised for typhoid in Vietnam in 2014 found that more severe disease occurred in about 15% including gastrointestinal bleeding (7%), hepatitis (5%), encephalopathy (3%), myocarditis (2%), intestinal perforation (1%), haemodynamic shock (1%) and death (0.5%).
Factors associated with more severe disease were:
- Older age.
- Longer duration of illness.
- Infection with an organism only partially susceptible to ciprofloxacin.
- 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 and 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 Oct62(2):142-50. Epub 2008 Aug 20.
Typhoid and paratyphoid: guidance, data and analysis; Public Health England
Bhan MK, Bahl R, Bhatnagar S; Typhoid and paratyphoid fever. Lancet. 2005 Aug 27-Sep 2366(9487):749-62.
Bhutta ZA; Current concepts in the diagnosis and treatment of typhoid fever, BMJ 2006333:78-82
Bhutta ZA. Current concepts in the diagnosis and treatment of typhoid fever; BMJ : British Medical Journal 2006333(7558):78-82.
Crump JA, Mintz ED; Global trends in typhoid and paratyphoid Fever. Clin Infect Dis. 2010 Jan 1550(2):241-6.
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 Jul9(4):206-12. Epub 2011 Jun 1.
Crump JA, Luby SP, Mintz ED; The global burden of typhoid fever. Bull World Health Organ. 2004 May82(5):346-53.
White NJ: Salmonella typhi (Typhoid Fever) and S. paratyphi (Paratyphoid Fever); Antimicrobe February, 2010
Public Health Operational Guidelines for Typhoid and Paratyphoid (Enteric Fever); Public Health England (February 2012)
Losse H; [Typhoid fever]. Schweiz Rundsch Med Prax. 1990 Aug 2179(34):976-82.
Bridges WO; The Differential Diagnosis of Typhoid Fever, JAMA.1902XXXVIII(20):1300-1302.
Typhoid; World Health Organization
Johnston V, Stockley JM, Dockrell D, et al; Fever in returned travellers presenting in the United Kingdom: recommendations J Infect. 2009 Jul59(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 Oct62(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
Sanchez-Vargas FM, Abu-El-Haija MA, Gomez-Duarte OG; Salmonella infections: an update on epidemiology, management, and prevention. Travel Med Infect Dis. 2011 Nov9(6):263-77. Epub 2011 Nov 25.
Pilot of Enhanced Surveillance of Enteric Fever in England, Wales and Northern Ireland 2006-2007; Health Protection Agency
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.
Butler T; Treatment of typhoid fever in the 21st century: promises and shortcomings. Clin Microbiol Infect. 2011 Jul17(7):959-63. doi: 10.1111/j.1469-0691.2011.03552.x.
Parry CM, Thompson C, Vinh H, et al; Risk factors for the development of severe typhoid fever in Vietnam. BMC Infect Dis. 2014 Feb 1014:73. doi: 10.1186/1471-2334-14-73.