Typhoid and paratyphoid fever

Synonyms: enteric fever

Epidemiology

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.

Typhoid fever

• Is caused by a Gram-negative organism Salmonella enterica subspecies enterica serovar Typhi (Salmonella typhi).

Paratyphoid fever

• 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 1⁴ .

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 illness¹ .

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} .

• The World Health Organization (WHO) estimates that globally 11-20 million people become ill from typhoid annually and between 128,000 and 161,000 people die. Poor sanitation and lack of clean drinking water in rural settings are significant causes. However, urbanisation, with overcrowding and inadequate water and sanitation systems, as well as climate change can further increase the global burden⁷ .

• 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^{8 9} .

• 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'⁸ .

• 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 typhoid⁴ .
  

Typhoid and paratyphoid fever in the UK

In 2017, 306 laboratory-confirmed symptomatic cases of S. typhi and S. paratyphi were
reported by Public Health England in England, Wales and Northern Ireland. This represents a
small (2%) decrease compared to the 313 cases reported in 2016. Cases of S. typhi and S. paratyphi have decreased by an average of 7% year on year since 2011. In 2017, 61% of cases were caused by S. typhi and 39% by S. paratyphi A and B. No cases of S. paratyphi C were reported in 2017. Cases of S. paratyphi B have remained at expected levels after an increase in 2015, which was found to be due to a cluster of cases associated with travel to the Middle East .

Risk factors

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.

Incubation period

• 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.

• 96% of cases of enteric fever had an onset date within 28 days of return from travel.

• 91% had an onset date within 21 days .

Presentation of typhoid fever^{8 10}

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.

Week one

• 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.

• Malaise.

• Headache.

• 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.

Week two

• 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.

Week three

• 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.

  • Encephalitis.

  • Neuropsychiatric symptoms: muttering, picking at clothes, confusion.

  • Metastatic abscesses.

  • Cholecystitis.

  • Endocarditis.

  • Osteitis.

  • 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.

Week four

• 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.

Carrier status

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.

• Hepatosplenomegaly.

• Rose spots (in about a third of patients).

• Constipation (more common than diarrhoea).

• Very rarely, neuropsychiatric symptoms.

• Very rarely, epileptiform seizures.

Differential diagnosis⁴

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.

• Epistaxis.

• 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.

• Splenomegaly.

• 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:

• Malaria.

• Amoebiasis.

• Influenza.

• Tuberculosis.

• Typhus.

• Viral haemorrhagic fever - eg, Ebola.

• Dengue.

• Non-typhoid infection with Salmonella spp.

• Campylobacter.

• Cholera.

• Typhus.

• Scrub typhus.

• Tuberculosis.

• Abdominal abscess.

• Yellow fever.

• African trypanosomiasis (sleeping sickness).

Investigations

Organism culture

Diagnosis is usually made by culture of the organism from faeces, urine or blood. Blood cultures are positive in 61% of cases. Bone marrow culture gives a higher yield, but is not often performed. Faeces, urine, or bile aspirate may be cultured, but a positive result may only indicate chronic faecal carriage rather than acute infection¹¹ .

Serology

The traditional serological test is Widal's test. It measures agglutinating antibodies against flagellar (H) and somatic (O) antigens of S. typhi. It is still used in developing countries because of its low cost, but is no longer considered a useful diagnostic tool to identify acute or recent infection. It has largely been replaced by newer serological methods such as standard immunoblotting and ELISA techniques .

Management

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.

General principles for the management of typhoid^{3 4 11}

• 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 mortality¹² .

• 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.

Antibiotic treatment of typhoid fever^{13 14 15 16 17}

• 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.

• Current national guidelines or local formularies should be consulted for the selection of antimicrobial based on regional susceptibility patterns.

• Drug resistance is a major problem. Older drugs such as chloramphenicol, ampicillin and trimethoprim have been replaced by fluoroquinolones, but these too have become less effective as resistance develops in South Asia and increasingly in Africa. Currently, extended spectrum cephalosporins, oral cefixime, parenteral ceftriaxone, and oral azithromycin are recommended options, with parenteral meropenem reserved as a last resort.

• The antibiotic is appropriately changed once sensitivities are available.

• Antibiotic treatment durations of 7-14 days or 5 days after fever resolution, whichever is longer, have traditionally been used. Patients on IV antibiotics can be switched to oral preparations as soon as clinically stable¹¹ .

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.

Complications

• 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 ¹¹

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 used¹⁴ . (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 from them 48 hours apart need to be negative before they are no longer considered to be at risk of passing on the infection.

Risk groups

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.

Co-travellers

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.

Non-travelling contacts

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.

Prognosis

In the days before antibiotics, mortality was 20%. The overall current mortality rate is less than 1% due to advances in treatment and the development of antibiotics. Early diagnosis and treatment avoids complications. In untreated patients, approximately 10% will relapse, and 4% will become chronic carriers¹⁰ .

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%)¹⁸ .

Factors associated with more severe disease were:

• Older age.

• Longer duration of illness.

• Infection with an organism only partially susceptible to ciprofloxacin.

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).

Dr Mary Lowth is an author or the original author of this leaflet.