Introduction

Typhoid fever refers to the systemic illness caused by the Salmonella typhi strain of the Salmonella enterica bacterium. Along with the Salmonella paratyphi A, B, and C strains of Salmonella enterica, these organisms collectively cause an illness known as enteric fever. Because the illnesses caused by Salmonella typhi and paratyphi bacteria are clinically identical, for this article, both terms are used interchangeably.¹

According to 2019 statistics from the World Health Organisation, there were 9.2 million annual cases of enteric fever, responsible for 110,000 deaths. The disease is endemic (always present) in many developing nations, particularly in Africa, South and Southeast Asia, where it predominantly affects children and young adults. Spread of the disease is by the faeco-oral route and proliferates as a consequence of contaminated water supplies, poor sanitation and inadequate hygiene, being particularly prevalent in countries lacking the infrastructure to provide clean water and adequate sanitation.² In developed nations, cases of enteric fever are largely seen in those returning from travel to an endemic area. 

Although the clinical features of enteric fever are well documented, there is a substantial amount of research demonstrating the unreliability of clinical symptoms in diagnosis, particularly in distinguishing it from other causes of systemic illness with fever. Confirmation of the diagnosis with either blood or bone marrow culture is traditionally considered the “gold-standard”, however if only a single blood sample is used (as is often the case in countries with more limited resources) rates of detection are only around 50-66%, additionally culture tests take time to yield a result. Bone marrow culture is rarely used due to the degree of invasiveness.³ There have been recent advances in immunological tests which provide a rapid and low-cost diagnostic option, however, the results are affected by previous infection with enteric fever and infection with other Salmonella species.² Other testing methods, such as polymerase chain reaction (PCR), are employed in high-income countries but are generally unavailable in developing nations due to cost and availability.³

Nevertheless, awareness of the clinical presentation of enteric fever is important to instigate prompt treatment with antibiotics which may help reduce the incidence of complications such as intestinal perforation. Although antibiotics can be used to treat enteric fever, there is a worrying worldwide rise in multidrug-resistant and extensively drug-resistant strains, with an estimated 2.5 million cases of multidrug-resistant Salmonella typhi infections worldwide.⁴

Clinical presentation of typhoid fever

Clinical signs of infection begin after an incubation period, which typically lasts 10-14 days (range 6-30 days). Initially, the bacteria are ingested and make their way to the small intestine, where they invade the cells in the terminal section of the small bowel by a variety of mechanisms, including invading the M cells overlying the Peyer’s patches (collections of lymphoid tissue involved in the gut’s immune response to pathogens). This is followed by the next phase of infection, called intracellular dissemination, where the bacteria spread throughout the body by living within the body’s immune cells such as macrophages, dendritic cells and phagocytes - at this stage, symptoms are yet to develop. The clinical illness develops as bacteria begin to build up in the bloodstream (bacteraemia) and thus spread to other organs, and the gallbladder is colonised. Peyer’s patches become a reservoir for infection and transmission of infection via the faeces. The release of bacterial toxins (endotoxins) can lead to damage to the gut, resulting in bleeding or even perforation and peritonitis.⁵

The clinical illness develops insidiously and may be characterised by the following symptoms:^1,6

• Fever - Typically 38-40 degrees C. Generally increasing in a stepwise manner, reaching its peak by day 3-4 of the illness.
• Chills
• Headache 
• Anorexia - loss of appetite
• Abdominal discomfort- generally diffuse discomfort, more localised or severe discomfort may indicate a complication such as perforation of the bowel
• Vomiting
• Diarrhoea - may be mild or severe, may or may not contain blood
• Constipation
• Upper respiratory symptoms such as cough and sore throat
• Malaise - tends to worsen in a stepwise manner over the first 3-4 days
• Myalgia - muscle aches and pains

Travel/ exposure history in typhoid fever

In suspected cases of enteric fever in developed countries, a travel history should be taken to ascertain the following information:^7,12

• Has the person travelled to or been normally resident in an area in which enteric fever is endemic, within the previous 30 days?
• Has there been any activity presenting an increased risk, e.g., drinking potentially contaminated water, eating undercooked or poorly prepared food, poor accommodation, or medical care abroad?
• The nature of the travel, e.g., vacation (resort), visiting friends and relatives, work (and nature of work), immigration from an endemic area
• Were other members of the household they visited or travelling companions also unwell?

Physical examination findings

In addition to the generalised and abdominal symptoms listed above, there are several physical findings which are variably present in typhoid fever. Certain physical findings, such as the presence of signs of sepsis and shock, are dependent on the severity of the illness. Others, such as dehydration due to diarrhoea and neurological symptoms including febrile seizures, are more likely to occur in children. Physical findings specific to enteric fever, such as Rose spots (a rash found in enteric fever), are not consistently present (found in only 25% of patients). The following are potential physical findings in enteric fever:^1,6,8

• Pallor, lethargy, clinical signs of dehydration, eg, sunken eyes, poor urine output, dry mouth and mucous membranes, sunken fontanelle in infants, reduced skin turgor, delayed capillary refill (the time it takes for colour to return to skin after it blanches under pressure)
• Signs of sepsis in severe cases - rapid thready pulse, low blood pressure, rapid shallow breathing, cold, poorly perfused extremities
• Fever > 38°C
• Rose spots- a rash consisting of small red flat, and slightly raised spots between 2-4mm in size (N.B., this is difficult to see in darker skin tones). Present in about 25% of patients.
• Haepatomegaly (enlargement of the liver), splenomegaly (enlargement of the spleen), or both (haepatosplenomegaly) - present in 29-50% of patients
• Jaundice
• Relative bradycardia or bradycardia, whilst not present in all patients a reduced heart rate or a heart rate lower than would be expected due to infection and sepsis
• Diffuse abdominal tenderness was noted on examination of the abdomen. The findings of guarding (sudden tensing of the abdominal muscles when pushing down over the abdomen) or rebound tenderness on abdominal examination are indicative of a complication such as bowel perforation or intestinal bleeding.
• Occasionally, if there is cardiac or pulmonary involvement, signs may be found in the lungs or heart, such as a cardiac rub in myocarditis (inflammation of the heart) or crackles heard in the chest in pneumonitis. Both are rare
• Abnormalities of the blood on checking complete blood count : Anaemia (low red blood cells), leukopenia (low white blood cells) and thrombocytopenia (low levels of platelets - the cell fragments that help blood to clot)

Complications of typhoid fever

Complications of typhoid fever generally occur some time after the initial illness has developed and are more frequent in cases not treated with antibiotics. Usually occurring 2-3 weeks after the initial onset of the illness, complications are found in about 26% of confirmed cases. Specific symptoms may be associated with these complications.⁹

Gastrointestinal complications

Gastrointestinal complications of typhoid fever include the following:⁹

• Severe diarrhoea - this may lead to dehydration and is a more common finding in children. Profuse diarrhoea is also associated with typhoid fever infections in patients with HIV
• Hepatitis (with or without jaundice) - Hepatitis is particularly common in children under the age of 5, with one study finding hepatitis in 36% of hospitalised children in this age group²
• Perforation of the small bowel - perforation of the bowel is usually the result of necrosis (death of tissue) in the Peyer’s patches at the terminal end of the small bowel. If it occurs, more severe abdominal pain, sepsis and signs of peritonitis (inflammation of the abdominal lining) may occur. Treatment involves antibiotics and surgery to repair the bowel. Perforation is more common over the age of 15, and recorded rates of perforation vary by region, with rates in Africa as high as 7.6%. The overall rate of perforation is around 1.6%. Perforation is a particularly important complication as it carries a high rate of mortality⁹

Neurological complications

Neurological complications are more common in children, occurring in around 25% of children hospitalised for typhoid fever. They include:^2,10

• Delirium (confusion caused by acute illness)
• Febrile seizures (fits brought about by high temperatures)
• Encephalopathy (inflammation of the brain)
• Psychosis (a psychiatric condition where the person struggles to distinguish reality)
• Ataxia (difficulties with movement)
• Muscle rigidity

Other complications

Complications involving the haematological system are the most common after gastrointestinal and neurological complications, with anaemia occurring in around 20% of hospitalised patients. Other blood abnormalities that may occur are low white cell and platelet levels. Disseminated intravascular coagulation (DIC) is a condition caused by disordered blood clotting pathways in which small clots form in the blood vessels, leading to depletion of blood clotting factors and abnormal bleeding As a result, it is a rare complication of typhoid fever. Blood clots in DIC can lead to multi-organ failure, which can be rapidly fatal.¹¹

Cardiovascular and respiratory complications of typhoid fever include inflammation of the heart muscle (myocarditis) and focal lung infections, including pneumonia and lung abscesses.¹¹

Osteomyelitis (infection of the bone) is almost exclusively found in patients who have sickle cell anaemia. Other rare complications include focal abscesses, which may be found in the soft tissues and the spleen and inappropriate secretion of ADH (antidiuretic hormone).¹¹

Differential diagnosis

The main difficulties faced by clinicians attempting to diagnose typhoid fever based on symptoms are the lack of specificity of many of the symptoms, such as fever and malaise and the finding that many of the traditionally taught symptoms of typhoid fever, such as cough and constipation, are frequently absent in laboratory-confirmed cases. One large study of laboratory-confirmed cases of enteric fever in Pakistan, Nepal, and Bangladesh found these signs to be frequently absent and concluded that clinical symptoms alone were a poor predictor of enteric fever infection. This is made more difficult by the presence of many other endemic causes of febrile illness in geographical areas where enteric fever is prevalent. The differential diagnosis of enteric fever is wide and includes bacterial and amoebic disease and viral illnesses. 

The following diseases should also be considered in the differential diagnosis in areas where these diseases are endemic, this also applies to travellers returning from these areas:^1,12

Bacterial / Amoebic disease:

• Malaria
• Bacterial Meningitis
• Amoebiasis
• Leptospirosis
• Scrub and Murine Typhus
• Brucellosis
• Bacterial Gastroenteritis (e.g Salmonella)

Viral disease

• COVID-19
• Influenza
• Viral Hepatitis
• Chikungunya
• Viral Meningitis
• Yellow Fever
• ‘Dengue Fever

Summary

Typhoid fever is caused by the Salmonella typhi bacteria. Along with illnesses caused by the closely related Salmonella paratyphi bacteria, these diseases are collectively referred to as enteric fever. Enteric fever is common in parts of the world with an infrastructure leading to a lack of clean water and adequate sanitation, such as sub-Saharan Africa and South and Southeast Asia, where enteric fever is endemic. 

Typhoid fever is a systemic illness characterised by a high fever, abdominal pain, diarrhoea or constipation, headache and malaise. Specific clinical signs include rose spots, high fever, jaundice and enlargement of the liver and spleen, however, these signs are not consistently present. Clinical research into the symptoms of laboratory-confirmed cases of typhoid fever reveals that many of the “textbook symptoms” of typhoid fever are frequently absent, making diagnosis on a clinical basis a difficult proposition. The “gold-standard” test is a positive blood or bone marrow culture for Salmonella typhi, however, facilities for testing in countries where typhoid fever is endemic may be lacking. This emphasises the need for rapid, reliable testing methods in the future. In developed countries, a comprehensive travel and exposure history is important to raise suspicion of the diagnosis.

Because of the variability and lack of specificity of symptoms in typhoid fever, there is a wide differential diagnosis of other causes of febrile systemic illnesses that also need to be considered, many of which are also endemic to parts of the world where typhoid fever is prevalent. This includes malaria, meningitis, yellow fever, bacterial food poisoning, dengue fever and influenza.