Typhoid fever is an infectious life-threatening disease of the digestive tract, and is still common where sanitation standards are low. Better prevention can reduce spreading of the disease, but new antibiotics and vaccines are needed. Genomic and proteomic research could provide better understanding of the disease.
Typhoid fever is a life-threatening infectious disease of the digestive tract caused by the bacterium Salmonella typhi. The disease lasts several weeks and convalescence takes some time. The incubation period is 10 to 20 days, depending on how large a dose of bacteria has been taken up. In the mild form, the pathogen is eliminated very early in the course of the infection and there are perhaps only mild symptoms.
S. typhi lives only in humans. Typhoid fever is acquired if a person ingests food or beverages that have been handled by a person who is shedding the bacteria. A small number of individuals recover from typhoid fever but continue to carry the bacteria. Both patients and carriers shed S. typhi in their stools. In many countries, people who have suffered from typhoid fever and who handle food or care for small children may be barred legally from going back to work until it has been determined that they no longer carry the bacteria. Another source of infection is sewage contaminated with S. typhi, which gets into the water used for drinking or washing food.
Classic typhoid fever has two phases. Once S. typhi has been ingested, it multiplies and spreads into the bloodstream. The body reacts with sustained fever as high as 40°C and the individual’s general condition becomes poor. People feel weak, vomit or have stomach pains, complain of headache, or loss of appetite. In some patients a rash of flat, rose-coloured spots appears. The bacterium penetrates further to the bone marrow, liver and bile ducts, from which it is excreted into the bowel contents. The diagnosis is confirmed by testing samples of stool or blood for the presence of S. typhi. The first phase lasts a week and towards the end the patient shows increasing listlessness and clouding of consciousness.
In the second phase, the pathogen penetrates the immune tissue of the small intestine, and the often violent small-bowel symptoms begin. In the second to third weeks of the disease, there are symptoms of intestinal infection, while the body temperature remains high. In the third week, the constipation is replaced by severe diarrhoea. The stools may also contain blood. It is not until the fourth or fifth week that the fever drops and the patient’s general condition slowly improves.
If appropriate antibiotic therapy starts in time, recovery begins within two to three days, and deaths rarely occur. However, if patients do not get treatment, as many as 20 per cent may die from complications of the infection. Typhoid fever has claimed the lives of several famous people, including Franz Schubert, Wilbur Wright, and the British prince consort Albert of Saxe-Coburg-Gotha.
Typhoid fever is still common in parts of the world where sanitation standards are low and water is likely to be contaminated with sewage. It is therefore mainly hygiene and sanitary conditions that determine its spread. In the developing world, it affects about 21.5 million people of all ages each year. In endemic areas, children aged one to five years are at the highest risk because of waning passively acquired maternal antibody and lack of immunity. In 2000, it was estimated that typhoid fever caused 220,000 deaths worldwide.
In industrialised regions such as the USA, Canada, Western Europe, Australia, and Japan, the incidence is low. In Europe and the USA, about 500 cases occur each year. Most of them are acquired while travelling abroad.
For severe cases, treatment requires admission to hospital and loss of fluid and salt is treated with fluid therapy as appropriate. Within the hospital setting, infected people are cared for in isolation. Timely therapy with antibiotics is crucial. Commonly prescribed medicines are either a penicillin compound, or a combination product of a sulphonamide plus diaminopyrimidine or an antibiotic of the gyrase-inhibitor type.
For prevention, two types of typhoid vaccine are available: (i) a live-attenuated oral preparation which consists of four doses. Every second day a capsule is swallowed. The vaccine needs two weeks to take effect; (ii) an intramuscularly injectable vaccine based on capsular polysaccharide which is easy to administer, since it only requires one dose. Typhoid vaccines lose effectiveness after several years. After oral immunisation, a booster is needed every five years. For the injectable form, a booster is recommended every three years. In endemic countries, the most effective strategy for reducing the incidence of typhoid fever is the institution of public health measures to ensure safe drinking water and sanitary disposal of excreta. These long-term measures reduce also the incidence of other enteric infections.
As resistance of bacteria to antibiotic medicines such as penicillin and the combination of sulphonamide/diaminopyrimidine is rising, clinical investigators are studying the effectiveness of other compounds, i.e. third generation cephalosporins, newly developed gyrase-inhibitors and macrolides in paediatric typhoid fever. As macrolides can be given orally, such formulations could provide an alternative for treatment of typhoid fever in children in developing countries, where medical resources are scarce.
Scientist are pursuing several vaccine projects to offer rapid, single-dose protection against typhoid fever. One oral vaccine is being tested in a phase 1 dose-ranging clinical trial to demonstrate safety and immunogenicity in humans. Other researchers are studying the immunisation of healthy volunteers with new oral attenuated S. typhi vaccine strains harbouring defined combined aroC and type III secretion mutations.
A third oral vaccine formulation has just completed phase 2 clinical evaluation using a simplified dosing regimen. The new formulation allows immediate administration after reconstitution in tap water. The vaccine primes both the mucosal immune system, the body’s first line of defence, as well as the systemic immune system. This is essential for a successful single dose approach. The problem with injected vaccines is that they generally elicit a systemic response, but only a low mucosal immune response.
Another typhoid vaccine candidate has to date been evaluated in three phase ½ clinical studies. The studies indicate that the vaccine is highly immunogenic, at a single dose, with a good safety profile. The clinical phase 3 development programme is now directed at obtaining efficacy data in areas endemic for typhoid fever. Children will form a key element of this efficacy study.
Researchers are investigating the complex interplay between immune cells and the mucosal barrier that interfaces with the intestine and its contents. Examples are the antigen-presenting dendritic cells that reside below the intestinal lining. The cells are regulated in their phagocytic activity by a specific chemokine receptor, CX3CR1. Loss of these activities in the absence of CX3CR1 correlates with increased susceptibility to bacteria suggesting a link between trans-epithelial sampling of antigen by dendritic cells and immune-mediated protection of the intestinal mucosa.
It has also been found, that a protein known as cystic fibrosis trans-membrane conductance regulator (CFTR) acts as a receptor for S. typhi. Cystic fibrosis (CF) develops in children who inherit two mutant copies – one from each parent – of the gene that encodes CFTR. Abnormal CFTR blocks the movement of chloride ions and water in the lungs and the digestive tract and causes the cells lining the organs to secrete sticky mucus. Since abnormal CFTR binds poorly to S. typhi, CF gene carriers would be protected from this infectious process. It is speculated that this finding could be useful in vaccine research, particularly in ongoing efforts to develop S. typhi-based vaccine delivery vehicles.
For better understanding of the molecular pathogenesis of typhoid fever, genomic and proteomic studies will reveal the possibility of new targets for diagnosis and treatment. But the importance of safe water, sanitation, and immunisation of people at risk remains paramount.