Typhoid is not a new disease, but remains a significant cause of morbidity and mortality in low- and middle-income countries. It is a bacterial infection passed from human to human through the consumption of food or water contaminated with fecal material from an infected individual. Typhoid disproportionately affects young children and adolescents aged 2 to 15 years in areas with poor access to clean water, sanitation and hygiene. Since typhoid only infects humans and there is no animal or environmental reservoir, we have every reason to believe that death and illness caused by typhoid can be reduced through an integrated prevention and treatment strategy including vaccines, dependable typhoid diagnostics, appropriate antibiotics, and improvements in clean water, sanitation and hygiene.
The disease: past and present
Typhoid has been common globally throughout history. Only in the beginning of the 20th century did we start making strides against typhoid in certain countries. The first vaccine was introduced in 1896 and its administration to the military had a significant impact on the number of wartime disease-related deaths. Antibiotics and improvements in water and sanitation, including the chlorination of drinking water, also helped stop the spread of typhoid.
Currently, typhoid is quite rare in North America and Western European unless associated with travel to endemic areas. Across much of Asia, Africa, and parts of South America and Oceania, the story is very different. Current estimates indicate that each year there are nearly 12 million cases and over 128,000 deaths attributable to typhoid, but these numbers are likely underestimates due to difficulties in surveillance and diagnostic challenges. In recent years, the number of cases is decreasing in Asia as water, sanitation and healthcare infrastructure are improving. There is less information available on the burden in Africa and South America. Typhoid is now one of the most common causes of fever as malaria is declining. Reliable data on typhoid incidence are scarce due to reporting issues and difficulty in correct diagnosis based on non-specific symptoms.
Typhoid causes a diverse range of clinical symptoms which start manifesting as early as four days following exposure. The most common symptom is a high fever. Various other symptoms may be reported, including abdominal pain, headache, diarrhea, constipation, loss of appetite, chills, fatigue, joint pain, coughing, vomiting, and rapid pulse. Rose spots on the chest are specific to typhoid, but only appear in some cases. Given that most of the symptoms are non-specific, typhoid is often misdiagnosed. Typhoid is often confused for other infectious fevers including malaria, tuberculosis, Dengue fever, and brucellosis.
Since typhoid cannot usually be identified purely by clinical symptoms, definitive diagnosis relies on laboratory analysis. Misdiagnosis leads to ineffective treatment and either inappropriate or delayed administration of antibiotics. Accurate diagnostic techniques will ensure that typhoid patients get the appropriate antibiotic treatment.
Current diagnostics, however, lack speed, sensitivity, and accuracy. The gold standard for diagnosing typhoid involves isolating the causative bacteria from the patient and growing it in a clinical laboratory. However, microbial culture facilities are not always available and bacterial growth and antibiotic sensitivity testing can take several days. Even when laboratory culture testing is possible, the bacterial level in blood is usually very low, making it difficult to recover: 10 to 70 percent of blood culture results from typhoid patients are false-negatives. Bone marrow often has a higher bacterial load, but acquiring bone marrow is painful and only undertaken in special circumstances. Another common method for diagnosing typhoid is the Widal test, which was developed over a century ago. This is performed on patient blood serum and detects antibodies produced by the patient’s immune system to recognize surface structures of the bacteria. Interpreting Widal test results is difficult in endemic areas where patients may be positive for typhoid-specific antibodies due to past exposure and not a current acute infection. Widal tests are known for high false-positive and false-negative rates. New diagnostics are under development that involve more sensitive serum tests and detection of bacteria in the blood using polymerase chain reaction.
Treatment, outcome, and chronic carriage
With appropriate antibiotics, the recovery rate from typhoid is very high. The first-line treatments of typhoid are traditionally chloramphenicol, ampicillin, or trimethoprim-sulfamethoxazole. With the rise of multidrug resistant (MDR) strains in the 1990s, alternative treatments have included fluoroquinolones, third-generation cephalosporins, and azithromycin. If untreated, typhoid can progress to complications such as intestinal perforation and even death, which occurs in about one percent of typhoid patients. If drug resistance increases, treatment of typhoid with antibiotics will no longer be an effective option.
In some cases, patients recover from the illness, but continue to harbour the bacteria as asymptomatic chronic carriers. This occurs in one to four percent of patients and is of great public health concern because carriers continue to shed the bacteria in their feces, which can spread the disease to others. The most famous typhoid carrier is Mary Mallon (“Typhoid Mary”) who was a cook in New York in the 1900s and infected many others. A risk factor for carriage is gallstones and the residual bacterial infection is often located in the gallbladder. Once carriage is identified, high doses of antibiotics or surgical removal of the gallbladder can resolve the infection.
The bacterial cause: Salmonella Typhi
Typhoid is caused by the bacteria Salmonella Typhi (official name: Salmonella enterica subspecies enterica, serovar Typhi). Salmonella are Gram negative rod-shaped bacteria belonging to the enterobacteriaceae family that also includes E. coli and Shigella. Salmonella includes many different subtypes that vary in terms of host range and the intensity of the disease they induce. Many Salmonella are able to infect a wide range of animals and cause self-limiting gastroenteritis and diarrhea. These are called non-typhoidal Salmonella and are sometimes responsible for food poisoning outbreaks. S. Typhi and Paratyphi A, however, have evolved into specialized strains capable of causing severe disease, but are limited to a single host – humans. The fact that these bacteria are host-restricted has important implications for disease management. Since S. Typhi has a poor survival rate outside the host, if we were able to prevent infections in humans with vaccines and improvements to water, sanitation, and hygiene, we could effectively eliminate S. Typhi as we have done for other pathogens with narrow host ranges such as polio.
S. Typhi is shed in the stool by infected humans. In areas without sewers or water sanitation, fecal matter can be present in the water which is then consumed by others. After the S. Typhi enters the digestive system, it passes to the gut where it crosses the intestinal barrier and is disseminated throughout the body. S. Typhi is taken up by macrophage cells of the immune system, but it remains in “stealth mode” by avoiding activation of the inflammatory response. One way that S. Typhi evades detection by the immune system is by producing a Vi-polysaccharide coat. S. Typhi also produces a toxin protein which is thought to be responsible for some of the symptoms of typhoid.
S. Paratyphi A also specifically infects humans, disseminates throughout the body and causes severe symptoms. Importantly, S. Paratyphi A does not encode Vi and many questions remain concerning the pathogenesis of paratyphoid.
Paratyphoid is indistinguishable from typhoid based on symptoms. It is caused by the genetically similar bacteria, S. Paratyphi A, and can only be distinguished by culture or serum diagnostics. It is estimated that there are 5.4 million cases of paratyphoid per year. In some regions, such as China and Nepal, the number of paratyphoid cases can exceed typhoid. It is a severe disease and no vaccines are currently available.
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