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Typhoid fever

Typhoid fever, also known as typhoid, is an orally contracted disease caused by Salmonella enterica serotype Typhi bacteria, also called Salmonella Typhi. Symptoms vary from mild to severe, and usually begin six to 30 days after exposure. Often there is a gradual onset of a high fever over several days. This is commonly accompanied by weakness, abdominal pain, constipation, headaches, and mild vomiting. Some people develop a skin rash with rose colored spots. In severe cases, people may experience confusion. Without treatment, symptoms may last weeks or months. Diarrhea may be severe, but is uncommon. Other people may carry it without being affected, but are still contagious. Typhoid fever is a type of enteric fever, along with paratyphoid fever. Salmonella enterica Typhi is believed to infect and replicate only within humans.

Signs and symptoms
Classically, the progression of untreated typhoid fever has three distinct stages, each lasting about a week. Over the course of these stages, the patient becomes exhausted and emaciated. • In the first week, the body temperature rises slowly, and fever fluctuations are seen with relative bradycardia (Faget sign), malaise, headache, and cough. A bloody nose (epistaxis) is seen in a quarter of cases, and abdominal pain is also possible. A decrease in the number of circulating white blood cells (leukopenia) occurs with eosinopenia and relative lymphocytosis; blood cultures are positive for S. enterica subsp. enterica serovar Typhi. The Widal test is usually negative. • In the second week, the person is often too tired to get up, with high fever in plateau around and bradycardia (sphygmothermic dissociation or Faget sign), classically with a dicrotic pulse wave. Delirium can occur, where the patient is often calm, but sometimes becomes agitated. This delirium has given typhoid the nickname "nervous fever". Rose spots appear on the lower chest and abdomen in around a third of patients. Rhonchi (rattling breathing sounds) are heard in the base of the lungs. The abdomen is distended and painful in the right lower quadrant, where a rumbling sound can be heard. Diarrhea can occur in this stage, but constipation is also common. The spleen and liver are enlarged (hepatosplenomegaly) and tender, and liver transaminases are elevated. The Widal test is strongly positive, with antiO and antiH antibodies. Blood cultures are sometimes still positive. • In the third week of typhoid fever, possible complications include: • The fever is still very high and oscillates very little over 24 hours. Dehydration ensues along with malnutrition, and the patient is delirious. A third of affected people develop a macular rash on the trunk. • Intestinal haemorrhage due to bleeding in congested Peyer's patches occurs; this can be very serious but is usually not fatal. • Intestinal perforation in the distal ileum is a critical complication and often fatal. It may occur without alarming symptoms until sepsis or diffuse peritonitis sets in. • Respiratory diseases such as pneumonia and acute bronchitisEncephalitis • Neuropsychiatric symptoms (described as "muttering delirium" or "coma vigil"), with picking at bedclothes or imaginary objects. • Metastatic abscesses, cholecystitis, endocarditis, and osteitis. • Low platelet count (thrombocytopenia) is sometimes seen. ==Causes==
Causes
(center) Bacteria The Gram-negative bacterium that causes typhoid fever is Salmonella enterica subsp. enterica serovar Typhi. Based on the MLST subtyping scheme, the two main sequence types of the S. Typhi are ST1 and ST2, which are widespread globally. Global phylogeographical analysis showed dominance of a haplotype 58 (H58), which probably originated in India during the late 1980s and is now spreading through the world with multi-drug resistance. A more detailed genotyping scheme was reported in 2016 and is now widely used. This scheme reclassified the nomenclature of H58 to genotype 4.3.1. Transmission Unlike other strains of Salmonella, humans are the only known typhoid carriers. An asymptomatic human carrier is someone who is still excreting typhoid bacteria in stool a year after the acute stage of the infection. == Diagnosis ==
Diagnosis
Diagnosis is made by any blood, bone marrow, or stool cultures and with the Widal test (demonstration of antibodies against Salmonella antigens O-somatic and H-flagellar). In epidemics and less wealthy countries, after excluding malaria, dysentery, or pneumonia, a therapeutic trial time with chloramphenicol is generally undertaken while awaiting the results of the Widal test and blood and stool cultures. Widal test The Widal test is used to identify specific antibodies in the serum of people with typhoid by using antigen-antibody interactions. In this test, the serum is mixed with a dead bacterial suspension of Salmonella with specific antigens. If the patient's serum contains antibodies against those antigens, they get attached to them, forming clumps. If clumping does not occur, the test is negative. The Widal test is time-consuming and prone to significant false positives. It may also be falsely negative in recently infected people. But unlike the Typhidot test, the Widal test quantifies the specimen with titres. Rapid diagnostic tests Rapid diagnostic tests such as Tubex, Typhidot, and Test-It have shown moderate diagnostic accuracy. Typhidot Typhidot is based on the presence of specific IgM and IgG antibodies to a specific 50Kd OMP antigen. This test is carried out on a cellulose nitrate membrane where a specific S. typhi outer membrane protein is attached as fixed test lines. It separately identifies IgM and IgG antibodies. IgM shows recent infection; IgG signifies remote infection.The sample pad of this kit contains colloidal gold-anti-human IgG or gold-anti-human IgM. If the sample contains IgG and IgM antibodies against those antigens, they will react and turn red. The typhidot test becomes positive within 2–3 days of infection. Tubex test The Tubex test contains two types of particles: brown magnetic particles coated with antigen and blue indicator particles coated with O9 antibody. During the test, if antibodies are present in the serum, they will attach to the brown magnetic particles and settle at the base, while the blue indicator particles remain in the solution, producing a blue color, which means the test is positive. If the serum does not have an antibody in it, the blue particles attach to the brown particles and settle at the bottom, producing a colorless solution, which means the test is negative. == Prevention ==
Prevention
at a school in San Augustine County, Texas, 1943 Sanitation and hygiene are important to prevent typhoid. It can spread only in environments where human feces can come into contact with food or drinking water. Careful food preparation and washing of hands are crucial to prevent typhoid. Industrialization contributed greatly to the elimination of typhoid fever, as it eliminated the public health hazards associated with having horse manure in public streets, which led to a large number of flies, which are vectors of many pathogens, including Salmonella spp. According to statistics from the U.S. Centers for Disease Control and Prevention, the chlorination of drinking water has led to dramatic decreases in the transmission of typhoid fever. Vaccination Two typhoid vaccines are licensed for use in the prevention of typhoid: To help decrease rates of typhoid fever in developing nations, the World Health Organization (WHO) endorsed the use of a vaccination program starting in 1999. Vaccination has proven effective at controlling outbreaks in high-incidence areas and is also very cost-effective: prices are normally less than US$1 per dose. Because the price is low, poverty-stricken communities are more willing to take advantage of the vaccinations. Although vaccination programs for typhoid have proven effective, they alone cannot eliminate typhoid fever. Results of a phase 3 trial of typhoid conjugate vaccine (TCV) in December 2019 reported 81% fewer cases among children. == Treatment ==
Treatment
Treatment for typhoid fever is most effective if started early. Oral rehydration therapy The rediscovery of oral rehydration therapy in the 1960s provided a simple way to prevent many of the deaths of diarrheal diseases in general. Antibiotics Where resistance is uncommon, the treatment of choice is a fluoroquinolone such as ciprofloxacin. Otherwise, a third-generation cephalosporin such as ceftriaxone or cefotaxime is the first choice. Cefixime is a suitable oral alternative. Properly treated, typhoid fever is not fatal in most cases. Antibiotics such as ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, amoxicillin, and ciprofloxacin have been commonly used to treat it. Treatment with antibiotics reduces the case-fatality rate to about 1%. Without treatment, some patients develop sustained fever, bradycardia, hepatosplenomegaly, abdominal symptoms, and occasionally pneumonia. In white-skinned patients, pink spots, which fade on pressure, appear on the skin of the trunk in up to 20% of cases. In the third week, untreated cases may develop gastrointestinal and cerebral complications, which may prove fatal in 10–20% of cases. The highest case fatality rates are reported in children under 4. Around 2–5% of those who contract typhoid fever become chronic carriers, as bacteria persist in the biliary tract after symptoms have resolved. Surgery Surgery is usually indicated if intestinal perforation occurs. One study found a 30-day mortality rate of 9% (8/88), and surgical site infections at 67% (59/88), with the disease burden borne predominantly by low-resource countries. For surgical treatment, most surgeons prefer simple closure of the perforation with drainage of the peritoneum. Small bowel resection is indicated for patients with multiple perforations. If antibiotic treatment fails to eradicate the hepatobiliary carriage, the gallbladder should be resected. Cholecystectomy is sometimes successful, especially in patients with gallstones, but is not always successful in eradicating the carrier state because of persisting hepatic infection. Typhoid resistant to these agents is known as multidrug-resistant typhoid. Ciprofloxacin resistance is an increasing problem, especially in the Indian subcontinent and Southeast Asia. Many centres are shifting from ciprofloxacin to ceftriaxone as the first line for treating suspected typhoid originating in South America, India, Pakistan, Bangladesh, Thailand, or Vietnam. Also, it has been suggested that azithromycin is better at treating resistant typhoid than both fluoroquinolone drugs and ceftriaxone. A separate problem exists with laboratory testing for reduced susceptibility to ciprofloxacin; current recommendations are that isolates should be tested simultaneously against ciprofloxacin (CIP) and against nalidixic acid (NAL), that isolates sensitive to both CIP and NAL should be reported as "sensitive to ciprofloxacin", and that isolates sensitive to CIP but not to NAL should be reported as "reduced sensitivity to ciprofloxacin". But an analysis of 271 isolates found that around 18% of isolates with reduced susceptibility to fluoroquinolones, the class to which CIP belongs (MIC 0.125–1.0 mg/L), would not be detected by this method. == Epidemiology ==
Epidemiology
In 2000, typhoid fever caused an estimated 21.7 million illnesses and 217,000 deaths. In 2013, it resulted in about 161,000 deaths – down from 181,000 in 1990. Outbreaks are also often reported in sub-Saharan Africa and Southeast Asia. In 2000, more than 90% of morbidity and mortality due to typhoid fever occurred in Asia. In the U.S., about 400 cases occur each year, 75% of which are acquired while traveling internationally. Before the antibiotic era, the case fatality rate of typhoid fever was 10–20%. Today, with prompt treatment, it is less than 1%, but 3–5% of people who are infected develop a chronic infection in the gall bladder. Since S. enterica subsp. enterica serovar Typhi is human-restricted, these chronic carriers become the crucial reservoir, which can persist for decades for further spread of the disease, further complicating its identification and treatment. Lately, the study of S. enterica subsp. enterica serovar Typhi associated with a large outbreak and a carrier at the genome level provides new insight into the pathogenesis of the pathogen. In industrialized nations, water sanitation and food handling improvements have reduced the number of typhoid cases. Third world nations have the highest rates. People in these areas often lack access to clean water, proper sanitation systems, and proper healthcare facilities. In these areas, such access to basic public-health needs is not expected in the near future. In 2004–2005, an outbreak in the Democratic Republic of Congo resulted in more than 42,000 cases and 214 deaths. In Europe, a report based on data for 2017 retrieved from The European Surveillance System (TESSy) on the distribution of confirmed typhoid and paratyphoid fever cases found that 22 EU/EEA countries reported a total of 1,098 cases, 90.9% of which were travel-related, mainly acquired during travel to South Asia. OutbreaksPlague of Athens (suspected) • "Burning Fever" outbreak among indigenous Americans. Between 1607 and 1624, 85% of the population at the James River died from a typhoid epidemic. The World Health Organization estimates the death toll was over 6,000 during this time. • Maidstone, Kent outbreak in 1897–1898: 1,847 patients were recorded to have typhoid fever. This outbreak is notable because it was the first time a typhoid vaccine was deployed during a civilian outbreak. Almoth Edward Wright's vaccine was offered to 200 healthcare providers, and of the 84 individuals who received the vaccine, none developed typhoid whereas 4 who had not been vaccinated became ill. • Jamaica Plain neighborhood, Boston in 1908 – linked to milk delivery. See the history section, "carriers" for further details. • Dushanbe, Tajikistan, in 1996–1997: 10,677 cases reported, 108 deaths. • Kinshasa, Democratic Republic of the Congo, in 2004: 43,000 cases and over 200 deaths. • Kampala, Uganda in 2015: 10,230 cases reported. ==History==
History
Early descriptions The plague of Athens, during the Peloponnesian War, was most likely an outbreak of typhoid fever. Definition and evidence of transmission The French doctors Pierre-Fidele Bretonneau and Pierre-Charles-Alexandre Louis are credited with describing typhoid fever as a specific disease, unique from typhus. Both doctors performed autopsies on individuals who died in Paris due to fever – and indicated that many had lesions on the Peyer's patches which correlated with distinct symptoms before death. British medics were skeptical of the differentiation between typhoid and typhus because both were endemic to Britain at that time. However, in France, only typhoid was present circulating in the population. Browicz was able to isolate and grow the bacilli but did not go as far as to insinuate or prove that they caused the disease. The bacterium's role in disease was speculated but not confirmed. Eberth is given credit for discovering the bacterium definitively by successfully isolating the same bacterium from 18 of 40 typhoid victims and failing to discover the bacterium present in any "control" victims of other diseases. Gaffky isolated the same bacterium as Eberth from the spleen of a typhoid victim, and was able to grow the bacterium on solid media. Chlorination of water Most developed countries had declining rates of typhoid fever throughout the first half of the 20th century due to vaccinations and advances in public sanitation and hygiene. In 1893, attempts were made to chlorinate the water supply in Hamburg, Germany, and in 1897 Maidstone, England, was the first town to have its entire water supply chlorinated. In 1905, following an outbreak of typhoid fever, the City of Lincoln, England, instituted permanent water chlorination. The first permanent disinfection of drinking water in the US was made in 1908 to the Jersey City, New Jersey, water supply. Credit for the decision to build the chlorination system has been given to John L. Leal. The chlorination facility was designed by George W. Fuller. Outbreaks in traveling military groups led to the creation of the Lyster bag in 1915: a bag with a faucet that can be hung from a tree or pole, filled with water, and comes with a chlorination tablet to drop into the water. In 1899, there were 24 cases of typhoid traced to a single milkman, whose wife had died of typhoid fever a week before the outbreak. The most notorious carrier of typhoid fever, but by no means the most destructive, was Mary Mallon, known as Typhoid Mary. Although other cases of human-to-human spread of typhoid were known at the time, the concept of an asymptomatic carrier, who was able to transmit disease, had only been hypothesized and not yet identified or proven. In recounts of Soper's pursuit of Mallon, his only remorse appears to be that he was not given enough credit for his relentless pursuit and publication of her personal identifying information, stating that the media "rob[s] me of whatever credit belongs to the discovery of the first typhoid fever carrier to be found in America." All cases were concluded to be due to a single milk farm worker, who was shedding large amounts of the typhoid pathogen in his urine. Within the same publication, the first official estimate of typhoid carriers is given: 2–5% of all typhoid patients, and distinguished between temporary carriers and chronic carriers. The Los Angeles County department of public health tracks typhoid carriers and reports the number of carriers identified within the county yearly; between 2006 and 2016 0–4 new cases of typhoid carriers were identified per year. Carriers may be released from their agreements upon fulfilling "release" requirements, based on completion of a personalized treatment plan designed with medical professionals. Denise Monack and Stanley Falkow described a mouse model of asymptomatic intestinal and systemic infection in 2004, and Monack went on to demonstrate that a subpopulation of superspreaders are responsible for the majority of transmission to new hosts, following the 80/20 rule of disease transmission, and that the intestinal microbiota likely plays a role in transmission. Monack's mouse model allows long-term carriage of Salmonella in mesenteric lymph nodes, spleen and liver. At that time, typhoid often killed more soldiers at war than were lost due to enemy combat. Wright further developed his vaccine at a newly opened research department at St Mary's Hospital Medical School in London in 1902, where he established a method for measuring protective substances (opsonin) in human blood. Wright's version of the typhoid vaccine was produced by growing the bacterium at body temperature in broth, then heating the bacteria to 60 °C to "heat inactivate" the pathogen, killing it, while keeping the surface antigens intact. The heat-killed bacteria was then injected into a patient. The British Army was the only combatant at the outbreak of the war to have its troops fully immunized against the bacterium. For the first time, their casualties due to combat exceeded those from disease. In 1909, Frederick F. Russell, a U.S. Army physician, adopted Wright's typhoid vaccine for use with the Army, and two years later, his vaccination program became the first in which an entire army was immunized. It eliminated typhoid as a significant cause of morbidity and mortality in the U.S. military. Typhoid vaccination for members of the American military became mandatory in 1911. Arthur Felix and Margaret Pitt also isolated the strain Ty2, which became the parent strain of Ty21a, the strain used as a live-attenuated vaccine for typhoid fever today. Antibiotics and resistance Chloramphenicol was isolated from Streptomyces by David Gotlieb during the 1940s. In 1948, American army doctors tested its efficacy in treating typhoid patients in Kuala Lumpur, Malaysia. Individuals who received a full course of treatment cleared the infection, whereas patients given a lower dose had a relapse. Asymptomatic carriers continued to shed bacilli despite chloramphenicol treatment – only ill patients were improved with chloramphenicol. Resistance to chloramphenicol became frequent in Southeast Asia by the 1950s, and today chloramphenicol is only used as a last resort due to the high prevalence of resistance. ==Terminology==
Terminology
The disease has been referred to by various names, often associated with symptoms, such as gastric fever, enteric fever, abdominal typhus, infantile remittent fever, slow fever, nervous fever, phytogenic fever, drain fever, and low fever. ==Society and culture==
Society and culture
Notable peopleEmperor Augustus of Rome – suspected based on historical record but not confirmed. • Albert, Prince Consort, husband of Queen Victoria of the United Kingdom, died 24 days after the first record of "feeling horribly ill". • Edward VII of the UK, son of Queen Victoria, while still Prince of Wales, had a near-fatal case of typhoid fever. • Tsar Nicholas II of Russia, survived, illness was circa 1900–1901. • Queen Wilhelmina of the Netherlands may have had an abortion in 1902 because of a typhoid infection she survived. • William Henry Harrison, the ninth President of the United States of America, died 32 days into his term, in 1841. This is the shortest term served by a United States President. • Wilbur Wright, co-inventor of the airplane with his brother Orville, died from typhoid in 1912 at the age of 45. Orville had typhoid in 1896, during which time Wilbur would read aloud to him, books by Otto Lilienthal, a German pioneer in human flight. This started the two men on their own pursuit of creating an airplane. • Stephen A. Douglas, a political opponent of Abraham Lincoln in 1858 and 1860, died of typhoid on 3 June 1861. • Ignacio Zaragoza, a Mexican general and politician, died at the age of 33 of typhoid fever on 8 September 1862. • Franz Schubert, songwriter and composer died of typhoid at age 31 on 19 November 1828. • William Wallace Lincoln, the son of US president Abraham and Mary Todd Lincoln, died at the age of 11 years of typhoid in 1862. • Princess Leopoldina of Brazil, daughter of Emperor Pedro II, died of typhoid in 1871. • Martha Bulloch Roosevelt, mother of president Theodore Roosevelt and paternal grandmother of Eleanor Roosevelt, died of typhoid fever in 1884. • Mary Mallon, "Typhoid Mary" – see history section, "carriers" for further details • Leland Stanford Jr., son of American tycoon and politician A. Leland Stanford and eponym of Leland Stanford Junior University, died of typhoid fever in 1884 at the age of 15. • Three of Louis Pasteur's five children died of typhoid fever. • Lizzie van Zyl, South African child inmate of the Bloemfontein concentration camp during the Second Boer War, died of typhoid fever in 1901. • Dr HJH 'Tup' Scott, captain of the 1886 Australian cricket team that toured England, died of typhoid in 1910. • Arnold Bennett, English novelist, died in 1932 of typhoid, two months after drinking a glass of water in a Paris hotel to prove it was safe. • Hakaru Hashimoto, a Japanese medical scientist, died of typhoid fever in 1934. • John Buford, Union cavalry officer during the Civil War, died of typhoid fever on 16 December 1863. == References ==
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