{{Short description|Disease caused by the bacteria Salmonella Typhi}} {{Distinguish|Typhus}} {{cs1 config|name-list-style=vanc|display-authors=4}} {{Use dmy dates|date=February 2026}} {{Infobox medical condition | name = Typhoid fever | treatment = Antibiotics, hydration, surgery in extreme cases. Quarantine to avoid exposing others (not commonly done in modern times). | synonym = Enteric fever, slow fever | prognosis = Likely to recover without complications if proper antibiotics are administered and diagnosed early. If the infecting strain is multi-drug resistant or extensively drug-resistant then the prognosis is more difficult to determine.<br />Among untreated acute cases, 10% will shed bacteria for three months after the initial onset of symptoms, and 2–5% will become chronic typhoid carriers.<ref name="LA county typhoid 2016" /><br />Some carriers are diagnosed by positive tissue specimens. Chronic carriers are by definition asymptomatic.<ref name = "LA county typhoid 2016" /> | symptoms = Fever that starts low and increases daily, possibly reaching as high as {{convert|104.9|°F}} Headache, weakness and fatigue, muscle aches, sweating, dry cough, loss of appetite, weight loss, stomach pain, diarrhea or constipation, rash, swollen stomach (enlarged liver or spleen) | causes = Gastrointestinal infection of ''Salmonella enterica'' serotype Typhi | prevention = Preventable by vaccine. Travelers to regions with higher typhoid prevalence are usually encouraged to get a vaccination before travel. | risks = Living in or traveling to areas where typhoid fever is established; working as a clinical microbiologist handling ''Salmonella typhi'' bacteria; having close contact with someone who is infected or has recently been infected with typhoid fever; drinking water polluted by sewage that contains ''Salmonella typhi'' | onset = 1–2 weeks after ingestion | duration = Usually 7–10 days after antibiotic treatment begins. Longer if there are complications or drug resistance. | image = | alt = Causative agent: Salmonella enterica serological variant Typhi (shown under a microscope with flagellar stain) | caption = Causative agent: ''Salmonella enterica'' serological variant Typhi (shown under a microscope with flagellar stain) }} '''Typhoid fever''', also known as '''typhoid''', is an orally contracted disease caused by ''Salmonella enterica'' serotype Typhi bacteria, also called '''''Salmonella'' Typhi'''.<ref name="Wain_2015" /><ref>{{Cite journal |first1=Ramkumar |last1=Mathur | first2 = Hyunju | last2 = Oh | first3 = Dekai | last3 = Zhang | first4 = Sung-Gyoo | last4 = Park | first5 = Jin | last5 = Seo | first6 = Alicia | last6 = Koblansky | first7 = Matthew S. | last7 = Hayden | last8 = Ghosh |first8=Sankar | date=October 2012 |title=A Mouse Model of Salmonella typhi Infection |journal=Cell |volume=151 |issue=3 |pages=590–602 |doi=10.1016/j.cell.2012.08.042 |issn=0092-8674 |pmc=3500584 |pmid=23101627}}</ref> Symptoms vary from mild to severe, and usually begin six to 30 days after exposure.<ref name="Newton_2014" /><ref name="CDC2013" /> Often there is a gradual onset of a high fever over several days.<ref name="Newton_2014">{{cite book |title=CDC health information for international travel 2014: the yellow book |vauthors=Newton AE |date=2014 |publisher=Oup USA |isbn=978-0-19-994849-9 |chapter=3 Infectious Diseases Related To Travel |chapter-url=http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-3-infectious-diseases-related-to-travel/typhoid-and-paratyphoid-fever |archive-url=https://web.archive.org/web/20150702125517/http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-3-infectious-diseases-related-to-travel/typhoid-and-paratyphoid-fever |archive-date=2 July 2015 |url-status=live}}</ref> This is commonly accompanied by weakness, abdominal pain, constipation, headaches, and mild vomiting.<ref>{{Cite web |title=Typhoid |url=https://www.who.int/news-room/fact-sheets/detail/typhoid |access-date=18 May 2024 |website=www.who.int |language=en}}</ref><ref name="CDC2013" /><ref name="CDC2013Tech" /> Some people develop a skin rash with rose colored spots.<ref name="CDC2013">{{cite web |date=14 May 2013 |title=Typhoid Fever |url=https://www.cdc.gov/typhoid-fever/index.html |url-status=live |archive-url=https://web.archive.org/web/20160606190251/http://www.cdc.gov/typhoid-fever/index.html |archive-date=6 June 2016 |access-date=28 March 2015 |website=cdc.gov}}</ref> In severe cases, people may experience confusion.<ref name="CDC2013Tech" /> Without treatment, symptoms may last weeks or months.<ref name="CDC2013" /> Diarrhea may be severe, but is uncommon.<ref name="CDC2013Tech" /> Other people may carry it without being affected, but are still contagious.<ref name="WHO2008" /> Typhoid fever is a type of enteric fever, along with paratyphoid fever.<ref name="Wain_2015" /> ''Salmonella enterica'' Typhi is believed to infect and replicate only within humans.<ref name="Pitzer_2019">{{cite journal |vauthors=Pitzer VE, Meiring J, Martineau FP, Watson CH, Kang G, Basnyat B, Baker S |date=October 2019 |title=The Invisible Burden: Diagnosing and Combatting Typhoid Fever in Asia and Africa |journal=Clinical Infectious Diseases |volume=69 |issue=Suppl 5 |pages=S395–S401 |doi=10.1093/cid/ciz611 |pmc=6792124 |pmid=31612938}}</ref>
<!-- Cause and diagnosis --> Typhoid is caused by the bacterium ''Salmonella enterica'' subsp. ''enterica'' serovar Typhi growing in the intestines, Peyer's patches, mesenteric lymph nodes, spleen, liver, gallbladder, bone marrow and blood.<ref name="CDC2013" /><ref name="CDC2013Tech">{{cite web |date=14 May 2013 |title=Typhoid Fever |url=https://www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever/technical.html |url-status=live |archive-url=https://web.archive.org/web/20150402183317/http://www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever/technical.html |archive-date=2 April 2015 |access-date=28 March 2015 |website=cdc.gov}}</ref> Typhoid is spread by ingesting food or water contaminated with the feces of an infected person.<ref name="WHO2008">{{cite journal |date=February 2008 |title=Typhoid vaccines: WHO position paper |url=https://www.who.int/wer/2008/wer8306.pdf?ua=1 |journal=Relevé Épidémiologique Hebdomadaire |volume=83 |issue=6 |pages=49–59 |pmid=18260212 |archive-url=https://web.archive.org/web/20150402103504/http://www.who.int/wer/2008/wer8306.pdf?ua=1 |archive-date=2 April 2015}}</ref> Risk factors include limited access to clean drinking water and poor sanitation.<ref name="Wain_2015" /> Those who have not yet been exposed to it and ingest contaminated drinking water or food are most at risk for developing symptoms.<ref name="CDC2013Tech" /> Only humans can be infected; there are no known animal reservoirs.<ref name="WHO2008" /> Salmonella typhi which causes typhoid fever is different from the other ''Salmonella'' bacteria that usually cause salmonellosis, a common type of food poisoning.<ref>{{cite web |title=Typhoid Fever: Causes, Symptoms & Treatment |url=https://my.clevelandclinic.org/health/diseases/17730-typhoid-fever}}</ref>
Diagnosis is performed by culturing and identifying ''S.'' Typhi from patient samples or detecting an immune response to the pathogen from blood samples.<ref name="CDC2013" /><ref name="Wain_2015" /><ref name="Crump_2010">{{cite journal |vauthors=Crump JA, Mintz ED |date=January 2010 |title=Global trends in typhoid and paratyphoid Fever |journal=Clinical Infectious Diseases |volume=50 |issue=2 |pages=241–246 |bibcode=2010CliID..50..241C |doi=10.1086/649541 |pmc=2798017 |pmid=20014951}}</ref> Recently, new advances in large-scale data collection and analysis have allowed researchers to develop better diagnostics, such as detecting changing abundances of small molecules in the blood that may specifically indicate typhoid fever.<ref>{{Cite book |title=Reproducible diagnostic metabolites in plasma from typhoid fever patients in Asia and Africa |vauthors=Näsström E, Parry CM, Thieu NT, Maude RR, de Jong HK, Fukushima M, Rzhepishevska O, Marks F, Panzner U, Im J, Jeon H |date=2017 |publisher=Umeå universitet, Kemiska institutionen |oclc=1234663430}}</ref> Diagnostic tools in regions where typhoid is most prevalent are quite limited in their accuracy and specificity, and the time required for a proper diagnosis, the increasing spread of antibiotic resistance, and the cost of testing are also hardships for under-resourced healthcare systems.<ref name="Pitzer_2019"/>
<!-- Prevention and treatment -->A typhoid vaccine can prevent about 40–90% of cases during the first two years.<ref name="Milligan_2018">{{cite journal |vauthors=Milligan R, Paul M, Richardson M, Neuberger A |date=May 2018 |title=Vaccines for preventing typhoid fever |journal=The Cochrane Database of Systematic Reviews |volume=2018 |issue=5 |doi=10.1002/14651858.CD001261.pub4 |pmc=6494485 |pmid=29851031 |article-number=CD001261}}</ref> The vaccine may have some effect for up to seven years.<ref name="Wain_2015"/> For those at high risk or people traveling to areas where it is common, vaccination is recommended.<ref name=WHO2008/> Other efforts to prevent it include providing clean drinking water, good sanitation, and handwashing.<ref name=CDC2013/><ref name=WHO2008/> Until an infection is confirmed as cleared, the infected person should not prepare food for others.<ref name=CDC2013/> Typhoid is treated with antibiotics such as azithromycin, fluoroquinolones, or third-generation cephalosporins.<ref name="Wain_2015"/> Resistance to these antibiotics has been developing, which has made treatment more difficult.<ref name="Wain_2015">{{cite journal |vauthors=Wain J, Hendriksen RS, Mikoleit ML, Keddy KH, Ochiai RL |date=March 2015 |title=Typhoid fever |journal=Lancet |volume=385 |issue=9973 |pages=1136–1145 |doi=10.1016/s0140-6736(13)62708-7 |pmc=11567078 |pmid=25458731 |s2cid=2409150}}</ref><ref>{{cite journal |vauthors=Chatham-Stephens K, Medalla F, Hughes M, Appiah GD, Aubert RD, Caidi H, Angelo KM, Walker AT, Hatley N, Masani S, Nash J, Belko J, Ryan ET, Mintz E, Friedman CR |date=January 2019 |title=Emergence of Extensively Drug-Resistant Salmonella Typhi Infections Among Travelers to or from Pakistan – United States, 2016–2018 |journal=MMWR. Morbidity and Mortality Weekly Report |volume=68 |issue=1 |pages=11–13 |doi=10.15585/mmwr.mm6801a3 |pmc=6342547 |pmid=30629573}}</ref><ref>{{cite journal |last1=Kuehn |first1=Rebecca |last2=Stoesser |first2=Nicole |last3=Eyre |first3=David |last4=Darton |first4=Thomas C |last5=Basnyat |first5=Buddha |last6=Parry |first6=Christopher Martin |date=24 November 2022 |title=Treatment of enteric fever (typhoid and paratyphoid fever) with cephalosporins |journal=Cochrane Database of Systematic Reviews |volume=2022 |issue=11 |doi=10.1002/14651858.CD010452.pub2 |pmc=9686137 |pmid=36420914 |article-number=CD010452}}</ref>
<!-- Epidemiology and history --> In 2015, 12.5 million new typhoid cases were reported.<ref name="Vos_2016">{{cite journal |vauthors=Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, Brown A, etal |date=October 2016 |title=Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015 |journal=Lancet |volume=388 |issue=10053 |pages=1545–1602 |doi=10.1016/S0140-6736(16)31678-6 |pmc=5055577 |pmid=27733282 |collaboration=GBD 2015 Disease and Injury Incidence and Prevalence Collaborators}}</ref> The disease is most common in India.<ref name="Wain_2015"/> Children are most commonly affected.<ref name="Wain_2015"/><ref name=WHO2008/> Typhoid decreased in the developed world in the 1940s as a result of improved sanitation and the use of antibiotics.<ref name=WHO2008/> Every year about 400 cases are reported in the U.S. and an estimated 6,000 people have typhoid.<ref name=CDC2013Tech/><ref>{{cite journal |vauthors=Jackson BR, Iqbal S, Mahon B |date=March 2015 |title=Updated recommendations for the use of typhoid vaccine—Advisory Committee on Immunization Practices, United States, 2015 |journal=MMWR. Morbidity and Mortality Weekly Report |volume=64 |issue=11 |pages=305–308 |pmc=4584884 |pmid=25811680}}</ref> In 2015, it resulted in about 149,000 deaths worldwide – down from 181,000 in 1990.<ref name="Wang_2016">{{cite journal |vauthors=Wang H, Naghavi M, Allen C, Barber RM, Bhutta ZA, Carter A, etal |date=October 2016 |title=Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015 |journal=Lancet |volume=388 |issue=10053 |pages=1459–1544 |doi=10.1016/s0140-6736(16)31012-1 |pmc=5388903 |pmid=27733281 |collaboration=GBD 2015 Mortality and Causes of Death Collaborators}}</ref><ref name="Abubakar_2015">{{cite journal |vauthors=Abubakar II, Tillmann T, Banerjee A, etal |date=January 2015 |title=Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 |journal=Lancet |volume=385 |issue=9963 |pages=117–171 |doi=10.1016/S0140-6736(14)61682-2 |pmc=4340604 |pmid=25530442 |collaboration=GBD 2013 Mortality and Causes of Death Collaborators}}</ref> Without treatment, the risk of death may be as high as 20%.<ref name=WHO2008/> With treatment, it is between 1% and 4%.<ref name="Wain_2015"/><ref name=WHO2008/>
Typhus is a different disease, caused by unrelated species of bacteria.<ref>{{cite journal |vauthors=Cunha BA |date=March 2004 |title=Osler on typhoid fever: differentiating typhoid from typhus and malaria |journal=Infectious Disease Clinics of North America |volume=18 |issue=1 |pages=111–125 |doi=10.1016/S0891-5520(03)00094-1 |pmid=15081508}}</ref> Owing to their similar symptoms, they were not recognized as distinct diseases until the 1800s. "Typhoid" means "resembling typhus".<ref>{{Cite book |last1=Evans |first1=Alfred S. |url=https://books.google.com/books?id=dPDdBgAAQBAJ&pg=PA839 |title=Bacterial Infections of Humans: Epidemiology and Control |last2=Brachman |first2=Philip S. |publisher=Springer |year=2013 |isbn=978-1-4615-5327-4 |page=839 |language=en}}</ref>
== 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.<ref>{{cite web |title=Typhoid |url=http://www.merriam-webster.com/dictionary/typhoid |url-status=live |archive-url=https://web.archive.org/web/20130702140640/http://www.merriam-webster.com/dictionary/typhoid |archive-date=2 July 2013 |access-date=24 June 2013 |publisher=Merriam Webster Dictionary}}</ref>{{better source needed|reason=need something better than a dictionary|date=May 2025}} * 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.<ref name="Kumar_2017">{{cite journal |vauthors=Kumar P, Kumar R |date=March 2017 |title=Enteric Fever |journal=Indian Journal of Pediatrics |volume=84 |issue=3 |pages=227–230 |doi=10.1007/s12098-016-2246-4 |pmid=27796818 |s2cid=3825885}}</ref> * In the second week, the person is often too tired to get up, with high fever in plateau around {{convert|39-40.5|°C|°F|abbr=on}} 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.{{citation needed|date=March 2023}} * 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 bronchitis ** Encephalitis ** 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.<ref>{{Cite web |title=Typhoid fever: MedlinePlus Medical Encyclopedia |url=https://medlineplus.gov/ency/article/001332.htm |access-date=21 April 2020 |website=medlineplus.gov |language=en}}</ref>
==Causes== [[File:ForskeligeVeje ad hvilkenBroen kan inficeres medTyfusbaciller.png|thumb|upright=1.3|A 1939 conceptual illustration showing various ways that typhoid bacteria can contaminate a water well (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.<ref name="Yap_2016">{{cite journal |vauthors=Yap KP, Ho WS, Gan HM, Chai LC, Thong KL |date=2016 |title=Global MLST of Salmonella Typhi Revisited in Post-genomic Era: Genetic Conservation, Population Structure, and Comparative Genomics of Rare Sequence Types |journal=Frontiers in Microbiology |volume=7 |page=270 |doi=10.3389/fmicb.2016.00270 |pmc=4774407 |pmid=26973639 |doi-access=free}}</ref> 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.<ref>{{cite journal |vauthors=Wong VK, Baker S, Pickard DJ, Parkhill J, Page AJ, Feasey NA, Kingsley RA, Thomson NR, Keane JA, Weill FX, Edwards DJ, Hawkey J, Harris SR, Mather AE, Cain AK, Hadfield J, Hart PJ, Thieu NT, Klemm EJ, Glinos DA, Breiman RF, Watson CH, Kariuki S, Gordon MA, Heyderman RS, Okoro C, Jacobs J, Lunguya O, Edmunds WJ, Msefula C, Chabalgoity JA, Kama M, Jenkins K, Dutta S, Marks F, Campos J, Thompson C, Obaro S, MacLennan CA, Dolecek C, Keddy KH, Smith AM, Parry CM, Karkey A, Mulholland EK, Campbell JI, Dongol S, Basnyat B, Dufour M, Bandaranayake D, Naseri TT, Singh SP, Hatta M, Newton P, Onsare RS, Isaia L, Dance D, Davong V, Thwaites G, Wijedoru L, Crump JA, De Pinna E, Nair S, Nilles EJ, Thanh DP, Turner P, Soeng S, Valcanis M, Powling J, Dimovski K, Hogg G, Farrar J, Holt KE, Dougan G |date=June 2015 |title=Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events |journal=Nature Genetics |volume=47 |issue=6 |pages=632–639 |doi=10.1038/ng.3281 |pmc=4921243 |pmid=25961941}}</ref> 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.<ref>{{cite journal |vauthors=Wong VK, Baker S, Connor TR, Pickard D, Page AJ, Dave J, Murphy N, Holliman R, Sefton A, Millar M, Dyson ZA, Dougan G, Holt KE |date=October 2016 |title=An extended genotyping framework for Salmonella enterica serovar Typhi, the cause of human typhoid |journal=Nature Communications |volume=7 |issue=1 |bibcode=2016NatCo...712827W |doi=10.1038/ncomms12827 |pmc=5059462 |pmid=27703135 |doi-access=free |article-number=12827}}</ref>
=== Transmission === Unlike other strains of ''Salmonella'', humans are the only known typhoid carriers.<ref name="Eng_2015" /> ''S. enterica'' subsp. enterica serovar Typhi is spread by the fecal-oral route from people who are infected and from asymptomatic carriers of the bacterium.<ref name="Eng_2015">{{cite journal |vauthors=Eng SK, Pusparajah P, Ab Mutalib NS, Ser HL, Chan KG, Lee LH |date=June 2015 |title=Salmonella:A review on pathogenesis, epidemiology and antibiotic resistance |journal=Frontiers in Life Science |volume=8 |issue=3 |pages=284–293 |doi=10.1080/21553769.2015.1051243 |doi-access=free}}</ref> An asymptomatic human carrier is someone who is still excreting typhoid bacteria in stool a year after the acute stage of the infection.<ref name="Eng_2015" />
== 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.<ref name="Ryan_2004">{{cite book |title=Sherris Medical Microbiology |publisher=McGraw Hill |year=2004 |isbn=978-0-8385-8529-0 |veditors=Ryan KJ, Ray CG |edition=4th}}</ref>
=== Widal test === {{Main|Widal test}} thumb|Widal test card The Widal test is used to identify specific antibodies in the serum of people with typhoid by using antigen-antibody interactions.<ref>{{Cite journal |last1=Mawazo |first1=Akili |last2=Bwire |first2=George M. |last3=Matee |first3=Mecky I. N. |date=5 June 2019 |title=Performance of Widal test and stool culture in the diagnosis of typhoid fever among suspected patients in Dar es Salaam, Tanzania |journal=BMC Research Notes |volume=12 |issue=1 |page=316 |doi=10.1186/s13104-019-4340-y |issn=1756-0500 |pmc=6551910 |pmid=31167646 |doi-access=free}}</ref>
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.<ref>{{cite book |title=Manson's Tropical Infectious Diseases. |vauthors=Feasey NA, Gordon MA |date=2014 |publisher=Saunders Ltd. |isbn=978-0-7020-5101-2 |veditors=Farrar J, Hotez P, Junghanss T, Kang G, Lalloo D, White NJ |edition=23rd |pages=337–348.e2 |chapter=Salmonella Infections |doi=10.1016/B978-0-7020-5101-2.00026-1}}</ref>
===Rapid diagnostic tests=== Rapid diagnostic tests such as Tubex, Typhidot, and Test-It have shown moderate diagnostic accuracy.<ref>{{cite journal |vauthors=Wijedoru L, Mallett S, Parry CM |date=May 2017 |title=Rapid diagnostic tests for typhoid and paratyphoid (enteric) fever |journal=The Cochrane Database of Systematic Reviews |volume=2017 |issue=5 |doi=10.1002/14651858.CD008892.pub2 |pmc=5458098 |pmid=28545155 |article-number=CD008892 |collaboration=Cochrane Infectious Diseases Group}}</ref>
==== 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.<ref name="Mehmood_2015">{{Cite journal |last1=Mehmood |first1=Khalid |last2=Sundus |first2=Ayesha |last3=Naqvi |first3=Iftikhar Haider |last4=Ibrahim |first4=Mohammad Faisal |last5=Siddique |first5=Osama |last6=Ibrahim |first6=Nida Faisal |date=2015 |title=Typhidot - A blessing or a menace |journal=Pakistan Journal of Medical Sciences |volume=31 |issue=2 |pages=439–443 |doi=10.12669/pjms.312.5934 |doi-broken-date=14 January 2026 |issn=1682-024X |pmc=4476358 |pmid=26101507}}</ref>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.<ref name="Mehmood_2015"/>
Two colored bands indicate a positive test. A single control band indicates a negative test. A single first fixed line or no band at all indicates an invalid test. Typhidot's biggest limitation is that it is not quantitative, just positive or negative.<ref>{{cite journal |vauthors=Lim PL, Tam FC, Cheong YM, Jegathesan M |date=August 1998 |title=One-step 2-minute test to detect typhoid-specific antibodies based on particle separation in tubes |journal=Journal of Clinical Microbiology |volume=36 |issue=8 |pages=2271–2278 |doi=10.1128/JCM.36.8.2271-2278.1998 |pmc=105030 |pmid=9666004}}</ref>
==== 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.{{citation needed|date=June 2022}}
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.<ref>{{Cite web |title=TYPHIDOT Rapid IgG/IgM (Combo) |url=https://www.reszonics.com/wp-content/uploads/2017/04/Reszon-IFU-TYPHIDOT-Rapid-IgG_IgM-combo-2014-04.pdf |access-date=14 November 2019 |website=Reszon Diagnostics International}}</ref>
== Prevention == [[File:Typhoid inoculation2.jpg|thumb|upright=1.3|Doctor administering a typhoid vaccination 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,<ref>{{cite web |title=The Great Horse Manure Crisis of 1894 |url=http://www.historic-uk.com/HistoryUK/HistoryofBritain/Great-Horse-Manure-Crisis-of-1894/ |url-status=live |archive-url=https://web.archive.org/web/20150525202107/http://www.historic-uk.com/HistoryUK/HistoryofBritain/Great-Horse-Manure-Crisis-of-1894/ |archive-date=25 May 2015}}</ref> which are vectors of many pathogens, including ''Salmonella'' spp.<ref>{{cite journal |vauthors=Cirillo VJ |date=2006 |title="Winged sponges": houseflies as carriers of typhoid fever in 19th- and early 20th-century military camps |journal=Perspectives in Biology and Medicine |volume=49 |issue=1 |pages=52–63 |doi=10.1353/pbm.2006.0005 |pmid=16489276 |s2cid=41428479}}</ref> 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.<ref>{{Cite web |date=10 October 2018 |title=History of Drinking Water Treatment {{!}} Drinking Water {{!}} Healthy Water {{!}} CDC |url=https://www.cdc.gov/healthywater/drinking/history.html |access-date=21 April 2020 |website=www.cdc.gov |language=en-us}}</ref>
===Vaccination=== Two typhoid vaccines are licensed for use in the prevention of typhoid:<ref name="Milligan_2018"/> the live, oral Ty21a vaccine (sold as Vivotif by Crucell Switzerland AG) and the injectable typhoid polysaccharide vaccine (sold as Typhim Vi by Sanofi Pasteur and Typherix by GlaxoSmithKline). Both are efficacious and recommended for travelers to areas where typhoid is endemic. Boosters are recommended every five years for the oral vaccine and every two years for the injectable form.<ref name="Milligan_2018"/> An older, killed whole-cell vaccine is still used in countries where the newer preparations are not available, but this vaccine is no longer recommended for use because it has more side effects (mainly pain and inflammation at the site of the injection).<ref>{{cite journal |vauthors=Marathe SA, Lahiri A, Negi VD, Chakravortty D |date=2012 |title=Typhoid fever & vaccine development: a partially answered question |journal=The Indian Journal of Medical Research |volume=135 |issue=2 |pages=161–169 |pmc=3336846 |pmid=22446857}}</ref> thumbtime=1:00|thumb|Vivotif – oral typhoid vaccine of live-attenuated ''S. enterica'' Typhi strain Ty21a 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.<ref name="Date_2015">{{cite journal |vauthors=Date KA, Bentsi-Enchill A, Marks F, Fox K |date=June 2015 |title=Typhoid fever vaccination strategies |journal=Vaccine |volume=33 |issue=Suppl 3 |pages=C55-C61 |doi=10.1016/j.vaccine.2015.04.028 |pmc=10644681 |pmid=25902360}}</ref> Although vaccination programs for typhoid have proven effective, they alone cannot eliminate typhoid fever.<ref name="Date_2015" /> Combining vaccines with public health efforts is the only proven way to control this disease.<ref name="Date_2015" />
Since the 1990s, the WHO has recommended two typhoid fever vaccines. The ViPS vaccine is given by injection and the Ty21a by capsules. Only people over age two are recommended to be vaccinated with the ViPS vaccine, and it requires a revaccination after 2–3 years, with a 55–72% efficacy. The Ty21a vaccine is recommended for people five and older, lasting 5–7 years with 51–67% efficacy. The two vaccines have proved safe and effective for epidemic disease control in multiple regions.<ref name="Date_2015"/>
A version of the vaccine combined with a hepatitis A vaccine is also available.<ref>{{cite web |title=Vivaxim Solution for injection |url=http://www.nps.org.au/medicines/immune-system/vaccines-and-immunisation/for-individuals/brands/vivaxim-solution-for-injection |archive-url=https://web.archive.org/web/20151001161831/http://www.nps.org.au/medicines/immune-system/vaccines-and-immunisation/for-individuals/brands/vivaxim-solution-for-injection |archive-date=1 October 2015 |access-date=10 April 2017 |website=NPS MedicineWise}}</ref>
Results of a phase 3 trial of typhoid conjugate vaccine (TCV) in December 2019 reported 81% fewer cases among children.<ref>{{cite news |date=4 December 2019 |title=Typhoid vaccine 'works fantastically well' |url=https://www.bbc.com/news/health-50587608?linkId=80686859 |access-date=17 January 2020 |work=BBC News |vauthors=Gallagher J}}</ref><ref>{{cite journal |vauthors=Shakya M, Colin-Jones R, Theiss-Nyland K, Voysey M, Pant D, Smith N, Liu X, Tonks S, Mazur O, Farooq YG, Clarke J, Hill J, Adhikari A, Dongol S, Karkey A, Bajracharya B, Kelly S, Gurung M, Baker S, Neuzil KM, Shrestha S, Basnyat B, Pollard AJ |date=December 2019 |title=Phase 3 Efficacy Analysis of a Typhoid Conjugate Vaccine Trial in Nepal |journal=The New England Journal of Medicine |volume=381 |issue=23 |pages=2209–2218 |doi=10.1056/NEJMoa1905047 |pmc=6785806 |pmid=31800986 |doi-access=free}}</ref>
== 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.<ref>{{Cite web |website=UpToDate |url=https://www.uptodate.com/contents/oral-rehydration-therapy |access-date=21 April 2020 |title=Oral rehydration therapy |first=Stephen |last=Freedman}}</ref>
===Antibiotics=== Where resistance is uncommon, the treatment of choice is a fluoroquinolone such as ciprofloxacin.<ref name="Parry_2009">{{cite journal |vauthors=Parry CM, Beeching NJ |date=June 2009 |title=Treatment of enteric fever |journal=BMJ |volume=338 |doi=10.1136/bmj.b1159 |pmid=19493937 |s2cid=3264721 |article-number=b1159}}</ref><ref name="Effa_2011">{{cite journal |vauthors=Effa EE, Lassi ZS, Critchley JA, Garner P, Sinclair D, Olliaro PL, Bhutta ZA |date=October 2011 |title=Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever) |url=https://ecommons.aku.edu/cgi/viewcontent.cgi?article=1078&context=pakistan_fhs_mc_women_childhealth_paediatr |journal=The Cochrane Database of Systematic Reviews |volume=2011 |issue=10 |doi=10.1002/14651858.CD004530.pub4 |pmc=6532575 |pmid=21975746 |article-number=CD004530}}</ref> Otherwise, a third-generation cephalosporin such as ceftriaxone or cefotaxime is the first choice.<ref>{{cite journal |vauthors=Soe GB, Overturf GD |year=1987 |title=Treatment of typhoid fever and other systemic salmonelloses with cefotaxime, ceftriaxone, cefoperazone, and other newer cephalosporins |journal=Reviews of Infectious Diseases |volume=9 |issue=4 |pages=719–736 |doi=10.1093/clinids/9.4.719 |jstor=4454162 |pmid=3125577}}</ref><ref>{{cite journal |vauthors=Wallace MR, Yousif AA, Mahroos GA, Mapes T, Threlfall EJ, Rowe B, Hyams KC |date=December 1993 |title=Ciprofloxacin versus ceftriaxone in the treatment of multiresistant typhoid fever |url=https://zenodo.org/record/1232516 |journal=European Journal of Clinical Microbiology & Infectious Diseases |volume=12 |issue=12 |pages=907–910 |doi=10.1007/BF01992163 |pmid=8187784 |s2cid=19358454}}</ref><ref>{{cite journal |vauthors=Dutta P, Mitra U, Dutta S, De A, Chatterjee MK, Bhattacharya SK |date=June 2001 |title=Ceftriaxone therapy in ciprofloxacin treatment failure typhoid fever in children |journal=The Indian Journal of Medical Research |volume=113 |pages=210–213 |pmid=11816954}}</ref><ref>{{cite journal |last1=Kovalenko |first1=A. N. |display-authors=etal |year=2011 |title=Особенности клиники, диагностики и лечения брюшного тифа у лиц молодого возраста |journal=Voen.-meditsinskii Zhurnal |volume=332 |issue=1 |pages=33–39}}</ref> Cefixime is a suitable oral alternative.<ref>{{cite journal |vauthors=Bhutta ZA, Khan IA, Molla AM |date=November 1994 |title=Therapy of multidrug-resistant typhoid fever with oral cefixime vs. intravenous ceftriaxone |journal=The Pediatric Infectious Disease Journal |volume=13 |issue=11 |pages=990–994 |doi=10.1097/00006454-199411000-00010 |pmid=7845753}}</ref><ref>{{cite journal |vauthors=Cao XT, Kneen R, Nguyen TA, Truong DL, White NJ, Parry CM |date=March 1999 |title=A comparative study of ofloxacin and cefixime for treatment of typhoid fever in children. The Dong Nai Pediatric Center Typhoid Study Group |journal=The Pediatric Infectious Disease Journal |volume=18 |issue=3 |pages=245–248 |doi=10.1097/00006454-199903000-00007 |pmid=10093945}}</ref>
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.<ref>Baron S et al.</ref>{{fcn|date=February 2026}} Treatment with antibiotics reduces the case-fatality rate to about 1%.<ref>{{cite web |date=February 2009 |title=Diarrhoeal Diseases |url=https://www.who.int/vaccine_research/diseases/diarrhoeal/en/index7.html |archive-url=https://web.archive.org/web/20111102190825/http://www.who.int/vaccine_research/diseases/diarrhoeal/en/index7.html |archive-date=2 November 2011 |access-date=25 April 2013 |website=World Health Organization}}</ref>
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.<ref>{{Cite web |title=Typhoid fever |url=https://www.who.int/ith/diseases/typhoidfever/en/ |archive-url=https://web.archive.org/web/20170727173454/http://www.who.int/ith/diseases/typhoidfever/en/ |archive-date=27 July 2017 |access-date=10 August 2017 |website=WHO}}</ref>
=== 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.<ref name="Anyomih_2018">{{cite journal |vauthors=Anyomih TK, Drake TM, Glasbey J, Fitzgerald JE, Ots R, et al |date=October 2018 |title=Management and Outcomes Following Surgery for Gastrointestinal Typhoid: An International, Prospective, Multicentre Cohort Study |journal=World Journal of Surgery |volume=42 |issue=10 |pages=3179–3188 |doi=10.1007/s00268-018-4624-8 |pmc=6132852 |pmid=29725797 |doi-access=free |collaboration=GlobalSurg Collaborative}}</ref>
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.<ref>{{cite journal |vauthors=Waddington CS, Darton TC, Pollard AJ |date=January 2014 |title=The challenge of enteric fever |journal=The Journal of Infection |series=Hot Topics in Infection and Immunity in Children - Papers from the 10th annual IIC meeting, Oxford, UK, 2012 |volume=68 |issue=Suppl 1 |pages=S38-S50 |doi=10.1016/j.jinf.2013.09.013 |pmid=24119827}}</ref><ref name="Gonzalez-Escobedo_2011"/>
=== Resistance === As resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and streptomycin is now common, these agents are no longer used as first-line treatment of typhoid fever.<ref>{{Cite web |title=Extensively Drug-Resistant Typhoid Fever in Pakistan – Watch – Level 1, Practice Usual Precautions – Travel Health Notices {{!}} Travelers' Health {{!}} CDC |url=https://wwwnc.cdc.gov/travel/notices/watch/xdr-typhoid-fever-pakistan |access-date=21 April 2020 |website=wwwnc.cdc.gov}}</ref> Typhoid resistant to these agents is known as multidrug-resistant typhoid.<ref>{{cite journal |vauthors=Zaki SA, Karande S |date=May 2011 |title=Multidrug-resistant typhoid fever: a review |journal=Journal of Infection in Developing Countries |volume=5 |issue=05 |pages=324–337 |doi=10.3855/jidc.1405 |pmid=21628808 |doi-access=free}}</ref>
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.<ref name="Effa_2011" /> Azithromycin can be taken by mouth and is less expensive than ceftriaxone, which is given by injection.<ref>{{cite journal |vauthors=Gibani MM, Britto C, Pollard AJ |date=October 2018 |title=Typhoid and paratyphoid fever: a call to action |journal=Current Opinion in Infectious Diseases |volume=31 |issue=5 |pages=440–448 |doi=10.1097/QCO.0000000000000479 |pmc=6319573 |pmid=30138141}}</ref>
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.<ref>{{cite journal |vauthors=Cooke FJ, Wain J, Threlfall EJ |date=August 2006 |title=Fluoroquinolone resistance in Salmonella Typhi |journal=BMJ |volume=333 |issue=7563 |pages=353–354 |doi=10.1136/bmj.333.7563.353-b |pmc=1539082 |pmid=16902221}}</ref>
== Epidemiology == {{Main|Epidemiology of typhoid fever}} {{owidslider |start = 2021 |list = Template:OWID/death rate typhoid paratyphoid fever children under 5#gallery |location = commons |caption = |title = |language = |file = link=|thumb|upright=1.6|Death rate typhoid paratyphoid fever children under 5 |startingView = World }} In 2000, typhoid fever caused an estimated 21.7 million illnesses and 217,000 deaths.<ref name="Crump_2010"/> It occurs most often in children and young adults between 5 and 19 years old.<ref name="who">{{cite web |title=Typhoid Fever |url=https://www.who.int/vaccine_research/diseases/diarrhoeal/en/index7.html |archive-url=https://web.archive.org/web/20111102190825/http://www.who.int/vaccine_research/diseases/diarrhoeal/en/index7.html |archive-date=2 November 2011 |access-date=28 August 2007 |publisher=World Health Organization}}</ref> In 2013, it resulted in about 161,000 deaths – down from 181,000 in 1990.<ref name="Abubakar_2015" /> Infants, children, and adolescents in south-central and Southeast Asia have the highest rates of typhoid.<ref name="Crump_2004">{{cite journal |vauthors=Crump JA, Luby SP, Mintz ED |date=May 2004 |title=The global burden of typhoid fever |journal=Bulletin of the World Health Organization |volume=82 |issue=5 |pages=346–353 |pmc=2622843 |pmid=15298225}}</ref> Outbreaks are also often reported in sub-Saharan Africa and Southeast Asia.<ref name="Muyembe-Tamfum_2009">{{cite journal |vauthors=Muyembe-Tamfum JJ, Veyi J, Kaswa M, Lunguya O, Verhaegen J, Boelaert M |date=January 2009 |title=An outbreak of peritonitis caused by multidrug-resistant Salmonella Typhi in Kinshasa, Democratic Republic of Congo |journal=Travel Medicine and Infectious Disease |volume=7 |issue=1 |pages=40–43 |doi=10.1016/j.tmaid.2008.12.006 |pmid=19174300}}</ref><ref name="Baddam_2012">{{cite journal |vauthors=Baddam R, Kumar N, Thong KL, Ngoi ST, Teh CS, Yap KP, Chai LC, Avasthi TS, Ahmed N |date=July 2012 |title=Genetic fine structure of a Salmonella enterica serovar Typhi strain associated with the 2005 outbreak of typhoid fever in Kelantan, Malaysia |journal=Journal of Bacteriology |volume=194 |issue=13 |pages=3565–3566 |doi=10.1128/jb.00581-12 |pmc=3434757 |pmid=22689247}}</ref><ref name="Yap_2012a">{{cite journal |vauthors=Yap KP, Teh CS, Baddam R, Chai LC, Kumar N, Avasthi TS, Ahmed N, Thong KL |date=September 2012 |title=Insights from the genome sequence of a Salmonella enterica serovar Typhi strain associated with a sporadic case of typhoid fever in Malaysia |journal=Journal of Bacteriology |volume=194 |issue=18 |pages=5124–5125 |doi=10.1128/jb.01062-12 |pmc=3430317 |pmid=22933756}}</ref> In 2000, more than 90% of morbidity and mortality due to typhoid fever occurred in Asia.<ref>{{Cite web |title=WHO | A study of typhoid fever in five Asian countries: Disease burden and implications for controls |url=https://www.who.int/bulletin/volumes/86/4/06-039818/en/ |archive-url=https://web.archive.org/web/20080714165057/http://www.who.int/bulletin/volumes/86/4/06-039818/en/ |archive-date=14 July 2008}}</ref> In the U.S., about 400 cases occur each year, 75% of which are acquired while traveling internationally.<ref>{{cite journal |vauthors=Matano LM, Morris HG, Wood BM, Meredith TC, Walker S |date=December 2016 |title=Accelerating the discovery of antibacterial compounds using pathway-directed whole cell screening |journal=Bioorganic & Medicinal Chemistry |volume=24 |issue=24 |pages=6307–6314 |doi=10.1016/j.bmc.2016.08.003 |pmc=5180449 |pmid=27594549}}</ref><ref>{{cite web |date=23 December 2013 |title=Typhoid Fever |url=http://www.floridahealth.gov/diseases-and-conditions/disease-reporting-and-management/disease-reporting-and-surveillance/_documents/gsi-typhoid-fever.pdf |archive-url=https://web.archive.org/web/20200809173212/http://www.floridahealth.gov/diseases-and-conditions/disease-reporting-and-management/disease-reporting-and-surveillance/_documents/gsi-typhoid-fever.pdf |archive-date=9 August 2020 |access-date=8 December 2019 |work=Florida Department of Health}}</ref>
Before the antibiotic era, the case fatality rate of typhoid fever was 10–20%. Today, with prompt treatment, it is less than 1%,<ref>Heymann, David L., ed. (2008), ''Control of Communicable Diseases Manual'', Washington, D.C.: American Public Health Association, pg 665. {{ISBN|978-0-87553-189-2}}.</ref> but 3–5% of people who are infected develop a chronic infection in the gall bladder.<ref name="Levine_1982">{{cite journal |vauthors=Levine MM, Black RE, Lanata C |date=December 1982 |title=Precise estimation of the numbers of chronic carriers of Salmonella typhi in Santiago, Chile, an endemic area |journal=The Journal of Infectious Diseases |volume=146 |issue=6 |pages=724–726 |doi=10.1093/infdis/146.6.724 |pmid=7142746}}</ref> 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.<ref name="Gonzalez-Escobedo_2011">{{cite journal |vauthors=Gonzalez-Escobedo G, Marshall JM, Gunn JS |date=January 2011 |title=Chronic and acute infection of the gall bladder by Salmonella Typhi: understanding the carrier state |journal=Nature Reviews. Microbiology |volume=9 |issue=1 |pages=9–14 |doi=10.1038/nrmicro2490 |pmc=3255095 |pmid=21113180}}</ref> 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.<ref name="Yap_2012b">{{cite journal |vauthors=Yap KP, Gan HM, Teh CS, Baddam R, Chai LC, Kumar N, Tiruvayipati SA, Ahmed N, Thong KL |date=November 2012 |title=Genome sequence and comparative pathogenomics analysis of a Salmonella enterica Serovar Typhi strain associated with a typhoid carrier in Malaysia |journal=Journal of Bacteriology |volume=194 |issue=21 |pages=5970–5971 |doi=10.1128/jb.01416-12 |pmc=3486090 |pmid=23045488}}</ref><ref name="Yap_2014">{{cite journal |vauthors=Yap KP, Gan HM, Teh CS, Chai LC, Thong KL |date=November 2014 |title=Comparative genomics of closely related Salmonella enterica serovar Typhi strains reveals genome dynamics and the acquisition of novel pathogenic elements |journal=BMC Genomics |volume=15 |issue=1 |doi=10.1186/1471-2164-15-1007 |pmc=4289253 |pmid=25412680 |doi-access=free |article-number=1007}}</ref>
In industrialized nations, water sanitation and food handling improvements have reduced the number of typhoid cases.<ref>{{cite journal |vauthors=Crump JA, Sjölund-Karlsson M, Gordon MA, Parry CM |date=October 2015 |title=Epidemiology, Clinical Presentation, Laboratory Diagnosis, Antimicrobial Resistance, and Antimicrobial Management of Invasive Salmonella Infections |journal=Clinical Microbiology Reviews |volume=28 |issue=4 |pages=901–937 |bibcode=2015CliMR..28..901C |doi=10.1128/CMR.00002-15 |pmc=4503790 |pmid=26180063}}</ref> 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.<ref>{{cite journal |vauthors=Khan MI, Pach A, Khan GM, Bajracharya D, Sahastrabuddhe S, Bhutta W, Tahir R, Soofi S, Thapa CB, Joshi N, Puri MK, Shrestha P, Upreti SR, Clemens JD, Bhutta Z, Ochiai RL |date=June 2015 |title=Typhoid vaccine introduction: An evidence-based pilot implementation project in Nepal and Pakistan |journal=Vaccine |volume=33 |issue=Suppl 3 |pages=C62-C67 |doi=10.1016/j.vaccine.2015.03.087 |pmid=25937612}}</ref>
In 2004–2005, an outbreak in the Democratic Republic of Congo resulted in more than 42,000 cases and 214 deaths.<ref name="who" /> Since November 2016, Pakistan has had an outbreak of extensively drug-resistant (XDR) typhoid fever.<ref>{{cite news |date=30 September 2019 |title=Extensively Drug-Resistant Typhoid Fever in Pakistan |url=https://wwwnc.cdc.gov/travel/notices/watch/xdr-typhoid-fever-pakistan |work=Centers for Disease Control and Prevention}}</ref>
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.<ref>{{cite web |date=October 2020 |title=Typhoid and paratyphoid fevers: Annual Epidemiological Report for 2017 |url=https://www.ecdc.europa.eu/sites/default/files/documents/AER_for_2017_typhoid_and_paratyphoid_fevers.pdf |access-date=20 July 2021 |publisher=European Centre for Disease Prevention and Control}}</ref>
===Outbreaks=== * Plague of Athens (suspected)<ref name="Papagrigorakis_2006" /> * Cocoliztli epidemics (suspected)<ref name="Vagene_2018">{{cite journal |last1=Vågene |first1=Åshild |display-authors=etal |date=2018 |title=Salmonella enterica genomes from victims of a major sixteenth-century epidemic in Mexico |url=https://www.biorxiv.org/content/10.1101/106740v2.full |journal=Nature Ecology & Evolution |volume=2 |issue=3 |pages=520–528 |bibcode=2018NatEE...2..520V |doi=10.1038/s41559-017-0446-6 |pmid=29335577 |s2cid=3358440}}</ref> * "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.<ref>{{Cite web |title=Disease & Death in Early America: Tully Area Historical Society |url=https://tullyhistoricalsociety.org/tahs/medical.php#epidemics |access-date=29 June 2021 |website=tullyhistoricalsociety.org}}</ref> * 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.<ref name="Adler_2016" /> * American army in the Spanish-American war: government records estimate over 21,000 troops had typhoid, resulting in 2,200 deaths.<ref name="Adler_2016" /> * In 1902, guests at mayoral banquets in Southampton and Winchester, England became ill and four died, including the Dean of Winchester, after consuming oysters. The infection was due to oysters sourced from Emsworth, where the oyster beds had been contaminated with raw sewage.<ref name="oyster1">{{cite web |date=10 February 2019 |title=Emsworth Oysters |url=http://www.emsworth.org.uk/news/emsworths-oysters-video-now-online |archive-url=https://web.archive.org/web/20160203191517/http://www.emsworth.org.uk/news/emsworths-oysters-video-now-online |archive-date=3 February 2016 |publisher=Emsworth Business Association }}</ref><ref>{{Cite report |url=https://archive.org/stream/b24914812#page/n0/mode/2up |title=Dr. H. Timbrell Bulstrode's report to the Local Government Board upon alleged oyster-borne enteric fever and other illness following the mayoral banquets at Winchester and Southampton, and upon enteric fever occurring simultaneously elsewhere and also ascribed to oysters |year=1903 |publisher=HMSO |location=London |page=1 |vauthors=Bulstrode HT }}</ref> * Jamaica Plain neighborhood, Boston in 1908 – linked to milk delivery. See the history section, "carriers" for further details.<ref name="Remember Jamaica Plain?_2007" /> * Outbreak in upper-class New Yorkers who employed Mary Mallon – 51 cases and 3 deaths from 1907 to 1915.<ref name="Soper_1939" /><ref name="Apple Podcasts" /> * Aberdeen, Scotland, in summer 1964 – traced back to contaminated canned beef sourced from Argentina sold in markets. More than 500 patients were quarantined in the hospital for a minimum of four weeks, and the outbreak was contained without any deaths.<ref>{{Cite news |date=26 June 2008 |title=Typhoid left city 'under siege' |url=http://news.bbc.co.uk/2/hi/uk_news/scotland/7471198.stm |access-date=29 June 2021 |language=en-GB}}</ref> * Dushanbe, Tajikistan, in 1996–1997: 10,677 cases reported, 108 deaths.<ref name="Appiah_2020">{{cite journal |vauthors=Appiah GD, Chung A, Bentsi-Enchill AD, Kim S, Crump JA, Mogasale V, Pellegrino R, Slayton RB, Mintz ED |date=June 2020 |title=Typhoid Outbreaks, 1989–2018: Implications for Prevention and Control |journal=The American Journal of Tropical Medicine and Hygiene |volume=102 |issue=6 |pages=1296–1305 |doi=10.4269/ajtmh.19-0624 |pmc=7253085 |pmid=32228795}}</ref> * Kinshasa, Democratic Republic of the Congo, in 2004: 43,000 cases and over 200 deaths.<ref name="Adler_2016" /> A prospective study of specimens collected in the same region between 2007 and 2011 revealed about one-third of samples obtained from patient samples were resistant to multiple antibiotics.<ref>{{cite journal |vauthors=Lunguya O, Lejon V, Phoba MF, Bertrand S, Vanhoof R, Verhaegen J, Smith AM, Keddy KH, Muyembe-Tamfum JJ, Jacobs J |date=15 November 2012 |title=Salmonella typhi in the democratic republic of the congo: fluoroquinolone decreased susceptibility on the rise |journal=PLOS Neglected Tropical Diseases |volume=6 |issue=11 |doi=10.1371/journal.pntd.0001921 |pmc=3499407 |pmid=23166855 |doi-access=free |article-number=e1921 |veditors=Ryan ET}}</ref> * Kampala, Uganda in 2015: 10,230 cases reported.<ref name="Appiah_2020" />
==History==
=== Early descriptions === The plague of Athens, during the Peloponnesian War, was most likely an outbreak of typhoid fever.<ref name="Adler_2016" /> During the war, Athenians retreated into a walled-in city to escape attack from the Spartans. This massive influx of humans into a concentrated space overwhelmed the water supply and waste infrastructure, likely leading to unsanitary conditions as fresh water became harder to obtain and waste became more difficult to collect and remove beyond the city walls.<ref name="Adler_2016" /> In 2006, examining the remains of a mass burial site from Athens from around the time of the plague (~430 B.C.) revealed that fragments of DNA similar to that of modern-day ''S.'' Typhi were detected, whereas ''Yersinia pestis'' (plague), ''Rickettsia prowazekii'' (typhus), ''Mycobacterium tuberculosis'', cowpox virus, and ''Bartonella henselae'' were not detected in any of the remains tested.<ref name="Papagrigorakis_2006">{{cite journal |vauthors=Papagrigorakis MJ, Yapijakis C, Synodinos PN, Baziotopoulou-Valavani E |date=May 2006 |title=DNA examination of ancient dental pulp incriminates typhoid fever as a probable cause of the Plague of Athens |journal=International Journal of Infectious Diseases |volume=10 |issue=3 |pages=206–214 |doi=10.1016/j.ijid.2005.09.001 |pmid=16412683 |doi-access=free}}</ref>
===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.<ref name="Adler_2016">{{Cite book |title=Typhoid fever: a history |vauthors=Adler R, Mara E |date=2016 |publisher=McFarland & Company |isbn=978-0-7864-9781-2 |location=Jefferson, North Carolina |oclc=934938999}}</ref> 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.<ref name="Adler_2016" /> Pierre-Charlles-Alexandre Louis also performed case studies and statistical analysis to demonstrate that typhoid was contagious – and that persons who already had the disease seemed to be protected.<ref name="Adler_2016" /> Afterward, several American doctors confirmed these findings, and then Sir William Jenner convinced any remaining skeptics that typhoid is a specific disease recognizable by lesions in the Peyer's patches by examining sixty-six autopsies from fever patients and concluding that the symptoms of headaches, diarrhea, rash spots, and abdominal pain were present only in patients who were found to have intestinal lesions after death; these observations solidified the association of the disease with the intestinal tract and gave the first clue to the route of transmission.<ref name="Adler_2016" />
In 1847, William Budd learned of an epidemic of typhoid fever in Clifton, and identified that all 13 of 34 residents who had contracted the disease drew their drinking water from the same well.<ref name="Adler_2016" /> Notably, this observation was two years before John Snow first published an early version of his theory that contaminated water was the central conduit for transmitting cholera. Budd later became health officer of Bristol ensured a clean water supply, and documented further evidence of typhoid as a water-borne illness throughout his career.<ref name="Adler_2016" />
===Cause=== Polish scientist Tadeusz Browicz described a short bacillus in the organs and feces of typhoid victims in 1874.<ref>{{cite journal |vauthors=Stachura J, Gałazka K |date=December 2003 |title=History and current status of Polish gastroenterological pathology |journal=Journal of Physiology and Pharmacology |volume=54 |issue=Suppl 3 |pages=183–192 |pmid=15075472}}</ref> 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.<ref name="Adler_2016" />
In April 1880, three months before Eberth's publication, Edwin Klebs described short and filamentous bacilli in the Peyer's patches in typhoid victims.<ref>{{Cite journal |date=7 September 1918 |title=Typhoid Fever Considered as a Problem of Scientific Medicine. |journal=JAMA: The Journal of the American Medical Association |volume=71 |issue=10 |page=847 |doi=10.1001/jama.1918.02600360063023 |hdl=2027/coo1.ark:/13960/t9d516735 |issn=0098-7484 |hdl-access=free}}</ref> The bacterium's role in disease was speculated but not confirmed.<ref name="Adler_2016" />
In 1880, Karl Joseph Eberth described a bacillus that he suspected was the cause of typhoid.<ref> {{cite journal |vauthors=Eberth CJ |date=1880 |title=Die Organismen in den Organen bei Typhus abdominalis |trans-title=Organisms in the [internal] organs in cases of Typhus abdominalis |url=http://babel.hathitrust.org/cgi/pt?id=hvd.32044093330488;view=1up;seq=74 |journal=Archiv für pathologische Anatomie und Physiologie |language=de |volume=81 |pages=58–74}}</ref><ref> {{cite journal |vauthors=Eberth CJ |date=1881 |title=Neue Untersuchungen über den Bacillus des Abdominaltyphus |trans-title=New investigations into the bacilli of abdominal typhoid |url=http://babel.hathitrust.org/cgi/pt?id=hvd.32044103035598;view=1up;seq=512 |journal=Archiv für pathologische Anatomie und Physiologie |language=de |volume=83 |pages=486–501}}</ref><ref> Eberth's findings were verified by Robert Koch {{cite journal |vauthors=Koch R |date=1881 |title=Zur Untersuchung von pathogenen Organismen |trans-title=On the investigation of pathogenic organisms |url=https://books.google.com/books?id=lD1AAAAAYAAJ&pg=PA1 |journal=Mitteilungen aus dem Kaiserlichen Gesundheitsamte |language=de |volume=1 |pages=1–49 |archive-url=https://web.archive.org/web/20170423081253/https://books.google.com/books?id=lD1AAAAAYAAJ&pg=PA45 |archive-date=23 April 2017}}</ref> 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.<ref name="Adler_2016" /> In 1884, pathologist Georg Theodor August Gaffky (1850–1918) confirmed Eberth's findings.<ref>{{cite journal |vauthors=Gaffky G |date=1884 |title=Zur aetiologie des abdominaltyphus. |trans-title=On the etiology of abdominal typhus |url=https://books.google.com/books?id=Y6lQAAAAYAAJ&pg=PA372 |journal=Mitteillungen aus dem Kaiserlichen Gesundheitsamt |language=de |volume=2 |pages=372–420 |archive-url=https://web.archive.org/web/20170423042158/https://books.google.com/books?id=Y6lQAAAAYAAJ&pg=PA372 |archive-date=23 April 2017}}</ref> Gaffky isolated the same bacterium as Eberth from the spleen of a typhoid victim, and was able to grow the bacterium on solid media.<ref name="Adler_2016" /> The organism was given names such as Eberth's bacillus, ''Eberthella'' Typhi, and Gaffky-Eberth bacillus.<ref name="Adler_2016" /> Today, the bacillus that causes typhoid fever goes by the scientific name ''Salmonella enterica'' serovar Typhi.<ref>{{Cite book |title=Atlas of Human Infectious Diseases |vauthors=Wertheim HF, Horby P, Woodall JP |date=2012 |publisher=John Wiley & Sons |isbn=978-1-4443-5467-6 |edition=1st |location=New York, NY |oclc=897547171}}</ref>
=== 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.<ref>{{cite journal |date=October 1897 |title=Typhoid Epidemic at Maidstone |journal=Journal of the Sanitary Institute |volume=18 |page=388}}</ref> In 1905, following an outbreak of typhoid fever, the City of Lincoln, England, instituted permanent water chlorination.<ref>{{cite web |title=A miracle for public health? |url=http://www.icis.com/Articles/2008/08/25/9150211/chlorine-cleans-water-for-millions-but-comes-under-attack-after-health.html |access-date=17 December 2012}}</ref> 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.<ref>{{cite book |title=Proceedings American Water Works Association. |vauthors=Leal JL |date=1909 |pages=100–109 |chapter=The Sterilization Plant of the Jersey City Water Supply Company at Boonton, N.J.}}</ref> The chlorination facility was designed by George W. Fuller.<ref>{{cite book |title=Proceedings American Water Works Association |vauthors=Fuller GW |date=1909 |pages=110–134 |chapter=Description of the Process and Plant of the Jersey City Water Supply Company for the Sterilization of the Water of the Boonton Reservoir.}}</ref>
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.<ref name="Adler_2016" /> The Lyster bag was essential for the survival of American soldiers in the Vietnam War.<ref name="Adler_2016" />
=== Direct transmission and carriers === [[File:Mary Mallon in hospital.jpg|thumb|upright=1.3|Mary Mallon ("Typhoid Mary") in a hospital bed (foreground): She was forcibly quarantined as a carrier of typhoid fever in 1907 for three years and then again from 1915 until she died in 1938.|right]] There were several occurrences of milk delivery men spreading typhoid fever throughout the communities they served. Although typhoid is not spread through milk itself, there were several examples of milk distributors in many locations watering their milk down with contaminated water, or cleaning the glass bottles the milk was placed in with contaminated water.<ref name="Adler_2016" /><ref name="Remember Jamaica Plain?_2007" /> Boston had two such cases around the turn of the 20th century.<ref name="Remember Jamaica Plain?_2007">{{Cite web |date=5 November 2007 |title=Typhoid Milkman |url=http://rememberjamaicaplain.blogspot.com/2007/11/typhoid-milkman.html |access-date=24 June 2021 |website=Remember Jamaica Plain?}}</ref> 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.<ref name="Remember Jamaica Plain?_2007" /> In 1908, J.J. Fallon, who was also a milkman, died of typhoid fever.<ref name="Remember Jamaica Plain?_2007" /> Following his death and confirmation of the typhoid fever diagnosis, the city conducted an investigation of typhoid symptoms and cases along his route and found evidence of a significant outbreak. A month after the outbreak was first reported, the ''Boston Globe'' published a short statement declaring the outbreak over, stating "[a]t Jamaica Plain there is a slight increase, the total being 272 cases. Throughout the city, there is a total of 348 cases."<ref name="Remember Jamaica Plain?_2007" /> There was at least one death reported during this outbreak: Mrs. Sophia S. Engstrom, aged 46.<ref name="Remember Jamaica Plain?_2007" /> Typhoid continued to ravage the Jamaica Plain neighborhood in particular throughout 1908, and several more people were reported dead due to typhoid fever, although these cases were not explicitly linked to the outbreak.<ref name="Remember Jamaica Plain?_2007" /> The Jamaica Plain neighborhood at that time was home to many working-class and poor immigrants, mostly from Ireland.<ref>{{Cite book |title=Local attachments: the making of an American urban neighborhood, 1850 to 1920 |vauthors=Von Hoffman A |date=1996 |publisher=Johns Hopkins University Press |oclc=1036707621}}</ref>
The most notorious carrier of typhoid fever, but by no means the most destructive, was Mary Mallon, known as Typhoid Mary.<ref name="Nova">{{cite web |title=Nova: The Most Dangerous Woman in America |url=https://www.pbs.org/wgbh/nova/typhoid/letter.html |url-status=live |archive-url=https://web.archive.org/web/20100426042928/http://www.pbs.org/wgbh/nova/typhoid/letter.html |archive-date=26 April 2010 |website=PBS}}</ref><ref name="Apple Podcasts">{{Cite web |title=Short Wave: Typhoid Mary: Lessons From An Infamous Quarantine on Apple Podcasts |url=https://podcasts.apple.com/kh/podcast/typhoid-mary-lessons-from-an-infamous-quarantine/id1482575855?i=1000482300467 |access-date=28 June 2021 |website=Apple Podcasts |language=en-GB}}</ref> 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.<ref name="Adler_2016" /> Mary Mallon became the first known example of an asymptomatic carrier of an infectious disease, making typhoid fever the first known disease being transmissible through asymptomatic hosts.<ref name="Adler_2016" /> The cases and deaths caused by Mallon were mainly upper-class families in New York City.<ref name="Adler_2016" /> At the time of Mallon's tenure as a personal cook for upper-class families, New York City reported 3,000 to 4,500 cases of typhoid fever annually.<ref name="Adler_2016" /> In the summer of 1906, two daughters of a wealthy family and maids working in their home became ill with typhoid fever.<ref name="Adler_2016" /> After investigating their home water sources and ruling out water contamination, the family hired civil engineer George Soper to conduct an investigation of the possible source of typhoid fever in the home.<ref name="Adler_2016" /> Soper described himself as an "epidemic fighter".<ref name="Adler_2016" /> His investigation ruled out many sources of food, and led him to question if the cook the family hired just prior to their household outbreak, Mallon, was the source.<ref name="Adler_2016" /> Since she had already left and begun employment elsewhere, he proceeded to track her down in order to obtain a stool sample.<ref name="Adler_2016" /> When he was able to finally meet Mallon in person he described her by saying "Mary had a good figure and might have been called athletic had she not been a little too heavy."<ref name="Soper_1939">{{Cite journal |vauthors=Soper GA |date=October 1939 |title=The Curious Career of Typhoid Mary |journal=Bulletin of the New York Academy of Medicine |volume=15 |issue=10 |pages=698–712 |issn=0028-7091 |pmc=1911442 |pmid=19312127}}</ref> 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."<ref name="Soper_1939"/> Ultimately, 51 cases and 3 deaths were suspected to be caused by Mallon.<ref>{{Cite web |date=27 March 2015 |title=10 Things You May Not Know About 'Typhoid Mary' |url=https://www.history.com/news/10-things-you-may-not-know-about-typhoid-mary |access-date=28 June 2021 |website=HISTORY |language=en |vauthors=Klein C}}</ref><ref name="Apple Podcasts" />
In 1924, the city of Portland, Oregon, experienced an outbreak of typhoid fever, consisting of 26 cases and 5 deaths, all deaths due to intestinal hemorrhage.<ref name="Sears_1924">{{cite journal |vauthors=Sears HJ, Garhart RW, Mack DW |date=October 1924 |title=A Milk Borne Epidemic of Typhoid Fever Traced to a Urinary Carrier |journal=American Journal of Public Health |volume=14 |issue=10 |pages=848–854 |doi=10.2105/ajph.14.10.848 |pmc=1355026 |pmid=18011334}}</ref> 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.<ref name="Sears_1924" /> Misidentification of the disease, due to inaccurate Widal test results, delayed identification of the carrier and proper treatment.<ref name="Sears_1924" /> Ultimately, it took four samplings of different secretions from all of the dairy workers in order to successfully identify the carrier.<ref name="Sears_1924" /> Upon discovery, the dairy worker was forcibly quarantined for seven weeks, and regular samples were taken, most of the time the stool samples yielding no typhoid and often the urine yielding the pathogen.<ref name="Sears_1924" /> The carrier was reported as being 72 years old and appearing in excellent health with no symptoms.<ref name="Sears_1924" /> Pharmaceutical treatment decreased the amount of bacteria secreted, however, the infection was never fully cleared from the urine, and the carrier was released "under orders never again to engage in the handling of foods for human consumption."<ref name="Sears_1924" /> At the time of release, the authors noted "for more than fifty years he has earned his living chiefly by milking cows and knows little of other forms of labor, it must be expected that the closest surveillance will be necessary to make certain that he does not again engage in this occupation."<ref name="Sears_1924" />
Overall, in the early 20th century the medical profession began to identify disease carriers and evidence of transmission independent of water contamination.<ref name="Adler_2016" /> In a 1933 American Medical Association publication, physicians' treatment of asymptomatic carriers is best summarized by the opening line "Carriers of typhoid bacilli are a menace".<ref name="Journal of the American Medical Association_1933">{{Cite journal |date=10 June 1933 |title=Typhoid Carriers and Their Treatment |journal=Journal of the American Medical Association |volume=100 |issue=23 |page=1866 |doi=10.1001/jama.1933.02740230044012 |issn=0002-9955}}</ref> 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.<ref name="Journal of the American Medical Association_1933" /> The authors further estimate that there are four to five chronic female carriers to every one male carrier, although offered no data to explain this assertion of a gender difference in the rate of typhoid carriers.<ref name="Journal of the American Medical Association_1933" /> As far as treatment, the authors suggest: "When recognized, carriers must be instructed as to the disposal of excreta as well as to the importance of personal cleanliness. They should be forbidden to handle food or drink intended for others, and their movements and whereabouts must be reported to the public health officers".<ref name="Journal of the American Medical Association_1933" /> Today, typhoid carriers exist all over the world, but the highest incidence of asymptomatic infection is likely to occur in South/Southeast Asian and Sub-Saharan countries.<ref name = "LA county typhoid 2016">{{cite book |title=Acute Communicable Disease Control: 2016 Annual Morbidity Report |date=2016 |page=133 |chapter=TYPHOID FEVER, ACUTE AND CARRIER |chapter-url=http://www.publichealth.lacounty.gov/acd/diseases/Typhoid.pdf |via=Los Angeles County Department of Public Health}}</ref><ref>{{cite journal |vauthors=Stanaway JD, Reiner RC, Blacker BF, Goldberg EM, Khalil IA, Troeger CE, etal |date=April 2019 |title=The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017 |journal=The Lancet. Infectious Diseases |volume=19 |issue=4 |pages=369–381 |bibcode=2019LanID..19..369S |doi=10.1016/S1473-3099(18)30685-6 |pmc=6437314 |pmid=30792131}}</ref> 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.<ref name="LA county typhoid 2016" /> Cases of typhoid fever must be reported within one working day from identification. As of 2018, chronic typhoid carriers must sign a "Carrier Agreement" and are required to test for typhoid shedding twice yearly, ideally every 6 months.<ref name="Los Angeles Department of Public Health_2018">{{Cite web |date=June 2018 |title=Acute Communicable Disease Control Manual (B-73): Typhoid Fever Carrier |url=http://publichealth.lacounty.gov/acd/procs/b73/DiseaseChapters/B73Typhoidfevercarrier.pdf |access-date=27 June 2021 |website=Los Angeles Department of Public Health}}</ref> Carriers may be released from their agreements upon fulfilling "release" requirements, based on completion of a personalized treatment plan designed with medical professionals.<ref name="Los Angeles Department of Public Health_2018" /> Fecal or gallbladder carrier release requirements: 6 consecutive negative feces and urine specimens submitted at 1-month or greater intervals beginning at least 7 days after completion of therapy.<ref name="Los Angeles Department of Public Health_2018" /> Urinary or kidney carrier release requirements: 6 consecutive negative urine specimens submitted at 1-month or greater intervals beginning at least 7 days after completion of therapy.<ref name="Los Angeles Department of Public Health_2018" />
Due to the nature of asymptomatic cases, many questions remain about how individuals can tolerate infection for long periods, how to identify such cases, and efficient options for treatment. Researchers are working to understand asymptomatic infection with ''Salmonella'' species by studying infections in laboratory animals, which will ultimately lead to improved prevention and treatment options for typhoid carriers. In 2002, John Gunn described the ability of ''Salmonella'' sp. to form biofilms on gallstones in mice, providing a model for studying carriage in the gallbladder.<ref>{{cite journal |vauthors=Prouty AM, Schwesinger WH, Gunn JS |date=May 2002 |title=Biofilm formation and interaction with the surfaces of gallstones by Salmonella spp |journal=Infection and Immunity |volume=70 |issue=5 |pages=2640–2649 |doi=10.1128/iai.70.5.2640-2649.2002 |pmc=127943 |pmid=11953406}}</ref> 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.<ref name="Monack_2004">{{cite journal |vauthors=Monack DM, Bouley DM, Falkow S |date=January 2004 |title=Salmonella typhimurium persists within macrophages in the mesenteric lymph nodes of chronically infected Nramp1+/+ mice and can be reactivated by IFNgamma neutralization |journal=The Journal of Experimental Medicine |volume=199 |issue=2 |pages=231–241 |doi=10.1084/jem.20031319 |pmc=2211772 |pmid=14734525}}</ref><ref>{{cite journal |vauthors=Lawley TD, Bouley DM, Hoy YE, Gerke C, Relman DA, Monack DM |date=January 2008 |title=Host transmission of Salmonella enterica serovar Typhimurium is controlled by virulence factors and indigenous intestinal microbiota |journal=Infection and Immunity |volume=76 |issue=1 |pages=403–416 |doi=10.1128/iai.01189-07 |pmc=2223630 |pmid=17967858}}</ref> Monack's mouse model allows long-term carriage of ''Salmonella'' in mesenteric lymph nodes, spleen and liver.<ref name="Monack_2004" />
=== Vaccine development === [[File:Almroth Wright c1900.jpg|thumb|upright=1.3|Almroth Edward Wright developed the first effective typhoid vaccine.]] British bacteriologist Almroth Edward Wright first developed an effective typhoid vaccine at the Army Medical School in Netley, Hampshire. It was introduced in 1896 and used successfully by the British during the Second Boer War in South Africa.<ref>{{cite web |title=Sir Almroth Edward Wright |url=http://www.britannica.com/EBchecked/topic/649457/Sir-Almroth-Edward-Wright |url-status=live |archive-url=https://web.archive.org/web/20131111031313/http://www.britannica.com/EBchecked/topic/649457/Sir-Almroth-Edward-Wright |archive-date=11 November 2013 |website=Encyclopædia Britannica}}</ref> 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.<ref>{{Cite journal |vauthors=Wright AE, Douglas SR |date=31 January 1904 |title=An experimental investigation of the rôle of the blood fluids in connection with phagocytosis |journal=Proceedings of the Royal Society of London |language=en |volume=72 |issue=477–486 |pages=357–370 |doi=10.1098/rspl.1903.0062 |issn=0370-1662 |s2cid=84388525}}</ref> 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.<ref name="Adler_2016" /> To show evidence of the vaccine's efficacy, Wright then collected serum samples from patients several weeks post-vaccination, and tested their serum's ability to agglutinate live typhoid bacteria. A "positive" result was represented by clumping of bacteria, indicating that the body was producing anti-serum (now called antibodies) against the pathogen.<ref name="Adler_2016" />
Citing the example of the Second Boer War, during which many soldiers died from easily preventable diseases, Wright convinced the British Army that 10 million vaccine doses should be produced for the troops being sent to the Western Front, thereby saving up to half a million lives during World War I.<ref>{{cite web |title=Library and Archive Catalogue |url=http://www2.royalsociety.org/DServe/dserve.exe?dsqIni=Dserve.ini&dsqApp=Archive&dsqCmd=Show.tcl&dsqDb=Persons&dsqPos=5&dsqSearch=%28Surname%3D%27wright%27%29 |access-date=1 November 2010 |publisher=Royal Society}}{{Dead link|date=July 2018|bot=InternetArchiveBot|fix-attempted=no}}</ref> 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.<ref>{{cite web |date=11 November 2014 |title=Medical lessons from World War I underscore need to keep developing antimicrobial drugs |url=https://www.minnpost.com/second-opinion/2014/11/medical-lessons-world-war-i-underscore-need-keep-developing-antimicrobial-dru |url-status=live |archive-url=https://web.archive.org/web/20160130210117/https://www.minnpost.com/second-opinion/2014/11/medical-lessons-world-war-i-underscore-need-keep-developing-antimicrobial-dru |archive-date=30 January 2016 |access-date=8 September 2017 |website=MinnPost}}</ref>
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.<ref name="USAMRMC">{{cite book |url=http://technologytransfer.amedd.army.mil/assets/docs/marketing/USAMRMC_history.pdf |title=USAMRMC: 50 Years of Dedication to the Warfighter 1958–2008 |publisher=U.S. Army Medical Research & Material Command (2008) |year=2008 |page=5 |asin=B003WYKJNY |access-date=27 March 2013 |archive-url=https://web.archive.org/web/20130214210353/http://technologytransfer.amedd.army.mil/assets/docs/marketing/USAMRMC_history.pdf |archive-date=14 February 2013}}</ref> Typhoid vaccination for members of the American military became mandatory in 1911.<ref name="Adler_2016" /> Before the vaccine, the rate of typhoid fever in the military was 14,000 or greater per 100,000 soldiers. By World War I, the rate of typhoid in American soldiers was 37 per 100,000.<ref name="Adler_2016" />
During the Second World War, the United States Army authorized the use of a trivalent vaccine – containing heat-inactivated Typhoid, Paratyphi A and Paratyphi B pathogens.<ref name="Adler_2016" />
In 1934, the discovery of the Vi capsular antigen by Arthur Felix and Miss S. R. Margaret Pitt enabled the development of the safer Vi Antigen vaccine – which is widely in use today.<ref>{{Cite journal |vauthors=Felix A, Pitt RM |date=July 1934 |title=A New Antigen of B. Typhosus |journal=The Lancet |language=en |volume=224 |issue=5787 |pages=186–191 |doi=10.1016/S0140-6736(00)44360-6}}</ref> 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.<ref>{{Cite journal |vauthors=Craigie J |date=1 November 1957 |title=Arthur Felix, 1887–1956 |journal=Biographical Memoirs of Fellows of the Royal Society |volume=3 |issue=3 |pages=53–79 |doi=10.1098/rsbm.1957.0005 |s2cid=72753150 |doi-access=free}}</ref>
=== Antibiotics and resistance === Chloramphenicol was isolated from ''Streptomyces'' by David Gotlieb during the 1940s.<ref name="Adler_2016" /> In 1948, American army doctors tested its efficacy in treating typhoid patients in Kuala Lumpur, Malaysia.<ref name="Adler_2016" /> Individuals who received a full course of treatment cleared the infection, whereas patients given a lower dose had a relapse.<ref name="Adler_2016" /> Asymptomatic carriers continued to shed bacilli despite chloramphenicol treatment – only ill patients were improved with chloramphenicol.<ref name="Adler_2016" /> 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.<ref name="Adler_2016" />
==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,<ref>{{Cite web |title=Typhoid Fever |url=https://cerid.uw.edu/diseases/typhoid-fever |archive-url=https://web.archive.org/web/20191208221407/https://cerid.uw.edu/diseases/typhoid-fever |archive-date=8 December 2019 |access-date=8 December 2019 |work=Center for Emerging and Re-emerging Infectious Diseases |publisher=University of Washington}}</ref> drain fever, and low fever.<ref>{{Cite news |date=6 April 1878 |title=TYPHOID OR DRAIN FEVER, AND HOW TO PREVENT ITS SPREADING. |url=https://trove.nla.gov.au/newspaper/article/82120702 |access-date=13 April 2020 |newspaper=The Warwick Examiner and Times}}</ref>
==Society and culture== ===Notable people=== {{see also|Category:Deaths from typhoid fever}} * Emperor Augustus of Rome – suspected based on historical record but not confirmed.<ref name="Adler_2016" /> He had either a liver abscess or typhoid fever, and survived by using ice baths and cold compresses as a means of treatment for his fever.<ref name="Adler_2016" /> The idea for this treatment was provided by Greek physician Antonius Musa.<ref name="Platner_2002">{{cite book |last1=Platner |first1=Samuel Ball |title=A Topographical Dictionary of Ancient Rome |last2=Ashby |first2=Thomas |date=2002 |publisher=Oxford University Press |isbn=978-0-19-925649-5}}</ref><ref name="Yapijakis_2009">{{cite journal |last1=Yapijakis |first1=C. |date=2009 |title=Hippocrates of Kos, the father of clinical medicine, and Asclepiades of Bithynia, the father of molecular medicine. Review. |journal=In Vivo (Athens, Greece) |volume=23 |issue=4 |pages=507–514 |pmid=19567383 |quote="The Greek physician Antonius Musa notably cured the emperor Augustus of typhoid fever with cold baths"}}</ref> * Prince Albert of Saxe-Coburg and Gotha, husband of Queen Victoria of the United Kingdom, died 24 days after the first record of "feeling horribly ill".<ref name="Adler_2016" /> Died 14 December 1861 after suffering<!-- ! check for tone --> loss of appetite, insomnia, fever, chills, profuse sweating, vomiting, rash spots, delusions, inability to recognize family members, worsening rash on abdomen, a change in tongue color, then finally a state of extreme fatigue.<ref name="Adler_2016" /> Attending physician William Jenner, an expert on typhoid fever at the time, diagnosed him.<ref>{{Cite book |title=The cult of the Prince Consort |vauthors=Darby E |date=1983 |publisher=Yale University Press |others=Nicola Smith |isbn=0-300-03015-0 |location=New Haven |oclc=10432279}}</ref> * Edward VII of the UK, son of Queen Victoria, while still Prince of Wales, had a near-fatal case of typhoid fever.<ref>{{cite ODNB |doi=10.1093/ref:odnb/32975 |url=http://www.oxforddnb.com/view/article/32975 |title=Edward VII (1841–1910) |author-link=Colin Matthew |vauthors=Matthew HC |date=September 2004 |publication-date=May 2006 |archive-url=https://web.archive.org/web/20160302022125/http://www.oxforddnb.com/view/article/32975 |archive-date=2 March 2016}}</ref> * Tsar Nicholas II of Russia, survived, illness was circa 1900–1901.<ref>{{Cite web |title=Nicholas II - At the Court of the Last Tsar - Chapter 1, Part 2, The Empress Alexandra |url=https://www.alexanderpalace.org/mossolov/one2.html |access-date=21 June 2021 |website=www.alexanderpalace.org}}</ref>{{Self-published inline|date=November 2021|certain=y}} * Queen Wilhelmina of the Netherlands may have had an abortion in 1902 because of a typhoid infection she survived.<ref>{{cite web |date=19 April 2023 |title=Hoogleraar heeft aanwijzingen voor abortus bij Wilhelmina: 'Monarchie hing aan zijden draadje' |trans-title=Professor has indication for abortion Wilhelmina: Monarchy was hanging by a thread |url=https://www.rtlnieuws.nl/nieuws/nederland/artikel/5379059/wilhelmina-abortus-juliana-tyfus-infectie-bevalling |website=RTL Nieuws |language=nl}}</ref><ref>{{cite web |author=Trudy Dehue |title=Egg Foetus Baby, A New History of Pregnancy |url=https://www.letterenfonds.nl/en/book/1603/egg-foetus-baby |archive-url=https://web.archive.org/web/20240317003500/https://www.letterenfonds.nl/en/book/1603/egg-foetus-baby |archive-date=17 March 2024 |access-date=6 December 2023 |website=Dutch foundation for literature}}</ref> * 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.<ref>{{cite news |date=29 September 2011 |title=Willie Lincoln's death: A private agony for a president facing a nation of pain |url=https://www.washingtonpost.com/lifestyle/style/willie-lincolns-death-a-private-agony-for-a-president-facing-a-nation-of-pain/2011/0929/gIQAv7Z7SL_story.html |archive-url=https://web.archive.org/web/20170401111805/https://www.washingtonpost.com/lifestyle/style/willie-lincolns-death-a-private-agony-for-a-president-facing-a-nation-of-pain/2011/09/29/gIQAv7Z7SL_story.html |archive-date=1 April 2017 |access-date=12 March 2017 |newspaper=The Washington Post |issn=0190-8286 |vauthors=Dennis B}}</ref> * Princess Leopoldina of Brazil, daughter of Emperor Pedro II, died of typhoid in 1871.<ref>{{cite web |date=7 June 2020 |title=Maldiçãp, febre e alucinações: a melancólica morte de Leopoldina de Bragança |url=https://aventurasnahistoria.uol.com.br/noticias/almanaque/maldicao-febre-e-alucinacoes-melancolica-morte-de-leopoldina-de-braganca.phtml |access-date=3 February 2022 |website=aventurasnahistoria.uol.com.br}}</ref> * 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.<ref>{{cite web |title=A History of Stanford |url=https://www.stanford.edu/about/history/ |access-date=4 July 2018 |website=Stanford University}}</ref> * Three of Louis Pasteur's five children died of typhoid fever.<ref name="Adler_2016" /> * Gerard Manley Hopkins, an English poet, died of typhoid fever in 1889.<ref>{{cite book |url=https://archive.org/details/gerardmanleyhopk0000unse_e4k5 |title=Gerard Manley Hopkins: A Life |vauthors=Ruggles E |date=1944 |publisher=Norton |url-access=registration}}</ref> * 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.<ref>{{Cite Australian Dictionary of Biography |volume=6 |year=1976 |title=Henry James Herbert Scott (1858–1910) |id2=scott-henry-james-herbert-4548 |first=Belinda F.|last=Scott |access-date=30 August 2025}}</ref> * 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.<ref>{{cite magazine |year=1959 |title=Straw for Silence |magazine=The Spectator |publisher=F.C. Westley |volume=203 |issn=0038-6952 |oclc=1766325}}</ref> * Hakaru Hashimoto, a Japanese medical scientist, died of typhoid fever in 1934.{{cn|date=February 2026}} * John Buford, Union cavalry officer during the Civil War, died of typhoid fever on 16 December 1863.{{cn|date=February 2026}}
== References == {{Reflist}}
== Further reading == {{refbegin}} * {{Cite web |website=Centers for Disease Control and Prevention |date=30 March 2021 |title=Typhoid and Paratyphoid Fever: Information for Health Professionals |url=https://www.cdc.gov/typhoid-fever/health-professional.html |access-date=27 June 2021}} * {{cite journal |last=Stanaway |first=Jeffrey D |date=April 2019 |title=The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017. |journal=The Lancet Infectious Diseases |volume=19 |issue=4 |pages=369–381 |bibcode=2019LanID..19..369S |doi=10.1016/S1473-3099(18)30685-6 |pmc=6437314 |pmid=30792131 |collaboration=GBD 2017 Typhoid and Paratyphoid Collaborators}} * {{Cite web |website=National Health Service |date=18 June 2018 |title=Typhoid Fever: Overview |url=https://www.nhs.uk/conditions/typhoid-fever/ |access-date=27 June 2021}} * {{Cite web |last=Public Health Agency of Canada |date=2010 |title=Pathogen Safety Data Sheets: Infectious Substances – Salmonella enterica spp. |url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/salmonella-enterica.html |access-date=28 June 2021}} * {{Cite web |date=31 January 2018 |title=Typhoid: Fact Sheet |url=https://www.who.int/news-room/fact-sheets/detail/typhoid |access-date=27 June 2021}} {{refend}} {{sister project links||d=Q83319|c=Category:Typhoid fever|n=Category:Typhoid|b=no|q=no|v=no|voy=no|m=no|mw=no|s=no|wikt=no|species=no}} {{Medical resources | DiseasesDB = 27829 | ICD11 = {{ICD11|1A07}} | ICD10 = {{ICD10|A|01|0|a|00}} | ICD9 = {{ICD9|002}} | ICDO = | OMIM = | MedlinePlus = 001332 | eMedicineSubj = oph | eMedicineTopic = 686 | eMedicine_mult = {{eMedicine2|med|2331}} | MeshID = D014435 }} {{Bacterial diseases}} {{Authority control}}
Category:Typhoid fever Category:Conditions diagnosed by stool test Category:Intestinal infectious diseases Category:Vaccine-preventable diseases Category:Waterborne diseases Category:Wikipedia emergency medicine articles ready to translate Category:Wikipedia medicine articles ready to translate