Trichuriasis , also known as  whipworm infection,  occurs through ingestion of whipworm eggs and is more common in warmer climates. Whipworm eggs are passed in the feces of infected persons, and if an infected person  defecates outdoors  or if untreated human feces is used as fertilizer, eggs are deposited on soil where they can mature into an infective stage. [ 5 ]  Ingestion of these eggs "can happen when hands or fingers that have contaminated dirt on them are put in the mouth or by consuming vegetables or fruits that have not been carefully cooked, washed or peeled." [ 5 ]  The eggs hatch in the small intestine, then move into the wall of the small intestine and develop. On reaching adulthood, the thinner end (the anterior of the worm) burrows into the large intestine, the thicker (posterior) end projecting into the  lumen , where it mates with nearby worms. The females can grow to 50 mm (2.0 in) long. [ 3 ]


Trichuris trichiura  can cause the serious disease Trichuris dysentery syndrome (TDS), with chronic dysentery, anemia, rectal prolapse, and poor growth. [ 8 ]  TDS is treated with  anthelminthics  as well as iron supplementation for anemia. [ 9 ]


Whipworm commonly infects patients also infected with  Giardia ,  Entamoeba histolytica ,  Ascaris lumbricoides , and  hookworms . [ 10 ]


Trichuris trichiura  can be treated with a single dose of  albendazole . [ 11 ]  In Kenya, half of a group of children, 98% of whom had  Trichuris trichiura  with or without infections by other  soil-transmitted helminths , were given albendazole, while the other half of the children received placebos. It was found that the children who received the drug grew significantly better than the group of children who did not receive the treatment. [ 12 ]   Another treatment that can be used is  mebendazole , or  flubendazole . [ 13 ]  The medication interferes with the parasite’s nutrient intake, which eventually leads to death.


However, it has been shown that both albendazole and mebendazole have low cure rate for  Trichuris thrichiura  specifically, with treatments only achieving cure rates 30,7% for albendazole and 42,1% for mebendazole. [ 14 ]


There is a worldwide distribution of  Trichuris trichiura , with an estimated one billion human infections. [ 15 ] [ 16 ] [ 17 ] [ 8 ]  However, it is chiefly tropical, especially in Asia and, to a lesser degree, in Africa and South America. Within the United States, infection is rare overall but may be common in the rural Southeast, where 2.2 million people are thought to be infected. Poor hygiene is associated with  trichuriasis  as well as the consumption of shaded moist soil, or food that may have been fecally contaminated. Children are especially vulnerable to infection due to their high exposure risk. Eggs are infective about 2–3 weeks after they are deposited in the soil under proper conditions of warmth and moisture, hence its tropical distribution.


A closely related species,  Trichuris suis , which typically infects pigs, is capable of infecting humans. This shows that the two species have very close evolutionary histories. However, morphology and developmental stages remain different, making them two separate species. [ 18 ]


WHO have since 2001 had a strategy for control of soil-transmitted helminths, including whipworms. This strategy entails treating at-risk individuals in the endemic areas. Risk groups for whipworm infections are children at preschool and school-aged children, people with specific high-risk jobs, women in reproductive and pregnant and breastfeeding women. The periodic treatment of the risk groups is done through either deworming campaigns or preventative chemotherapy. [ 19 ]


The  hygiene hypothesis  suggests that various immunological disorders that have been observed in humans only within the last 100 years, such as  Crohn's disease , or that have become more common during that period as hygienic practices have become more widespread, may result from a lack of exposure to parasitic worms ( helminths ) during childhood. The use of  Trichuris suis  ova (TSO, or pig whipworm eggs) by Weinstock, et al., as a therapy for treating Crohn's disease [ 20 ] [ 21 ] [ 22 ]  and to a lesser extent  ulcerative colitis [ 23 ]  are two examples that support this hypothesis. There is also anecdotal evidence that treatment of  inflammatory bowel disease  (IBD) with TSO decreases the incidence of  asthma , [ 24 ] [ self-published source? ]   allergy , [ 25 ]  and other inflammatory disorders. [ 26 ]  Some scientific evidence suggests that the course of  multiple sclerosis  may be very favorably altered by helminth infection; [ 27 ]  TSO is being studied as a treatment for this disease. [ 28 ] [ 29 ]


Defecography


Caroline Pomeroy, PhD July 9th, 2019.


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. [ 1 ]


Typhoid fever , also known simply as  typhoid , is a disease caused by  Salmonella enterica   serotype  Typhi bacteria, also called  Salmonella typhi . [ 2 ] [ 3 ]  Symptoms vary from mild to severe, and usually begin six to 30 days after exposure. [ 4 ] [ 5 ]  Often there is a gradual onset of a high  fever  over several days. [ 4 ]  This is commonly accompanied by weakness,  abdominal pain ,  constipation ,  headaches , and mild vomiting. [ 6 ] [ 5 ] [ 7 ]  Some people develop a skin rash with  rose colored spots . [ 5 ]  In severe cases, people may experience confusion. [ 7 ]  Without treatment, symptoms may last weeks or months. [ 5 ]   Diarrhea  may be severe, but is uncommon. [ 7 ]  Other people may carry it without being affected, but are still contagious. [ 8 ]  Typhoid fever is a type of  enteric  fever, along with  paratyphoid fever . [ 2 ]   Salmonella  enterica  Typhi is believed to infect and replicate only within humans. [ 9 ]


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 . [ 5 ] [ 7 ]  Typhoid is spread by eating or drinking food or water contaminated with the  feces  of an infected person. [ 8 ]  Risk factors include limited access to clean drinking water and poor  sanitation . [ 2 ]  Those who have not yet been exposed to it and ingest contaminated drinking water or food are most at risk for developing symptoms. [ 7 ]  Only humans can be infected; there are no known animal reservoirs. [ 8 ]   Salmonella Typhi which causes typhoid fever is different than the other  Salmonella  bacteria that usually cause  salmonellosis , a common type of food poisoning. [ 10 ]


Diagnosis is performed by culturing and identifying  S. enterica typhi  from patient samples or  detecting an immune response to the pathogen from blood samples . [ 5 ] [ 2 ] [ 11 ]  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. [ 12 ]  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. [ 9 ]


A  typhoid vaccine  can prevent about 40–90% of cases during the first two years. [ 13 ]  The vaccine may have some effect for up to seven years. [ 2 ]  For those at high risk or people traveling to areas where it is common, vaccination is recommended. [ 8 ]  Other efforts to prevent it include providing clean  drinking water , good  sanitation , and  handwashing . [ 5 ] [ 8 ]  Until an infection is confirmed as cleared, the infected person should not prepare food for others. [ 5 ]  Typhoid is treated with  antibiotics  such as  azithromycin ,  fluoroquinolones , or  third-generation cephalosporins . [ 2 ]  Resistance to these antibiotics has been developing, which has made treatment more difficult. [ 2 ] [ 14 ] [ 15 ]


In 2015, 12.5 million new typhoid cases were reported. [ 16 ]  The disease is most common in India. [ 2 ]  Children are most commonly affected. [ 2 ] [ 8 ]  Typhoid decreased in the  developed world  in the 1940s as a result of improved sanitation and the use of antibiotics. [ 8 ]  Every year about 400 cases are reported in the U.S. and an estimated 6,000 people have typhoid. [ 7 ] [ 17 ]  In 2015, it resulted in about 149,000 deaths worldwide – down from 181,000 in 1990. [ 18 ] [ 19 ]  Without treatment, the risk of death may be as high as 20%. [ 8 ]  With treatment, it is between 1% and 4%. [ 2 ] [ 8 ]


Typhus  is a different disease, caused by unrelated species of bacteria. [ 20 ]  Owing to their similar symptoms, they were not recognized as distinct diseases until the 1800s. "Typhoid" means "resembling typhus". [ 21 ]


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. [ 22 ]


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. [ 25 ]  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 . [ 26 ]  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. [ 27 ]


Unlike other strains of  Salmonella , humans are the only known typhoid carriers. [ 28 ]   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. [ 28 ]  An asymptomatic human carrier is someone who is still excreting typhoid bacteria in stool a year after the acute stage of the infection. [ 28 ]


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. [ 29 ]


The  Widal  test is used to identify specific antibodies in the serum of people with typhoid by using antigen-antibody interactions. [ 30 ]


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 . [ 31 ]


Rapid diagnostic tests such as Tubex, Typhidot, and Test-It have shown moderate diagnostic accuracy. [ 32 ]


Typhidot is based on the presence of specific IgM and IgG antibodies to a specific 50 Kd  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. [ citation needed ]


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. [ citation needed ]


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. [ 33 ]


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 ]


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. [ 34 ]


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, [ 35 ]  which are  vectors  of many pathogens, including  Salmonella  spp. [ 36 ]  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. [ 37 ]


Two  typhoid vaccines  are licensed for use in the prevention of typhoid: [ 13 ]  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. [ 13 ]  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). [ 38 ]


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. [ 39 ]  Although vaccination programs for typhoid have proven effective, they alone cannot eliminate typhoid fever. [ 39 ]  Combining vaccines with public health efforts is the only proven way to control this disease. [ 39 ]


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. [ 39 ]


A version of the vaccine combined with a  hepatitis A  vaccine is also available. [ 40 ]


Results of a phase 3 trial of typhoid  conjugate vaccine  (TCV) in December 2019 reported 81% fewer cases among children. [ 41 ] [ 42 ]


The rediscovery of  oral rehydration therapy  in the 1960s provided a simple way to prevent many of the deaths of  diarrheal  diseases in general. [ 43 ]


Where resistance is uncommon, the treatment of choice is a  fluoroquinolone  such as  ciprofloxacin . [ 44 ] [ 45 ]  Otherwise, a third-generation cephalosporin such as  ceftriaxone  or  cefotaxime  is the first choice. [ 46 ] [ 47 ] [ 48 ] [ 49 ]   Cefixime  is a suitable oral alternative. [ 50 ] [ 51 ]


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. [ 52 ]  Treatment with antibiotics reduces the case-fatality rate to about 1%. [ 53 ]


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. [ 54 ]


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. [ 55 ]


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. [ 56 ] [ 57 ]


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. [ 58 ]  Typhoid resistant to these agents is known as multidrug-resistant typhoid. [ 59 ]


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. [ 45 ]  Azithromycin can be taken by mouth and is less expensive than ceftriaxone, which is given by injection. [ 60 ]


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. [ 61 ]


In 2000, typhoid fever caused an estimated 21.7 million illnesses and 217,000 deaths. [ 11 ]  It occurs most often in children and young adults between 5 and 19 years old. [ 62 ]  In 2013, it resulted in about 161,000 deaths – down from 181,000 in 1990. [ 19 ]  Infants, children, and adolescents in south-central and Southeast Asia have the highest rates of typhoid. [ 63 ]  Outbreaks are also often reported in sub-Saharan Africa and Southeast Asia. [ 64 ] [ 65 ] [ 66 ]  In 2000, more than 90% of morbidity and mortality due to typhoid fever occurred in Asia. [ 67 ]  In the U.S., about 400 cases occur each year, 75% of which are acquired while traveling internationally. [ 68 ] [ 69 ]


Before the antibiotic era, the  case fatality rate  of typhoid fever was 10–20%. Today, with prompt treatment, it is less than 1%, [ 70 ]  but 3–5% of people who are infected develop a chronic infection in the gall bladder. [ 71 ]  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. [ 57 ]  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. [ 72 ] [ 73 ]


In industrialized nations, water sanitation and food handling improvements have reduced the number of typhoid cases. [ 74 ]  Third world nations have the highest rates. These areas 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. [ 75 ]


In 2004–2005 an outbreak in the  Democratic Republic of Congo  resulted in more than 42,000 cases and 214 deaths. [ 62 ]  Since November 2016,  Pakistan  has had an outbreak of extensively  drug-resistant  (XDR) typhoid fever. [ 76 ]


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 . [ 77 ]


The  plague of Athens , during the  Peloponnesian War , was most likely an outbreak of typhoid fever. [ 82 ]  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. [ 82 ]  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 modern-day  S.  Typhi  DNA 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. [ 79 ]


It is possible that the Roman emperor  Augustus Caesar  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. [ 82 ]  There is a statue of the Greek physician,  Antonius Musa , [ 90 ]  who treated his fever. [ 91 ]


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. [ 82 ]  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. [ 82 ]  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. [ 82 ]  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. [ 82 ]


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. [ 82 ]  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. [ 82 ]


Polish scientist  Tadeusz Browicz  described a short bacillus in the organs and feces of typhoid victims in 1874. [ 92 ]  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. [ 82 ]


In April 1880, three months before Eberth's publication,  Edwin Klebs  described short and  filamentous  bacilli in the  Peyer's patches  in typhoid victims. [ 93 ]  The bacterium's role in disease was speculated but not confirmed. [ 82 ]


In 1880,  Karl Joseph Eberth  described a bacillus that he suspected was the cause of typhoid. [ 94 ] [ 95 ] [ 96 ]   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. [ 82 ]  In 1884, pathologist  Georg Theodor August Gaffky  (1850–1918) confirmed Eberth's findings. [ 97 ]  Gaffky isolated the same bacterium as Eberth from the spleen of a typhoid victim, and was able to grow the bacterium on solid media. [ 82 ]  The organism was given names such as Eberth's bacillus,  Eberthella  Typhi, and Gaffky-Eberth bacillus. [ 82 ]  Today, the bacillus that causes typhoid fever goes by the scientific name  Salmonella enterica  serovar Typhi. [ 98 ]


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. [ 99 ]   In 1905, following an outbreak of typhoid fever, the City of  Lincoln, England , instituted permanent water chlorination. [ 100 ]   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 . [ 101 ]  The  chlorination  facility was designed by  George W. Fuller . [ 102 ]


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. [ 82 ]  The Lyster bag was essential for the survival of American soldiers in the  Vietnam War . [ 82 ]


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. [ 82 ] [ 85 ]   Boston  had two such cases around the turn of the 20th century. [ 85 ]  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. [ 85 ]  In 1908, J.J. Fallon, who was also a milkman, died of typhoid fever. [ 85 ]   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." [ 85 ]  There was at least one death reported during this outbreak: Mrs. Sophia S. Engstrom, aged 46. [ 85 ]  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. [ 85 ]  The Jamaica Plain neighborhood at that time was home to many working-class and poor immigrants, mostly from  Ireland . [ 103 ]


The most notorious carrier of typhoid fever, but by no means the most destructive, was  Mary Mallon , known as Typhoid Mary. [ 104 ] [ 87 ]  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. [ 82 ]  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. [ 82 ]  The cases and deaths caused by Mallon were mainly upper-class families in New York City. [ 82 ]  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. [ 82 ]  In the summer of 1906 two daughters of a wealthy family and maids working in their home became ill with typhoid fever. [ 82 ]  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. [ 82 ]  Soper described himself as an "epidemic fighter". [ 82 ]  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. [ 82 ]  Since she had already left and begun employment elsewhere, he proceeded to track her down in order to obtain a stool sample. [ 82 ]   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." [ 86 ]  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." [ 86 ]  Ultimately, 51 cases and 3 deaths were suspected to be caused by Mallon. [ 105 ] [ 87 ]


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 . [ 106 ]  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. [ 106 ]  Misidentification of the disease, due to inaccurate Widal test results, delayed identification of the carrier and proper treatment. [ 106 ]  Ultimately, it took four samplings of different secretions from all of the dairy workers in order to successfully identify the carrier. [ 106 ]  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. [ 106 ]  The carrier was reported as being 72 years old and appearing in excellent health with no symptoms. [ 106 ]  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." [ 106 ]  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." [ 106 ]


Overall, in the early 20th century the medical profession began to identify disease carriers and evidence of transmission independent of water contamination. [ 82 ]  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". [ 107 ]  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. [ 107 ]  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. [ 107 ]  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". [ 107 ]


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. [ 1 ] [ 108 ]  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. [ 1 ]  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. [ 109 ]  Carriers may be released from their agreements upon fulfilling "release" requirements, based on completion of a personalized treatment plan designed with medical professionals. [ 109 ]  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. [ 109 ]  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. [ 109 ]


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. [ 110 ]   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. [ 111 ] [ 112 ]   Monack 's mouse model allows long-term carriage of  Salmonella  in  mesenteric lymph nodes ,  spleen  and  liver . [ 111 ]


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. [ 113 ]  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. [ 114 ]  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. [ 82 ]  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. [ 82 ]


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 . [ 115 ]  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. [ 116 ]


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. [ 117 ]  Typhoid vaccination for members of the American military became mandatory in 1911. [ 82 ]  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. [ 82 ]


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. [ 82 ]


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. [ 118 ]  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. [ 119 ]


Chloramphenicol  was isolated from  Streptomyces  by  David Gotlieb  during the 1940s. [ 82 ]  In 1948 American army doctors tested its efficacy in treating typhoid patients in  Kuala Lumpur , Malaysia. [ 82 ]  Individuals who received a full course of treatment cleared the infection, whereas patients given a lower dose had a relapse. [ 82 ]  Asymptomatic carriers continued to shed bacilli despite chloramphenicol treatment – only ill patients were improved with chloramphenicol. [ 82 ]  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. [ 82 ]


The disease has been referred to by various names, often associated with symptoms, such as gastric fever, enteric fever, abdominal typhus, infantile remittant fever, slow fever, nervous fever, pythogenic fever, [ 120 ]  drain fever, and low fever. [ 121 ]


Ulcerative colitis  ( UC ) is one of the two types of  inflammatory bowel disease  (IBD), with the other type being  Crohn's disease . [ 1 ]  It is a  long-term condition  that results in  inflammation  and  ulcers  of the  colon  and  rectum . [ 1 ] [ 7 ]  The primary symptoms of active disease are  abdominal pain  and  diarrhea  mixed with  blood  ( hematochezia ). [ 1 ]   Weight loss ,  fever , and  anemia  may also occur. [ 1 ]  Often, symptoms come on slowly and can range from mild to severe. [ 1 ]  Symptoms typically occur intermittently with periods of no symptoms between flares. [ 1 ]  Complications may include abnormal dilation of the colon ( megacolon ), inflammation of the eye, joints, or liver, and  colon cancer . [ 1 ] [ 3 ]


The cause of UC is unknown. [ 1 ]  Theories involve  immune system dysfunction ,  genetics , changes in the  normal gut bacteria , and environmental factors. [ 1 ] [ 8 ]  Rates tend to be higher in the developed world with some proposing this to be the result of  less exposure to intestinal infections , or to a  Western diet  and lifestyle. [ 7 ] [ 9 ]  The removal of the appendix at an early age may be protective. [ 9 ]  Diagnosis is typically by  colonoscopy  with  tissue biopsies . [ 1 ]


Several medications are used to treat symptoms and bring about and maintain remission, including  aminosalicylates  such as  mesalazine  or  sulfasalazine ,  steroids ,  immunosuppressants  such as  azathioprine , and   biologic therapy . [ 1 ]   Removal of the colon by surgery  may be necessary if the disease is severe, does not respond to treatment, or if complications such as colon cancer develop. [ 1 ]   Removal of the colon and rectum  generally cures the condition. [ 1 ] [ 9 ]


People with ulcerative colitis usually present with  diarrhea  mixed with  blood , [ 12 ]  of gradual onset that persists for an extended period of time (weeks). It is estimated that 90% of people experience rectal bleeding (of varying severity), 90% experience watery or loose stools with increased stool frequency (diarrhea), and 75-90% of people experience bowel urgency. [ 13 ]  Additional symptoms may include fecal incontinence, mucous rectal discharge, and nocturnal defecations. [ 12 ]  With  proctitis  (inflammation of the rectum), people with UC may experience urgency or  rectal tenesmus , which is the urgent desire to evacuate the bowels but with the passage of little stool. [ 12 ]  Tenesmus may be misinterpreted as  constipation , due to the urge to defecate despite small volume of stool passage. Bloody diarrhea and abdominal pain may be more prominent features in severe disease. [ 12 ]  The severity of abdominal pain with UC varies from mild discomfort to very painful bowel movements and abdominal cramping. [ 14 ]  High frequency of bowel movements, weight loss, nausea, fatigue, and fever are also common during disease flares. Chronic bleeding from the GI tract, chronic inflammation, and iron deficiency often leads to  anemia , which can affect quality of life. [ 15 ]


The clinical presentation of ulcerative colitis depends on the extent of the disease process. [ 16 ]  Up to 15% of individuals may have severe disease upon initial onset of symptoms. [ 12 ]  A substantial proportion (up to 45%) of people with a history of UC without any ongoing symptoms (clinical remission) have objective evidence of ongoing inflammation. [ 17 ]  Ulcerative colitis is associated with a generalized inflammatory process that can affect many parts of the body. Sometimes, these associated extra-intestinal symptoms are the initial signs of the disease. [ 18 ]


In contrast to Crohn's disease, which can affect areas of the gastrointestinal tract outside of the colon, ulcerative colitis is usually confined to the colon. Inflammation in ulcerative colitis is usually continuous, typically involving the rectum, with involvement extending proximally (to  sigmoid colon , ascending colon, etc.). [ 19 ]  In contrast, inflammation with Crohn's disease is often patchy, with so-called "skip lesions" (intermittent regions of inflamed bowel). [ 20 ]


The disease is classified by the extent of involvement, depending on how far the disease extends: [ 14 ]   proctitis  (rectal inflammation), left sided colitis (inflammation extending to descending colon), and extensive colitis (inflammation proximal to the descending colon). [ 19 ]  Proctosigmoiditis describes inflammation of the rectum and sigmoid colon. Pancolitis describes involvement of the entire colon, extending from the rectum to the cecum. While usually associated with Crohn's disease,  ileitis  (inflammation of the ileum) also occurs in UC. About 17% of individuals with UC have ileitis. [ 21 ]  Ileitis more commonly occurs in the setting of pancolitis (occurring in 20% of cases of pancolitis), [ 12 ]  and tends to correlate with the activity of colitis. This so-called "backwash ileitis" can occur in 10–20% of people with  pancolitis  and is believed to be of little clinical significance. [ 22 ]


In addition to the extent of involvement, UC is also characterized by severity of disease. [ 19 ]  Severity of disease is defined by symptoms, objective markers of inflammation (endoscopic findings, blood tests), disease course, and the impact of the disease on day-to-day life. [ 19 ]  Most patients are categorized through endoscopy and fecal calprotectin levels. Indicators of low risk for future complications in mild and moderate UC include the following parameters: exhibiting less than 6 stools daily and lack of fever/weight loss. Other indicators include lack of extraintestinal symptoms, low levels of the inflammatory markers  C-reactive protein  (CRP), and  erythrocyte sedimentation rate  (ESR), and fecal  calprotectin , and later age of diagnosis (over 40 years). [ 23 ]  Mild disease correlates with fewer than four stools daily; in addition, mild urgency and rectal bleeding may occur intermittently. [ 19 ]   Mild disease lacks  systemic  signs of toxicity (e.g. fever, chills, weight changes) and exhibits normal levels of the serum inflammatory markers ESR and CRP. [ 23 ]


Moderate to severe disease correlates with more than six stools daily, frequent bloody stools and urgency. [ 19 ]  Moderate abdominal pain, low-grade  fever , 38 to 39 °C (100 to 102 °F), and anemia may develop. [ 19 ]  ESR and CRP are usually elevated. [ 19 ]


The Mayo Score, which incorporates a combination of clinical symptoms (stool frequency and amount of rectal bleeding) with endoscopic findings and a physicians assessment of severity, is often used clinically to classify UC as mild, moderate or severe. [ 13 ]


Acute-Severe Ulcerative Colitis (ASUC) is a severe form which presents acutely and with severe symptoms. This fulminant type is associated with severe symptoms (usually diarrhea, rectal bleeding and abdominal pain) and is usually associated with systemic symptoms including fever. [ 13 ]  It is associated with a high mortality rate as compared to milder forms of UC, with a 3-month and 12 month mortality rate of 0.84% and 1% respectively. [ 13 ]  People with fulminant UC may have inflammation extending beyond just the mucosal layer, causing impaired colonic motility and leading to  toxic megacolon . Toxic megacolon represents a medical emergency, one often treated surgically. If the  serous membrane  is involved, a colonic  perforation  may ensue, which has a 50% mortality rate in people with UC. [ 24 ]  Other complications include  hemorrhage ,  venous thromboembolism , and secondary infections of the colon including  C. difficile  or  cytomegalovirus  colitis. [ 13 ]


Ulcerative colitis may improve and enter remission. [ 19 ]


UC is characterized by immune dysregulation and systemic inflammation, which may result in  symptoms  and  complications  outside the colon. Commonly affected organs include: eyes, joints, skin, and liver. [ 28 ]  The frequency of such extraintestinal manifestations has been reported as between 6 and 47%. [ 29 ] [ 30 ]


UC may affect the mouth. About 8% of individuals with UC develop oral manifestations. [ 31 ]  The two most common oral manifestations are  aphthous stomatitis  and  angular cheilitis . [ 31 ]  Aphthous stomatitis is characterized by ulcers in the mouth, which are benign, noncontagious and often recurrent. Angular chelitis is characterized by redness at the corners of the mouth, which may include painful sores or breaks in the skin. [ 31 ]  Very rarely, benign pustules may occur in the mouth (pyostomatitis vegetans). [ 31 ]


UC may affect the eyes manifesting in scleritis, iritis, and conjunctivitis. Patients may be asymptomatic or experience redness, burning, or itching in eyes. Inflammation may occur in the interior portion of the eye, leading to  uveitis  and  iritis . [ 32 ]  Uveitis can cause blurred vision and eye pain, especially when exposed to light ( photophobia ). Untreated, uveitis can lead to permanent vision loss. [ 32 ]  Inflammation may also involve the white part of the eye ( sclera ) or the overlying connective tissue ( episclera ), causing conditions called  scleritis  and  episcleritis . [ 33 ]  Ulcerative colitis is most commonly associated with uveitis and episcleritis. [ 34 ]


UC may cause several joint manifestations, including a type of rheumatologic disease known as  seronegative arthritis , which may affect few large joints (oligoarthritis), the  vertebra  ( ankylosing spondylitis ) or several small joints of the hands and feet (peripheral arthritis). [ 28 ]  Often the insertion site where muscle attaches to bone ( entheses ) becomes inflamed ( enthesitis ). Inflammation may affect the  sacroiliac joint  ( sacroiliitis ). [ 18 ]  It is estimated that around 50% of IBD patients suffer from migratory arthritis. Synovitis, or inflammation of the synovial fluid surrounding a joint, can occur for months and recur in later times but usually does not erode the joint. The symptoms of arthritis include  joint pain , swelling, and  effusion , and often leads to significant morbidity. [ 18 ]  Ankylosing spondylitis and sacroilitis usually occur independent of bowel disease activity in UC. [ 13 ]


Ulcerative colitis may affect the skin. The most common type of skin manifestation,  erythema nodosum , presents in up to 3% of UC patients. It develops as raised, tender red nodules usually appearing on the outer areas of the arms or legs, especially in the anterior tibial area (shins). [ 34 ]  The nodules have diameters that measure approximately 1–5 cm. Erythema nodosum is due to inflammation of the underlying subcutaneous tissue ( panniculitis ), and biopsy will display focal panniculitis (although is often unnecessary in diagnosis). In contrast to joint-related manifestations, erythema nodosum often occurs alongside intestinal disease. Thus, treatment of UC can often lead to resolution of skin nodules. [ 35 ]


Another skin condition associated with UC is pyoderma gangrenosum, which presents as deep skin ulcerations. Pyoderma gangrenosum is seen in about 1% of patients with UC and its formation is usually independent of bowel inflammation. [ 13 ]  Pyoderma gangrenosum is characterized by painful lesions or  nodules  that become  ulcers  which progressively grow. The ulcers are often filled with sterile pus-like material. In some cases, pyoderma gangrenosum may require injection with corticosteroids. [ 28 ]  Treatment may also involve inhibitors of tumor necrosis factor (TNF), a cytokine that promotes cell survival. [ 35 ]


Other associations determined between the skin and ulcerative colitis include a skin condition known as  hidradenitis suppurativa  (HS). This condition represents a chronic process in which follicles become occluded leading to recurring inflammation of nodules and abscesses and even  fistulas  tunnels in the skin that drain fluid. [ 36 ]


Ulcerative colitis may affect the circulatory and endocrine system. UC increases the risk of blood clots in both arteries and veins; [ 37 ] [ 38 ] [ 39 ]  painful swelling of the lower legs can be a sign of  deep venous thrombosis , while difficulty breathing may be a result of  pulmonary embolism  (blood clots in the lungs). The risk of blood clots is about threefold higher in individuals with IBD. [ 38 ]  The risk of venous thromboembolism is high in ulcerative colitis due to hypercoagulability from inflammation, especially with active or extensive disease. [ 37 ]  Additional risk factors may include surgery, hospitalization, pregnancy, the use of corticosteroids and tofacitinib, a JAK inhibitor. [ 37 ]


Osteoporosis  may occur related to systemic inflammation or prolonged steroid use in the treatment of UC, which increases the risk of bone fractures. [ 18 ]   Clubbing , a deformity of the ends of the fingers, may occur. [ 18 ]   Amyloidosis  may occur, especially with severe and poorly controlled disease, which usually presents with protein in the urine ( proteinuria ) and  nephritic syndrome . [ 18 ]


Ulcerative colitis (UC) has a significant association with  primary sclerosing cholangitis  (PSC), a progressive inflammatory disorder of small and large  bile ducts . Up to 70-90% of people with primary sclerosing cholangitis have ulcerative colitis. [ 34 ]  As many as 5% of people with UC may progress to develop primary sclerosing cholangitis. [ 28 ] [ 40 ]  PSC is more common in men, and often begins between 30 and 40 years of age. [ 28 ]  It can present asymptomatically or exhibit symptoms of itchiness (pruritis) and fatigue. Other symptoms include systemic signs such as fever and night sweats. Such symptoms are often associated with a bacterial episodic version of PSC. Upon physical exam, one may discern enlarged liver contours (hepatomegaly) or enlarged spleen (splenomegaly) as well as areas of excoriation. Yellow coloring of the skin, or jaundice, may also be present due to excess of bile byproduct buildup (bilirubin) from the biliary tract.


In diagnosis, lab results often reveal a pattern indicative of biliary disease (cholestatic pattern). This is often displayed by markedly elevated alkaline phosphatase levels and milder or no elevation in liver enzyme levels. Results of  endoscopic retrograde cholangiography  (ERC) may show bile ducts with thicker walls, areas of dilation or narrowing.  However, some patients with UC and PSC have inflammation that has significantly affected only ramified  intrahepatic bile ducts  of smaller diameter, also known as "small ducts", which are not visualized by ERC. [ 41 ] : 604, 609


In some cases, primary sclerosing cholangitis occurs several years before the bowel symptoms of ulcerative colitis develop. [ 34 ]  PSC does not parallel the onset, extent, duration, or activity of the colonic inflammation in ulcerative colitis. [ 34 ]  In addition, colectomy does not have an impact on the course of primary sclerosing cholangitis in individuals with UC. [ 34 ]  PSC is associated with an increased risk of colorectal cancer and  cholangiocarcinoma  (bile duct cancer). [ 34 ] [ 28 ]  PSC is a progressive condition, and may result in cirrhosis of the liver. [ 28 ]  No specific therapy has been proven to affect the long-term course of PSC. [ 28 ]


Ulcerative colitis is an  autoimmune disease  characterized by  T-cells  infiltrating the colon. [ 43 ]  No direct causes for UC are known, but factors such as genetics, environment, and an overactive immune system play a role. [ 1 ]  UC is associated with comorbidities that produce symptoms in many areas of the body outside the digestive system.


A genetic component to the cause of UC can be hypothesized based on aggregation of UC in families, variation of prevalence between different ethnicities,  genetic markers  and  linkages . [ 44 ]  In addition, the identical  twin   concordance  rate is 10%, whereas the  dizygotic twin  concordance rate is only 3%. [ 44 ] [ 45 ]  Between 8 and 14% of people with ulcerative colitis have a family history of inflammatory bowel disease. [ 12 ]  In addition, people with a first degree relative with UC have a four-fold increase in their risk of developing the disease. [ 12 ]


Twelve regions of the  genome  may be linked to UC, including, in the order of their discovery, chromosomes 16, 12, 6, 14, 5, 19, 1, and 3, [ 46 ]  but none of these  loci  has been consistently shown to be at fault, suggesting that the disorder is influenced by multiple genes. For example, chromosome band 1p36 is one such region thought to be linked to inflammatory bowel disease. [ 47 ]  Some of the putative regions encode transporter proteins such as  OCTN1  and  OCTN2 . Other potential regions involve cell scaffolding proteins such as the  MAGUK family .  Human leukocyte antigen  associations may even be at work. In fact, this linkage on chromosome 6 may be the most convincing and consistent of the genetic candidates. [ 46 ]


Multiple autoimmune disorders are associated with ulcerative colitis, including  celiac disease , [ 48 ]   psoriasis , [ 49 ]   lupus erythematosus , [ 50 ]   rheumatoid arthritis , [ 51 ]   episcleritis , and  scleritis . [ 32 ]  Ulcerative colitis is also associated with  acute intermittent porphyria . [ 52 ]


Many hypotheses have been raised for environmental factors contributing to the pathogenesis of ulcerative colitis, including  diet ,  breastfeeding  and medications. Breastfeeding may have a protective effect in the development of ulcerative colitis. [ 53 ] [ 54 ]  One study of  isotretinoin  found a small increase in the rate of UC. [ 55 ]


As the colon is exposed to many dietary substances which may encourage  inflammation , dietary factors have been hypothesized to play a role in the  pathogenesis  of both ulcerative colitis and Crohn's disease. However, research does not show a link between diet and the development of ulcerative colitis. Few studies have investigated such an association; one study showed no  association  of refined  sugar  on the number of people affected of ulcerative colitis. [ 56 ]  High intake of  unsaturated fat  and  vitamin B6  may enhance the risk of developing ulcerative colitis. [ 57 ]  Other identified dietary factors that may influence the development and/or relapse of the disease include meat protein and alcoholic beverages. [ 58 ] [ 59 ]  Specifically, sulfur has been investigated as being involved in the cause of ulcerative colitis, but this is controversial. [ 60 ]   Sulfur restricted diets  have been investigated in people with UC and animal models of the disease. The theory of sulfur as an etiological factor is related to the  gut microbiota  and mucosal sulfide detoxification in addition to the diet. [ 61 ] [ 62 ] [ 63 ]


As a result of  a class-action lawsuit and community settlement  with  DuPont , three  epidemiologists  conducted studies on the population surrounding a chemical plant that was exposed to PFOA at levels greater than in the general population. The studies concluded that there was an association between  PFOA  exposure and six health outcomes, one of which being ulcerative colitis. [ 64 ]


Levels of  sulfate-reducing bacteria  tend to be higher in persons with ulcerative colitis, which could indicate higher levels of  hydrogen sulfide  in the intestine. An alternative theory suggests that the symptoms of the disease may be caused by toxic effects of the hydrogen sulfide on the cells lining the intestine. [ 65 ]


Infection by  Mycobacterium avium , subspecies  paratuberculosis , has been proposed as the ultimate cause of both ulcerative colitis and Crohn's disease. [ 66 ]


An increased amount of colonic sulfate-reducing bacteria has been observed in some people with ulcerative colitis, resulting in higher concentrations of the toxic gas hydrogen sulfide. Human colonic mucosa is maintained by the colonic epithelial barrier and immune cells in the lamina propria (see  intestinal mucosal barrier ). The  short-chain fatty acid   n -butyrate gets oxidized through the  beta oxidation  pathway into carbon dioxide and ketone bodies. It has been shown that  n -butyrate helps supply nutrients to this epithelial barrier. Studies have proposed that hydrogen sulfide plays a role in impairing this beta-oxidation pathway by interrupting the short chain acetyl-CoA dehydrogenase, an enzyme within the pathway. Furthermore, it has been suggested that the protective effect of smoking in ulcerative colitis is due to the  hydrogen cyanide  from cigarette smoke reacting with hydrogen sulfide to produce the non-toxic isothiocyanate, thereby inhibiting sulfides from interrupting the pathway. [ 68 ]  An unrelated study suggested that the sulfur contained in red meats and alcohol may lead to an increased risk of relapse for people in remission. [ 65 ]


Other proposed mechanisms driving the pathophysiology of ulcerative colitis involve an abnormal immune response to the normal  gut microbiota . This involves abnormal activity of  antigen presenting cells  (APCs) including  dendritic cells  and  macrophages . Normally, dendritic cells and macrophages patrol the intestinal epithelium and  phagocytose  (engulf and destroy) pathogenic microorganisms and present parts of the microorganism as  antigens  to  T-cells  to stimulate differentiation and activation of the T-cells. [ 13 ]  However, in ulcerative colitis, aberrant activity of dendritic cells and macrophages results in them phagocytosing bacteria of the normal gut microbiome. After ingesting the microbiome bacterium, the APCs release the cytokine  TNFα  which stimulates inflammatory signaling and recruits inflammatory cells to the intestines, leading to the inflammation that is characteristic of ulcerative colitis. [ 13 ]  The TNF inhibitors, including  infliximab ,  adalimumab  and  golimumab , are used to inhibit this step during the treatment of ulcerative colitis. [ 13 ]  After phagocytosing the microbe, the APCs then enter the  mesenteric lymph nodes  where they present antigens to naive T-cells while also releasing the pro-inflammatory cytokines  IL-12  and  IL-23  which lead to T cell differentiation into  Th1  and  Th17  T-cells. [ 13 ]  IL-12 and IL-23 signaling is blocked by the biologic  ustekinumab  and IL-23 is blocked by  guselkumab ,  mirikizumab  and  risankizumab , medications that are used in the treatment of ulcerative colitis. [ 13 ]  From the mesenteric lymph node, the T-cells then enter the intestinal lymphatic venule which provides transport to the intestinal epithelium where they mediate further inflammation characteristic of ulcerative colitis. [ 13 ]  The T-cells exit the lymphatic venule via the adhesion protein mucosal vascular addressin cell adhesion molecule 1  MAdCAM-1 , the ulcerative colitis biologic treatment  vedolizumab  inhibits T-cell migration out of the lymphatic venules by blocking binding to MAdCAM-1. [ 13 ]  While the medications  ozanimod  and  etrasimod  inhibit the  sphingosine-1-phosphate receptor  to prevent T-cell migration into the efferent lymphatic venules. [ 13 ]  Once the mature Th1 and Th17 T-cells exit the efferent lymphatic venule, they travel to the intestinal mucosa and cause further inflammation. T-cell mediated inflammation is thought to be driven by the  JAK-STAT  intracellular T-cell signaling pathway, leading to the  transcription ,  translation  and release of inflammatory cytokines. This T-cell JAK-STAT signaling is inhibited by the medications  tofacitinib ,  filgotinib  and  upadacitinib  which are used in the treatment of ulcerative colitis. [ 13 ]


The initial  diagnostic  workup for ulcerative colitis consists of a complete history and physical examination, assessment of signs and symptoms, laboratory tests and endoscopy. [ 69 ]  Severe UC can exhibit high erythrocyte sedimentation rate (ESR), decreased albumin (a protein produced by the liver), and various changes in electrolytes. As discussed previously, UC patients often also display elevated alkaline phosphatase. Inflammation in the intestine may also cause higher levels of fecal calprotectin or lactoferrin. [ 70 ]


Specific testing may include the following: [ 19 ] [ 71 ]


Although ulcerative colitis is a disease of unknown causation, inquiry should be made as to unusual factors believed to trigger the disease. [ 19 ]


The  simple clinical colitis activity index  was created in 1998 and is used to assess the severity of symptoms. [ 72 ]


The best test for diagnosis of ulcerative colitis remains  endoscopy , which is examination of the internal surface of the bowel using a flexible camera. Initially, a flexible sigmoidoscopy may be completed to establish the diagnosis. [ 73 ]  The physician may elect to limit the extent of the initial exam if severe colitis is encountered to minimize the risk of  perforation  of the colon. However, a complete colonoscopy with entry into the terminal ileum should be performed to rule out Crohn's disease, and assess extent and severity of disease. [ 73 ]  Endoscopic findings in ulcerative colitis include:  erythema  (redness of the  mucosa ),  friability  of the mucosa, superficial ulceration, and loss of the vascular appearance of the colon. When present, ulcerations may be confluent. Pseudopolyps may be observed. [ 74 ]


Ulcerative colitis is usually continuous from the rectum, with the rectum almost universally being involved. Perianal disease is rare. The degree of involvement endoscopically ranges from proctitis (rectal inflammation) to left sided colitis (extending to descending colon), to extensive colitis (extending proximal to descending colon). [ 14 ]


Biopsies  of the mucosa are taken during endoscopy to confirm the diagnosis of UC and differentiate it from Crohn's disease, which is managed differently clinically. Histologic findings in ulcerative colitis includes: distortion of  crypt  architecture, crypt abscesses, and inflammatory cells in the mucosa (lymphocytes, plasma cells, and granulocytes). [ 28 ]  Unlike the transmural inflammation seen in Crohn's disease, the inflammation of ulcerative colitis is limited to the mucosa. [ 28 ]


Blood and stool tests serve primarily to assess disease severity, level of inflammation and rule out causes of infectious colitis.  All individuals with suspected ulcerative colitis should have stool testing to rule out infection. [ 12 ]


A  complete blood count  may demonstrate anemia, leukocytosis, or thrombocytosis. [ 12 ]  Anemia may be caused by inflammation or bleeding. Chronic blood loss may lead to iron deficiency as a cause for anemia, particularly microcytic anemia (small red blood cells), which can be evaluated with a serum  ferritin ,  iron ,  total iron-binding capacity  and  transferrin saturation . Anemia may be due to a complication of treatment from azathioprine, which can cause low blood counts, [ 75 ]  or sulfasalazine, which can result in folate deficiency. Thiopurine metabolites (from azathioprine) and a folate level can help. [ 76 ]


UC may cause high levels of inflammation throughout the body, which may be quantified with serum inflammatory markers, such as CRP and ESR.  However, elevated inflammatory markers are not specific for UC and elevations are commonly seen in other conditions, including infection. In addition, inflammatory markers are not uniformly elevated in people with ulcerative colitis.  Twenty five percent of individuals with confirmed inflammation on endoscopic evaluation have a normal CRP level. [ 19 ]   Serum albumin  may also be low related to inflammation, in addition to loss of protein in the GI tract associated with bleeding and colitis.  Low serum levels of vitamin D  are associated with UC, although the significance of this finding is unclear. [ 77 ]


Specific antibody markers may be elevated in ulcerative colitis. Specifically,  perinuclear antineutrophil cytoplasmic antibodies  (pANCA) are found in 70 percent of cases of UC. [ 19 ]  Antibodies against  Saccharomyces cerevisiae  may be present, but are more often positive in Crohn's disease compared with ulcerative colitis.  However, due to poor accuracy of these serolologic tests, they are not helpful in the diagnostic evaluation of possible inflammatory bowel disease. [ 19 ] [ 28 ]


Several stool tests may help quantify the extent of inflammation present in the colon and rectum.   Fecal calprotectin  is elevated in inflammatory conditions affecting the colon, and is useful in distinguishing irritable bowel syndrome (noninflammatory) from a flare in inflammatory bowel disease. [ 19 ]  Fecal calprotectin is 88% sensitive and 79% specific for the diagnosis of ulcerative colitis. [ 19 ]  If the fecal calprotectin is low, the likelihood of inflammatory bowel disease are less than 1 percent. [ 12 ]   Lactoferrin  is an additional nonspecific marker of intestinal inflammation. [ 78 ]


Overall, imaging tests, such as  x-ray  or CT scan, may be helpful in assessing for complications of ulcerative colitis, such as perforation or toxic megacolon. Bowel ultrasound (US) is a cost-effective, well-tolerated, non-invasive and readily available tool for the management of patients with inflammatory bowel disease (IBD), including UC, in clinical practice. [ 79 ]  Some studies demonstrated that bowel ultrasound is an accurate tool for assessing disease activity in people with ulcerative colitis. [ 80 ] [ 81 ]  Imaging is otherwise of limited use in diagnosing ulcerative colitis. [ 12 ] [ 28 ]  Magnetic resonance imaging (MRI) is necessary to diagnose underlying PSC. [ 28 ]


Abdominal xray is often the test of choice and may display nonspecific findings in cases of mild or moderate ulcerative colitis. In circumstances of severe UC, radiographic findings may include thickening of the mucosa, often termed "thumbprinting", which indicates swelling due to fluid displacement (edema). Other findings may include colonic dilation and stool buildup evidencing constipation. [ 70 ]


Similar to xray, in mild ulcerative colitis, double contrast barium enema often shows nonspecific findings. Conversely, barium enema may display small buildups of barium in microulcerations. Severe UC can be characterized by various polyps, colonic shortening, loss of haustrae (the small bulging pouches in the colon), and narrowing of the colon. It is important to note that barium enema should not be conducted in patients exhibiting very severe symptoms as this may slow or stop stool passage through the colon causing ileus and toxic megacolon. [ 70 ]


Other methods of imaging include computed tomography (CT) and magnetic resonance imaging (MRI). Both may depict colonic wall thickening but have decreased ability to find early signs of wall changes when compared to barium enema. In cases of severe ulcerative colitis, however, they often exhibit equivalent ability to detect colonic changes. [ 70 ]


Doppler ultrasound is the last means of imaging that may be used. Similar to the imaging methods mentioned earlier, this may show some thickened bowel wall layers. In severe cases, this may show thickening in all bowel wall layers (transmural thickness). [ 70 ]


Several conditions may present in a similar manner as ulcerative colitis and should be excluded. Such conditions include: Crohn's disease, infectious colitis,  nonsteroidal anti-inflammatory drug  enteropathy, and  irritable bowel syndrome . Alternative causes of colitis should be considered, such as  ischemic colitis  (inadequate blood flow to the colon),  radiation colitis  (if prior exposure to  radiation therapy ), or  chemical colitis .  Pseudomembranous colitis  may occur due to  Clostridioides difficile  infection  following administration of antibiotics.  Entamoeba histolytica  is a protozoan parasite that causes intestinal inflammation. A few cases have been misdiagnosed as UC with poor outcomes occurring due to the use of corticosteroids. [ 82 ]


The most common disease that mimics the symptoms of ulcerative colitis is Crohn's disease, as both are inflammatory bowel diseases that can affect the colon with similar symptoms. It is important to differentiate these diseases since their courses and treatments may differ. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis. [ 83 ]  Crohn's disease can be distinguished from ulcerative colitis in several ways. Characteristics that indicate Crohn's include evidence of disease around the anus (perianal disease). This includes anal fissures and abscesses as well as fistulas, which are abnormal connections between various bodily structures. [ 84 ]


Infectious colitis is another condition that may present in similar manner to ulcerative colitis. Endoscopic findings are also oftentimes similar. One can discern whether a patient has infectious colitis by employing tissue cultures and stool studies. Biopsy of the colon is another beneficial test but is more invasive.


Other forms of colitis that may present similarly include radiation and diversion colitis. Radiation colitis occurs after irradiation and often affects the rectum or sigmoid colon, similar to ulcerative colitis. Upon histology radiation colitis may indicate eosinophilic infiltrates, abnormal epithelial cells, or fibrosis. Diversion colitis, on the other hand, occurs after portions of bowel loops have been removed. Histology in this condition often shows increased growth of lymphoid tissue.


In patients who have undergone transplantation, graft versus host disease may also be a differential diagnosis. This response to transplantation often causes prolonged diarrhea if the colon is affected. Typical symptoms also include rash. Involvement of the upper gastrointestinal tract may lead to difficulty swallowing or ulceration. Upon histology, graft versus host disease may present with crypt cell necrosis and breakdown products within the crypts themselves. [ 85 ]


Standard treatment for ulcerative colitis depends on the extent of involvement and disease severity. The goal is to induce remission initially with medications, followed by the administration of maintenance medications to prevent a relapse. The concept of induction of remission and maintenance of remission is very important. The medications used to induce and maintain a remission somewhat overlap, but the treatments are different. Physicians first direct treatment to inducing remission, which involves relief of symptoms and mucosal healing of the colon's lining, and then longer-term treatment to maintain remission and prevent complications. [ 91 ]


For acute stages of the disease, a  low fiber diet  may be recommended. [ 92 ] [ 93 ] [ 94 ]


The first-line maintenance medication for ulcerative colitis in remission is  mesalazine  (also known as mesalamine or 5-ASA). [ 95 ] [ 96 ]  For patients with active disease limited to the  left colon  (descending colon) or proctitis, mesalazine is also the first-line agent, and a combination of  suppositories  and oral mesalazine may be tried. Adding  corticosteroids  such as  prednisone  is also common in active disease, especially if remission is not achieved through mesalazine monotherapy, [ 95 ] [ 96 ]  but they are not used in long-term treatment as their risks then outweigh their benefits. Immunosuppressive medications such as  azathioprine  and  biological agents  such as  infliximab ,  adalimumab ,  ustekinumab ,  vedolizumab , or  risankizumab  are given in severe disease or if a patient cannot achieve remission with mesalazine and corticosteroids. [ 97 ] [ 98 ]  As an alternative to mesalazine, one of its  prodrugs  such as  sulfasalazine  may be chosen for treatment of active disease or maintenance therapy, [ 99 ]  but the prodrugs have greater potential for serious side effects and have not been demonstrated to be superior to mesalazine in large trials. [ 100 ]


A formulation of  budesonide  was approved by the U.S.  Food and Drug Administration  (FDA) for treatment of active ulcerative colitis in January 2013. [ 101 ] [ 102 ]  In 2018,  tofacitinib  was approved for treatment of moderately to severely active ulcerative colitis in the United States, the first oral medication indicated for long term use in this condition. [ 103 ]  The evidence on  methotrexate  does not show a benefit in producing remission in people with ulcerative colitis. [ 104 ]   Cyclosporine  is effective for severe UC [ 97 ]  and  tacrolimus  has also shown benefits. [ 105 ] [ 106 ] [ 107 ] [ 108 ]   Etrasimod  was approved for medical use in the United States in October 2023. [ 109 ]


Sulfasalazine has been a major agent in the therapy of mild to moderate ulcerative colitis for over 50 years. In 1977, it was shown that 5-aminosalicylic acid (5-ASA,  mesalazine /mesalamine) was the therapeutically active component in sulfasalazine. [ 110 ]   Many 5-ASA drugs have been developed with the aim of delivering the active compound to the large intestine to maintain therapeutic efficacy but with reduction of the side effects associated with the sulfapyridine moiety in sulfasalazine.  Oral 5-ASA drugs are particularly effective in inducing and in maintaining remission in mild to moderate ulcerative colitis. [ 111 ] [ 112 ]   Rectal suppository, foam or liquid enema formulations of 5-ASA are used for colitis affecting the rectum, sigmoid or descending colon, and have been shown to be effective especially when combined with oral treatment. [ 113 ]


Biologic treatments such as the  TNF inhibitors   infliximab ,  adalimumab , and  golimumab  are commonly used to treat people with UC who are no longer responding to corticosteroids.  Tofacitinib  and  vedolizumab  can also produce good clinical remission and response rates in UC. [ 8 ]  Biologics may be used early in treatment (step down approach), or after other treatments have failed to induce remission (step up approach); the strategy should be individualized. [ 114 ]


Unlike aminosalicylates, biologics can cause serious side effects such as an increased risk of developing extra-intestinal cancers, [ 115 ]   heart failure ; and weakening of the immune system, resulting in a  decreased ability of the immune system to clear infections  and reactivation of latent infections such as  tuberculosis . For this reason, people on these treatments are closely monitored and are often tested for hepatitis and tuberculosis annually. [ 116 ] [ 117 ]


Etrasimod, a once-daily oral sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5 with no detectable activity on S1P 2 or 3, is in development for treatment of immune-mediated diseases, including ulcerative colitis, and was shown in 2 randomized trials to be effective and well tolerated as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. [ 118 ]


Unlike  Crohn's disease , ulcerative colitis has a lesser chance of affecting smokers than non-smokers. [ 119 ] [ 120 ]  In select individuals with a history of previous tobacco use, resuming low dose smoking may improve signs and symptoms of active ulcerative colitis, [ 121 ]  but it is not recommended due to the overwhelmingly negative  health effects of tobacco . [ 122 ]  Studies using a  transdermal nicotine  patch have shown clinical and histological improvement. [ 123 ]  In one double-blind, placebo-controlled study conducted in the  United Kingdom , 48.6% of people with UC who used the nicotine patch, in conjunction with their standard treatment, showed complete resolution of symptoms. Another randomized, double-blind, placebo-controlled, single-center clinical trial conducted in the  United States  showed that 39% of people who used the patch showed significant improvement, versus 9% of those given a placebo. [ 124 ]  However, nicotine therapy is generally not recommended due to side effects and inconsistent results. [ 125 ] [ 126 ] [ 127 ]


The gradual loss of blood from the gastrointestinal tract, as well as chronic inflammation, often leads to anemia, and professional guidelines suggest routinely monitoring for anemia with blood tests repeated every three months in active disease and annually in quiescent disease. [ 128 ]  Adequate disease control usually improves anemia of chronic disease, but iron deficiency anemia should be treated with iron supplements. The form in which treatment is administered depends both on the severity of the anemia and on the guidelines that are followed. Some advise that  parenteral iron  be used first because people respond to it more quickly, it is associated with fewer gastrointestinal side effects, and it is not associated with compliance issues. [ 129 ]  Others require oral iron to be used first, as people eventually respond and many will tolerate the side effects. [ 128 ] [ 130 ]


Anticholinergic  drugs, more specifically  muscarinic antagonists , are sometimes used to treat abdominal cramps in connection with ulcerative colitis through their calming effect on colonic  peristalsis  (reducing both amplitude and frequency) and  intestinal tone . [ 131 ] [ 132 ]  Some medical authorities suggest over-the-counter anticholinergic drugs as potential helpful treatments for abdominal cramping in mild ulcerative colitis. [ 133 ]  However, their use is contraindicated especially in moderate to severe disease states because of the potential for anticholinergic treatment to induce  toxic megacolon  in patients with colonic inflammation. [ 134 ]  Toxic megacolon is a state in which the colon is abnormally distended, and may in severe or untreated cases lead to colonic  perforation , sepsis, and death. [ 135 ]


Many patients affected by ulcerative colitis need immunosuppressant therapies, which may be associated with a higher risk of contracting opportunistic infectious diseases. [ 136 ]
Many of these potentially harmful diseases, such as  Hepatitis B ,  Influenza ,  chickenpox ,  herpes zoster virus ,  pneumococcal pneumonia , or  human papilloma virus , can be prevented by vaccines. Each drug used in the treatment of IBD should be classified according to the degree of immunosuppression induced in the patient. Several guidelines suggest investigating patients' vaccination status before starting any treatment and performing vaccinations against vaccine preventable diseases when required. [ 137 ] [ 138 ]
Compared to the rest of the population, patients affected by IBD are known to be at higher risk of contracting some vaccine-preventable diseases. [ 139 ]  Patients treated with  Janus kinase inhibitor  showed higher risk of   Shingles . [ 140 ]   Nevertheless, despite the increased risk of infections, vaccination rates in IBD patients are known to be suboptimal and may also be lower than vaccination rates in the general population. [ 141 ] [ 142 ]


Unlike in Crohn's disease, the gastrointestinal aspects of ulcerative colitis can generally be cured by  surgical removal of the large intestine , though extraintestinal symptoms may persist. This procedure is necessary in the event of:  exsanguinating   hemorrhage , frank perforation, or documented or strongly suspected  carcinoma . Surgery is also indicated for people with severe colitis or toxic megacolon. People with symptoms that are disabling and do not respond to drugs may wish to consider whether surgery would improve the quality of life. [ 14 ]


The removal of the entire large intestine, known as a  proctocolectomy , results in a permanent ileostomy – where a  stoma  is created by pulling the terminal ileum through the abdomen. Intestinal contents are emptied into a removable  ostomy bag  which is secured around the stoma using adhesive. [ 146 ]


Another surgical option for ulcerative colitis that is affecting most of the large bowel is called the  ileal pouch-anal anastomosis (IPAA) . This is a two- or three-step procedure. In a three-step procedure, the first surgery is a  sub-total colectomy , in which the large bowel is removed, but the rectum remains in situ, and a temporary ileostomy is made. The second step is a  proctectomy  and formation of the ileal pouch (commonly known as a "j-pouch"). This involves removing the large majority of the remaining rectal stump and creating a new "rectum" by fashioning the end of the small intestine into a pouch and attaching it to the anus. After this procedure, a new type of ileostomy is created (known as a loop ileostomy) to allow the anastomoses to heal. The final surgery is a take-down procedure where the ileostomy is reversed and there is no longer the need for an ostomy bag. When done in two steps, a proctocolectomy – removing both the colon and rectum – is performed alongside the pouch formation and loop ileostomy. The final step is the same take-down surgery as in the three-step procedure. Time taken between each step can vary, but typically a six- to twelve-month interval is recommended between the first two steps, and a minimum of two to three months is required between the formation of the pouch and the ileostomy take-down. [ 14 ]


While the ileal pouch procedure removes the need for an ostomy bag, it does not restore normal bowel function. In the months following the final operation, patients typically experience 8–15 bowel movements a day. Over time this number decreases, with many patients reporting 4–6 bowel movements after one year post-op. While many patients have success with this procedure, there are a number of known complications.  Pouchitis , inflammation of the ileal pouch resulting in symptoms similar to ulcerative colitis, is relatively common. Pouchitis can be acute, remitting, or chronic however treatment using antibiotics, steroids, or biologics can be highly effective. Other complications include fistulas, abscesses, and pouch failure. Depending on the severity of the condition, pouch revision surgery may need to be performed. In some cased the pouch may need to be de-functioned or removed and an ileostomy recreated. [ 147 ] [ 148 ]


The risk of cancer arising from an ileal pouch anal anastomosis is low. [ 149 ]  However, annual surveillance with  pouchoscopy  may be considered in individuals with risk factors for dysplasia, such as a history of dysplasia or colorectal cancer, a history of PSC, refractory pouchitis, and severely inflamed atrophic pouch mucosa. [ 149 ]


In a number of randomized clinical trials,  probiotics  have demonstrated the potential to be helpful in the treatment of ulcerative colitis. Specific types of probiotics such as  Escherichia coli  Nissle  have been shown to induce remission in some people for up to a year. [ 150 ]


A  Cochrane  review of  controlled trials  using various probiotics found low-certainty evidence that probiotic supplements may increase the probability of clinical remission. [ 151 ]  People receiving probiotics were 73% more likely to experience disease remission and over 2x as likely to report improvement in symptoms compared to those receiving a placebo, with no clear difference in minor or serious adverse effects. [ 151 ]  Although there was no clear evidence of greater remission when probiotic supplements were compared with  5‐aminosalicylic acid  treatment as a  monotherapy , the likelihood of remission was 22% higher if probiotics were used in combination with 5-aminosalicylic acid therapy. [ 151 ]


It is unclear whether probiotics help to prevent future relapse in people with stable disease activity, either as a monotherapy or  combination therapy . [ 152 ]


Fecal microbiota transplant  involves the infusion of human probiotics through fecal enemas. Ulcerative colitis typically requires a more prolonged bacteriotherapy treatment than  Clostridioides difficile  infection does to be successful, possibly due to the time needed to heal the ulcerated epithelium. The response of ulcerative colitis is potentially very favorable with one study reporting 67.7% of people experiencing complete remission. [ 153 ]  Other studies found a benefit from using fecal microbiota transplantation. [ 154 ] [ 155 ] [ 156 ]


A variety of alternative medicine therapies have been used for ulcerative colitis, with inconsistent results.  Curcumin (turmeric)  therapy, in conjunction with taking the medications  mesalamine  or  sulfasalazine , may be effective and safe for maintaining remission in people with quiescent ulcerative colitis. [ 157 ] [ 158 ]  The effect of  curcumin  therapy alone on quiescent ulcerative colitis is unknown. [ 158 ]


Treatments using  cannabis  or cannabis oil are uncertain. So far, studies have not determined its effectiveness and safety. [ 159 ]


Many interventions have been considered to manage abdominal pain in people with ulcerative colitis, including  FODMAPs  diet,  relaxation  training,  yoga ,  kefir  diet and stellate  ganglion block  treatment. It is unclear whether any of these are safe or effective at improving pain or reducing  anxiety  and  depression . [ 160 ]


Diet can play a role in symptoms of patients with ulcerative colitis. [ 161 ]


The most avoided foods by patients are spicy foods, dairy products, alcohol, fruits and vegetables and carbonated beverages; these foods are mainly avoided during remission and to prevent relapse. In some cases, especially in the flares period, the dietary restrictions of these patients can be very severe and can lead to a compromised nutritional state. Some patients tend to eliminate gluten spontaneously, despite not having a definite diagnosis of  Coeliac disease , because they believe that gluten can exacerbate gastrointestinal symptoms. [ 162 ]


Many studies found that patients with IBD reported a higher frequency of depressive and anxiety disorders than the general population, and most studies confirm that women with IBD are more likely than men to develop affective disorders and show that up to 65% of them may have  depression disorder  and  anxiety disorder . [ 163 ] [ 164 ]


A meta analysis of interventions to improve mood (including talking therapy,  antidepressants , and exercise) in people with inflammatory bowel disease found that they reduced inflammatory markers such as  C-reactive protein  and  faecal calprotectin . Psychological therapies reduced inflammation more than antidepressants or exercise. [ 165 ] [ 166 ]


Poor prognostic factors include: age < 40 years upon diagnosis, extensive colitis, severe colitis on endoscopy, prior hospitalization, elevated CRP and low serum albumin. [ 19 ]


People with ulcerative colitis usually have an intermittent course, with periods of disease inactivity alternating with "flares" of disease. People with proctitis or left-sided colitis usually have a more benign course: only 15% progress proximally with their disease, and up to 20% can have sustained remission in the absence of any therapy. A subset of people experience a course of disease progress rapidly. In these cases, there is usually a failure to respond to medication and surgery often is performed within the first few years of disease onset. [ 167 ] [ 168 ]  People with more extensive disease are less likely to sustain remission, but the rate of remission is independent of the severity of the disease. [ 169 ]  Several risk factors are associated with eventual need for colectomy, including: prior hospitalization for UC, extensive colitis, need for systemic steroids, young age at diagnosis, low serum albumin, elevated inflammatory markers (CRP & ESR), and severe inflammation seen during colonoscopy. [ 97 ] [ 19 ]  Surgical removal of the large intestine is necessary in some cases. [ 19 ]


The risk of  colorectal cancer  is significantly increased in people with ulcerative colitis after ten years if involvement is beyond the  splenic flexure . People with backwash ileitis might have an increased risk for colorectal carcinoma. [ 170 ]  Those people with only proctitis usually have no increased risk. [ 19 ]  It is recommended that people have screening  colonoscopies  with random biopsies to look for  dysplasia  after eight years of disease activity, at one to two year intervals. [ 171 ]


People with ulcerative colitis are at similar [ 172 ]  or perhaps slightly increased overall risk of  death  compared with the background population. [ 173 ]  However, the distribution of causes-of-death differs from the general population. [ 172 ]  Specific risk factors may predict worse outcomes and a higher risk of mortality in people with ulcerative colitis, including  C. difficile  infection [ 19 ]  and  cytomegalovirus infection  (due to reactivation). [ 174 ]


Together with  Crohn's disease , about 11.2 million people were affected as of 2015 [update] . [ 175 ]  Each year it newly occurs in 1 to 20 per 100,000 people, and 5 to 500 per 100,000 individuals are affected. [ 7 ] [ 9 ]  The disease is more common in North America and Europe than other regions. [ 9 ]  Often it begins in people aged 15 to 30 years, or among those over 60. [ 1 ]  Males and females appear to be affected in equal proportions. [ 7 ]  It has also become more common since the 1950s. [ 7 ] [ 9 ]  Together, ulcerative colitis and Crohn's disease affect about a million people in the United States. [ 176 ]  With appropriate treatment the risk of death appears the same as that of the general population. [ 3 ]  The first description of ulcerative colitis occurred around the 1850s. [ 9 ]


Each year, ulcerative colitis newly occurs in 1 to 20 per 100,000 people (incidence), and there are a total of 5–500 per 100,000 individuals with the disease (prevalence). [ 7 ] [ 9 ]  In 2015, a worldwide total of 47,400 people died due to inflammatory bowel disease (UC and Crohn's disease). [ 6 ]  The peak onset is between 30 and 40 years of age, [ 12 ]  with a second peak of onset occurring in the 6th decade of life. [ 177 ]  Ulcerative colitis is equally common among men and women. [ 12 ] [ 7 ]  With appropriate treatment the risk of death appears similar to that of the general population. [ 3 ]  UC has become more common since the 1950s. [ 7 ] [ 9 ]


The geographic distribution of UC and Crohn's disease is similar worldwide, [ 178 ]  with the highest number of new cases a year of UC found in  Canada ,  New Zealand  and the  United Kingdom . [ 179 ]  The disease is more common in North America and Europe than other regions. [ 9 ]  In general, higher rates are seen in northern locations compared to southern locations in  Europe [ 180 ]  and the United States. [ 181 ]  UC is more common in western Europe compared with eastern Europe. [ 182 ]   Worldwide, the prevalence of UC varies from 2 to 299 per 100,000 people. [ 5 ]  Together, ulcerative colitis and Crohn's disease affect about a million people in the United States. [ 176 ]


As with Crohn's disease, the rates of UC are greater among  Ashkenazi Jews  and decreases progressively in other persons of Jewish descent, non-Jewish Caucasians, Africans, Hispanics, and Asians. [ 22 ]  Appendectomy prior to age 20 for appendicitis [ 183 ]  and current tobacco use [ 184 ]  are protective against development of UC. [ 12 ]  However, former tobacco use is associated with a higher risk of developing the disease. [ 184 ] [ 12 ]


As of 2004 [update] , the number of new cases of UC in the United States was between 2.2 and 14.3 per 100,000 per year. [ 185 ]  The number of people affected in the United States in 2004 was between 37 and 246 per 100,000. [ 185 ]


In Canada, between 1998 and 2000, the number of new cases per year was 12.9 per 100,000 population or 4,500 new cases. The number of people affected was estimated to be 211 per 100,000 or 104,000. [ 186 ]


In the United Kingdom 10 per 100,000 people newly develop the condition a year while the number of people affected is 243 per 100,000. Approximately 146,000 people in the United Kingdom have been diagnosed with UC. [ 187 ]


The term ulcerative colitis was first used by  Samuel Wilks  in 1859. The term entered general medical vocabulary afterwards in 1888 with  William Hale-White  publishing a report of various cases of "ulcerative colitis". [ 188 ]


UC was the first subtype of IBD to be identified. [ 188 ]


Helminthic therapy  using the  whipworm   Trichuris suis  has been shown in a  randomized control trial  from Iowa to show benefit in people with ulcerative colitis. [ 189 ]  The therapy tests the  hygiene hypothesis  which argues that the absence of  helminths  in the colons of people in the developed world may lead to inflammation. Both helminthic therapy and fecal microbiota transplant induce a characteristic  Th2  white cell response in the diseased areas, which was unexpected given that ulcerative colitis was thought to involve Th2 overproduction. [ 189 ]


Alicaforsen  is a first generation antisense oligodeoxynucleotide designed to bind specifically to the human  ICAM-1  messenger  RNA  through Watson-Crick base pair interactions in order to subdue expression of ICAM-1. [ 190 ]  ICAM-1 propagates an inflammatory response promoting the extravasation and activation of  leukocytes  (white blood cells) into inflamed tissue. [ 190 ]  Increased expression of ICAM-1 has been observed within the  inflamed  intestinal mucosa of ulcerative colitis patients, where ICAM-1 over production correlated with disease activity. [ 191 ]  This suggests that ICAM-1 is a potential therapeutic target in the treatment of ulcerative colitis. [ 192 ]


Gram positive bacteria present in the lumen could be associated with extending the time of relapse for ulcerative colitis. [ 193 ]


A series of drugs in development looks to disrupt the inflammation process by selectively targeting an  ion channel  in the inflammation signaling cascade known as KCa3.1. [ 194 ]  In a preclinical study in rats and mice, inhibition of KCa3.1 disrupted the production of Th1 cytokines IL-2 and TNF-α and decreased colon inflammation as effectively as  sulfasalazine . [ 194 ]


Neutrophil extracellular traps [ 195 ]  and the resulting degradation of the extracellular matrix [ 196 ]  have been reported in the colon mucosa in ulcerative colitis patients in clinical remission, indicating the involvement of the innate immune system in the etiology. [ 195 ]


Fexofenadine , an antihistamine drug used in treatment of allergies, has shown promise in a combination therapy in some studies. [ 197 ] [ 198 ]  Opportunely, low gastrointestinal absorption (or high absorbed drug gastrointestinal secretion) of fexofenadine results in higher concentration at the site of inflammation. Thus, the drug may locally decrease histamine secretion by involved gastrointestinal mast cells and alleviate the inflammation. [ 198 ]


There is evidence that  etrolizumab  is effective for ulcerative colitis, with phase 3 trials underway as of 2016. [ 8 ] [ 199 ] [ 200 ] [ 201 ]  Etrolizumab is a humanized monoclonal antibody that targets the β7 subunit of integrins α4β7 and αEβ7, ultimately blocking migration and retention of leukocytes in the intestinal mucosa. [ 200 ]  As of early 2022,  Roche  halted clinical trials for the use of etrolizumab in the treatment of ulcerative colitis. [ 202 ]


A type of  leukocyte apheresis , known as granulocyte and monocyte adsorptive apheresis, still requires large-scale trials to determine whether or not it is effective. [ 203 ]  Results from small trials have been tentatively positive. [ 204 ]