Interest in understanding the role of bacteria in stomach diseases was rekindled in the 1970s, with the visualization of bacteria in the stomachs of people with gastric ulcers. [ 201 ]  The bacteria had also been observed in 1979, by Robin Warren, who researched it further with Barry Marshall from 1981. After unsuccessful attempts at culturing the bacteria from the stomach, they finally succeeded in visualizing colonies in 1982, when they unintentionally left their  Petri dishes  incubating for five days over the  Easter  weekend. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by bacterial infection and not by  stress  or  spicy food , as had been assumed before. [ 202 ]


Some skepticism was expressed initially, but within a few years multiple research groups had verified the association of  H. pylori  with gastritis and, to a lesser extent, ulcers. [ 203 ]  To demonstrate  H. pylori  caused gastritis and was not merely a bystander, Marshall drank a beaker of  H. pylori  culture. He became ill with nausea and vomiting several days later. An endoscopy 10 days after inoculation revealed signs of gastritis and the presence of  H. pylori . These results suggested  H. pylori  was the causative agent. Marshall and Warren went on to demonstrate antibiotics are effective in the treatment of many cases of gastritis. In 1994, the  National Institutes of Health  stated most recurrent duodenal and gastric ulcers were caused by  H. pylori , and recommended antibiotics be included in the treatment regimen. [ 204 ]


The bacterium was initially named  Campylobacter pyloridis , then renamed  C. pylori  in 1987 ( pylori  being the  genitive  of  pylorus , the circular opening leading from the stomach into the duodenum, from the  Ancient Greek  word  πυλωρός , which means  gatekeeper [ 205 ] ). [ 206 ]  When  16S ribosomal RNA   gene sequencing  and other research showed in 1989 that the bacterium did not belong in the genus  Campylobacter , it was placed in its own  genus ,  Helicobacter  from the Ancient Greek  έλιξ  ( hělix ) "spiral" or "coil". [ 205 ] [ 207 ]


In October 1987, a group of experts met in Copenhagen to found the European Helicobacter Study Group (EHSG), an international multidisciplinary research group and the only institution focused on  H. pylori . [ 208 ]  The Group is involved with the Annual International Workshop on Helicobacter and Related Bacteria, [ 209 ]  (renamed as the European Helicobacter and Microbiota Study Group [ 210 ] ), the Maastricht Consensus Reports (European Consensus on the management of  H. pylori ), [ 211 ] [ 212 ] [ 213 ] [ 214 ]  and other educational and research projects, including two international long-term projects:


Results from  in vitro  studies suggest that  fatty acids , mainly  polyunsaturated fatty acids , have a bactericidal effect against  H. pylori , but their  in vivo  effects have not been proven. [ 218 ]


The antibiotic resistance provided by biofilms has generated much research into targeting the mechanisms of  quorum sensing  used in the formation of biofilms. [ 88 ]


A suitable vaccine for  H. pylori , either prophylactic or therapeutic, is an ongoing research aim. [ 8 ]  The  Murdoch Children's Research Institute  is working at developing a vaccine that instead of specifically targeting the bacteria, aims to inhibit the inflammation caused that leads to the associated diseases. [ 147 ]


Gastric organoids  can be used as models for the study of  H. pylori  pathogenesis. [ 95 ]


Bismuth subcitrate potassium  is a  bismuth  salt used in combination with antibiotics and a  proton pump inhibitor  for the treatment of  Helicobacter pylori  infections. [ 1 ] [ 2 ]


A fixed-dose combination with the antibiotics  metronidazole  and  tetracycline  is sold under the trade name  Pylera . [ 3 ]


A known side effect of bismuth salts is harmless and reversible darkening of tongue and stool by formation of bismuth  sulfite . [ 3 ]  Other side effects of bismuth containing combination therapies are often difficult to assign to a specific component. [ citation needed ]


Bismuth absorption is increased by  ranitidine  and  omeprazole . [ 3 ]


The mechanism of action of bismuth is not known. It has been reasoned to interfere with the function of the bacterial  cell membrane ,  protein  and  cell wall  synthesis, the enzyme  urease ,  cell adhesion ,  ATP synthesis , and iron transport mechanisms. [ 3 ]


Bismuth subcitrate potassium is a salt of  bismuth  (Bi 3+ ),  potassium  (K + ) and  citrate  ( C 6 H 4 O 4− 7 ) in a  molar  ratio of about 1:5:2, with 3 moles of water. It contains about 25.6% ( mass percent ) bismuth, which is the active  moiety , and 22.9% potassium. [ 3 ] [ 4 ]  Other sources give somewhat different ratios of the constituents.


The drug combination  bismuth subcitrate/metronidazole/tetracycline  (trade name  Pylera ) is used for the treatment of  peptic ulcer  with an infection by the bacterium  Helicobacter pylori . [ 1 ]  It is taken  by mouth . [ 1 ]


It is available as a  generic medication . [ 2 ]


This combination is used together with  omeprazole  as a 'quadruple therapy' for the  eradication of  H. pylori  and for preventing  peptic ulcers  that are caused by this bacterium. [ 3 ]


The drug must not be taken by pregnant women, because tetracycline is known to cause tooth and bone defects in unborn children. It is also contraindicated in breastfeeding women, children up to 12 years of age, and by patients with impaired liver or renal (kidney) function, because no studies in such persons have been conducted. Tetracycline is also likely to be harmful in liver patients. [ 3 ]


Common side effects include diarrhea, nausea and  dysgeusia  (distortion of the sense of taste), especially a metallic taste. These effects are known from the drug's components as well as from other antibiotics. A very rare but dangerous reaction is  Stevens–Johnson syndrome , a life-threatening condition affecting the skin, which has also been described under metronidazole and tetracycline as separate drugs. [ 3 ]


Metronidazole in combination with alcohol causes severe reactions such as vomiting and flushes in many patients. Tetracycline resorption is reduced by dairy products,  antacids  and other products containing  calcium ,  magnesium ,  aluminium  as well as  iron . [ 3 ]


Bismuth subcitrate potassium is a salt of  bismuth  (Bi 3+ ),  potassium  (K + ) and  citrate  (C 6 H 5 O 7 3− ), containing about 25.6% ( mass percent ) bismuth, which is the active  moiety , and 22.9% potassium. Tetracycline is contained as the  hydrochloride , and metronidazole as the pure substance. [ 3 ]


In molecular biology,  CagZ  is a  protein  produced by  Helicobacter pylori  ( Campylobacter pylori ). It is a 23 kDa protein consisting of a single compact L-shaped domain, composed of seven  alpha-helices  that run  antiparallel  to each other. 70% of the amino acids are in  alpha-helix  conformation and no  beta-sheet  is present. CagZ is essential for the translocation of the  pathogenic  protein CagA into host  cells . [ 1 ]


Helicobacter pylori  eradication protocols  is a standard name for all treatment protocols for  peptic ulcers  and  gastritis  in the presence of  Helicobacter pylori  infection. The primary goal of the treatment is not only temporary relief of symptoms but also total elimination of  H. pylori  infection. Patients with active duodenal or gastric ulcers and those with a prior  ulcer  history should be tested for  H. pylori . Appropriate therapy should be given for eradication. Patients with  MALT lymphoma  should also be tested and treated for  H. pylori  since eradication of this infection can induce remission in many patients when the  tumor  is limited to the stomach. Several consensus conferences, including the Maastricht Consensus Report, recommend testing and treating several other groups of patients but there is limited evidence of benefit. This includes patients diagnosed with gastric  adenocarcinoma  (especially those with early-stage disease), patients found to have  atrophic gastritis  or intestinal metaplasia, as well as first-degree relatives of patients with gastric adenocarcinoma since the relatives themselves are at increased risk of gastric cancer partly due to the intrafamilial transmission of  H. pylori . To date, it remains controversial whether to test and treat all patients with  functional dyspepsia ,  gastroesophageal reflux disease , or other non-GI disorders as well as asymptomatic individuals. [ 1 ]


The success of  H. pylori  cure depends on the type and duration of therapy, patient compliance and bacterial factors such as  antibiotic resistance . Patients most often fail to respond to initial  H. pylori  eradication therapy because of noncompliance or antibiotic resistance. Patients should be queried about any side effects, missed doses, and completion of therapy. As culture with antibiotic sensitivities is not routinely performed when a  H. pylori  infection is diagnosed, it is generally recommended that different antibiotics be given at higher doses for 14 days. [ 2 ]


Achieving optimal eradication of  H. pylori  has proven difficult. Combination regimens that use two or three antibiotics with a  proton pump inhibitor  and/or  bismuth  are required to achieve adequate rates of eradication and to reduce the number of failures due to antibiotic resistance. In the United States, up to 50% of strains are resistant to metronidazole and 13% are resistant to clarithromycin. At present, experts disagree on the optimal regimen. [ 3 ]


In areas of low  clarithromycin  resistance, including the United States, a 14-day course of "triple therapy" with an oral proton pump inhibitor, clarithromycin 500 mg, and  amoxicillin  1 g (or, if  penicillin  allergic,  metronidazole  500 mg), all given twice daily for 14 days, is recommended for first-line therapy.  This regimen can achieve rates of eradication in up to 70% of cases. [ 4 ]


A 14-day course of "quadruple therapy" with a proton pump inhibitor, bismuth,  tetracycline , and  metronidazole  or  tinidazole  is a more complicated but also more effective regimen. In a 2011 randomized, controlled trial, the per protocol eradication rates were 93% with quadruple therapy and 70% with triple therapy. Bismuth-based quadruple therapy is recommended as first line therapy for patients in areas with high clarithromycin resistance (> 20%), in patients who have previously been treated with a macrolide antibiotic, or as second-line therapy for patients whose infection persists after an initial course of triple therapy. Several studies reported eradication rates of > 90% using a 10-day sequential regimen consisting of four drugs: a proton pump inhibitor and amoxicillin for 5 days, followed by a proton pump inhibitor, clarithromycin, and tinidazole for 5 days. However, subsequent studies confirmed equivalent or superior efficacy when all four drugs were given concomitantly for 10 days (non-bismuth quadruple therapy). [ 5 ] [ 6 ]


Sequential therapy is a newer approach that combines a 5-day course of a "dual therapy" using a proton pump inhibitor in combination with amoxicillin, with a sequential second 5-day course of the standard "triple therapy". [ 3 ]  High-dose dual therapy has comparable efficacy with bismuth-containing quadruple therapy, with fewer adverse effects and higher compliance. [ 7 ]  Although initial studies promisingly reported higher eradication rates, [ 3 ]  there is no superiority compared to the other therapies except in the presence of clarithromycin resistant organisms. In regions of high clarithromycin resistance, there is a high rate of eradication with a 14-day quadruple therapy consisting of a proton pump inhibitor, amoxicillin, clarithromycin, and  nitroimidazole ; still, the latter not available in the United States. [ 4 ]


A number of other eradication regimens have been proposed. In the Table below they are compared to with standard regimes.


Recent meta-analyses have proposed two adjuvant therapies which may help in the eradication of  H. pylori . Periodontal therapy or what is known as  scaling and root planing  and  probiotics  both need further studies to confirm their adjuvant role. [ citation needed ]


A 2016 systematic review has found that periodontal therapy (the use of mouthwash, tooth brushing, and manual removal of dental plaques) may have a role as an added treatment for short- and long-term follow up. For these results to be confirmed with regards eradication and non-recurrence, larger studies need to be carried out. [ 11 ]


Some studies have recently evaluated the role of the yeast  Saccharomyces boulardii  as a coadjutant in the eradication of  H. pylori  and in the prevention of the secondary effects of  antibiotic  therapy such as  antibiotic-associated diarrhea . A meta-analysis showed that supplementation with  S. boulardii  significantly increased the  H. pylori  eradication rate and reduced the risk of overall  H. pylori  therapy-related adverse effects. [ 12 ]  In a cohort of patients in Korea who received  S. boulardii  for 4 weeks during and after a 1-week course of standard triple therapy, eradication rates were 10% higher than for those who did not receive the supplement. [ citation needed ]


Other studies in which  Bifidobacterium  spp.  and  Lactobacillus acidophilus  have been administered revealed no significant difference in eradication rates in patients who were infected with strains susceptible to both antibiotics and who were treated with standard triple therapy. Further studies will be necessary to clarify the exact role of the  probiotics  in the eradication treatment. [ 13 ]


One of the first "eradication protocols", if not the first, was used by  J. Robin Warren  and  Barry Marshall . Barry Marshall treated his own  gastritis , which developed following intentional ingestion of  H. pylori   culture . He used  bismuth  salt and  metronidazole . This treatment effectively cured his gastritis and eliminated the  H. pylori  infection.  This is not the current eradication protocol. [ citation needed ]


One of the first "modern" eradication protocols was a one-week triple therapy, which the Sydney gastroenterologist  Thomas Borody  formulated in 1987. [ 14 ]  As of 2006, a standard triple therapy is  amoxicillin ,  clarithromycin , and a  proton pump inhibitor  such as  omeprazole , [ 15 ]   lansoprazole ,  pantoprazole , or  esomeprazole . Protocols with metronidazole were also in use. [ 15 ]
An example of a fixed-dose combination is PantoPac, containing pantoprazole, clarithromycin, and amoxicillin. [ citation needed ]


Giving  acetylcysteine  before antibiotic treatment was effective in overcoming  H. pylori  antibiotic resistance in a study with 40 patients who had at least four eradication failures in their history. The researchers believe it works by inhibiting the formation of  biofilm . [ 16 ]


Whereas the conventional  proton pump inhibitor -based triple therapy is effective, there is research in using longer acid suppression therapies, in particular, using  potassium competitive acid blocker  triple and dual therapy. In particular,  vonoprazan  is approved by the  US Food and Drug Administration  (FDA) for H. pylori eradication. [ 17 ]


helicoCARE direct  is a  Helicobacter pylori  whole-blood  antibody test  that was introduced worldwide in 2006. It is manufactured by  CARE diagnostica . It is an  immunochromatographic  test which detects the presence of  antibodies  against  H. pylori  in whole-blood samples. This test is suitable for screening large populations for  peptic ulcer  disease. [ 1 ]


Omeprazole/amoxicillin/rifabutin , sold under the brand name  Talicia , is a  fixed-dose combination  medication used for the treatment of  Helicobacter pylori  infection. [ 1 ]  It is taken  by mouth . [ 1 ]


It was approved for medical use in the United States in November 2019. [ 2 ]


This systemic  antibiotic -related article is a  stub . You can help Wikipedia by  expanding it .


Rifasutenizol  is an  investigational new drug  developed by TenNor Therapeutics, primarily aimed at treating  Helicobacter pylori  infections. [ 1 ]  It is a novel multi-targeting small molecule that functions as a bacterial DNA-directed  RNA polymerase  inhibitor. [ 2 ]  This drug has been granted  Qualified Infectious Disease Product  and  Fast Track designations  by the  U.S. FDA . [ 3 ] [ 4 ] [ 5 ]


This is a  timeline of the events relating to the discovery that peptic ulcer disease and some cancers are caused by  H. pylori . In 2005,  Barry Marshall  and  Robin Warren  were awarded the  Nobel Prize in Physiology or Medicine  for their discovery that  peptic ulcer disease  (PUD) was primarily caused by  Helicobacter pylori , a  bacterium  with affinity for acidic environments, such as the  stomach . As a result, PUD that is associated with  H. pylori  is currently treated with  antibiotics  used to eradicate the infection. For decades prior to their discovery, it was widely believed that PUD was caused by excess  acid  in the  stomach . During this time, acid control was the primary method of treatment for PUD, to only partial success. Among other effects, it is now known that acid suppression alters the stomach milieu to make it less amenable to  H. pylori  infection.


Before the 1950s, there were many microbiological descriptions of bacteria in the stomach and in gastric acid secretions, lending credence to both the infective theory and the hyperacidity theory as being causes of peptic ulcer disease. A single study, conducted in 1954, did not find evidence of bacteria on biopsies of the stomach stained traditionally; this effectively established the acid theory as  dogma . This paradigm was altered when Warren and Marshall effectively proved  Koch's postulates  for causation of PUD by  H. pylori  through a series of experiments in the 1980s; however, an extensive effort was required to convince the medical community of the relevance of their work. Now, all major gastrointestinal societies agree that  H. pylori  is the primary nondrug cause of PUD worldwide, and advocate its eradication as essential to treatment of gastric and duodenal ulcers. Additionally,  H. pylori  has been associated with  lymphomas  and  adenocarcinomas  of the stomach, and has been classified by the  World Health Organization  as a  carcinogen . Advances in  molecular biology  in the late 20th century led to the sequencing of the  H. pylori  genome, resulting in a better understanding of  virulence factors  responsible for its colonization and infection, on the DNA level.


Ascariasis  is a disease caused by the parasitic  roundworm   Ascaris lumbricoides . [ 1 ]  Infections have no symptoms in more than 85% of cases, especially if the number of worms is small. [ 1 ]  Symptoms increase with the number of worms present and may include  shortness of breath  and fever at the beginning of the disease. [ 1 ]  These may be followed by symptoms of abdominal swelling, abdominal pain, and  diarrhea . [ 1 ]  Children are most commonly affected, and in this age group the infection may also cause poor weight gain,  malnutrition , and learning problems. [ 1 ] [ 2 ] [ 5 ]


Infection occurs by ingesting food or drink contaminated with  Ascaris  eggs from feces. [ 2 ]  The eggs hatch in the  intestines , the larvae burrow through the gut wall, and migrate to the lungs via the blood. [ 2 ]  There they break into the  alveoli  and pass up the  trachea , where they are coughed up and may be swallowed. [ 2 ]  The larvae then pass through the stomach a second time into the intestine, where they become adult worms. [ 2 ]  It is a type of  soil-transmitted helminthiasis  and part of a group of diseases called  helminthiases . [ 6 ]


Prevention is by improved  sanitation , which includes improving access to toilets and proper disposal of  feces . [ 1 ] [ 7 ]  Handwashing with soap appears protective. [ 8 ]  In areas where more than 20% of the population is affected, treating everyone at regular intervals is recommended. [ 1 ]  Reoccurring infections are common. [ 2 ] [ 9 ]  There is no  vaccine . [ 2 ]  Treatments recommended by the  World Health Organization  are the medications  albendazole ,  mebendazole ,  levamisole , or  pyrantel pamoate . [ 2 ]  Other effective agents include  tribendimidine  and  nitazoxanide . [ 2 ]


About 0.8 to 1.2 billion people globally have ascariasis, with the most heavily affected populations being in  sub-Saharan Africa ,  Latin America , and Asia. [ 1 ] [ 10 ] [ 11 ]  This makes ascariasis the most common form of  soil-transmitted helminthiasis . [ 10 ]  As of 2010 it caused about 2,700 deaths a year, down from 3,400 in 1990. [ 12 ]  Another type of  Ascaris  infects pigs. [ 1 ]  Ascariasis is classified as a  neglected tropical disease . [ 6 ]


In populations where  worm infections  are widespread, it is common to find that most people are infected by a small number of worms, while a small number of people are heavily infected. This is characteristic of many types of worm infections. [ 1 ] [ 13 ]  Those people who are infected with only a small number of worms usually have no symptoms. [ 14 ]


As larval stages travel through the body, they may cause visceral damage,  peritonitis  and  inflammation , enlargement of the  liver  or  spleen , and an  inflammation of the lungs . Pulmonary manifestations take place during larval migration and may present as  Loeffler's syndrome , a transient respiratory illness associated with blood eosinophilia and pulmonary infiltrates with radiographic shadowing. [ 15 ]


The worms can occasionally cause intestinal blockage when large numbers get tangled into a bolus or they may migrate from the small intestine, which may require surgery. [ 17 ]  More than 796  A. lumbricoides  worms weighing up to 550 g (19 oz) were recovered at autopsy from a two-year-old South African girl. The worms had caused torsion and gangrene of the  ileum , which was interpreted as the cause of death. [ 18 ]


The worms lack teeth. However, they can rarely cause bowel perforations by inducing  volvulus  and closed-loop obstruction. [ citation needed ]


Bowel obstruction  may occur in up to 0.2 per 1000 per year. [ 1 ]  A worm may block the  ampulla of Vater , or go into the  main pancreatic duct , resulting in acute  pancreatitis  with raised serum levels of  amylase  and  lipase . Occasionally, a worm can travel through the biliary tree and even into the  gallbladder , causing acute  cholangitis  or acute  cholecystitis . [ 19 ] [ citation needed ]


Ascariasis may result in  allergies  to shrimp and  dustmites  due to the shared  antigen ,  tropomyosin ; this has not been confirmed in the laboratory. [ 20 ] [ 21 ]


The worms in the intestine may cause  malabsorption  and  anorexia , which contribute to  malnutrition . [ 22 ]  The malabsorption may be due to a loss of brush border enzymes, erosion and flattening of the villi, and inflammation of the  lamina propria . [ 23 ]


Ascaris  have an aversion to some general anesthetics and may exit the body, sometimes through the mouth, when an infected individual is put under  general anesthesia . [ 24 ]


The source of infection is from objects contaminated with fecal matter containing eggs. [ 2 ]  Ingestion of infective eggs from soil contaminated with human feces or contaminated vegetables and water is the primary route of infection. Infectious eggs may occur on objects such as hands, money, and furniture. [ 2 ]  Transmission from human to human by direct contact is impossible. [ 25 ]


Transmission comes through municipal recycled wastewater into crop fields. This is quite common in emerging industrial economies and poses serious risks for local crop sales and exports of contaminated vegetables. A 1986 outbreak of ascariasis in Italy was traced to irresponsible wastewater recycling used to grow  Balkan  vegetable exports. [ 26 ]


The number of  ova  (eggs) in  sewage  or in crops that were irrigated with raw or partially treated sewage, is a measure of the degree of ascariasis incidence. [ citation needed ]  For example:


The first appearance of eggs in stools is 60–70 days. In larval ascariasis, symptoms occur 4–16 days after infection. The final symptoms are gastrointestinal discomfort, colic and vomiting, fever, and observation of live worms in stools. Some patients may have pulmonary symptoms or neurological disorders during the migration of the larvae. There are generally few or no symptoms. A  bolus  of worms may obstruct the intestine; migrating larvae may cause  pneumonitis  and  eosinophilia . Adult worms have a lifespan of 1–2 years which means that individuals may be infected all their lives as worms die and new worms are acquired. [ 13 ]


Eggs can survive potentially for 15 years and a single worm may produce 200,000 eggs a day. [ 2 ]  They maintain their position by swimming against the intestinal flow. [ 30 ]


Ascaris  takes most of its nutrients from the partially digested host food in the intestine. There is some evidence that it can secrete  enzyme inhibitors , presumably to protect itself from digestion by the hosts' enzymes. Children are often more severely affected. [ 1 ]


Most  diagnoses  are made by identifying the appearance of the  worm  or eggs in feces. Due to the large quantity of eggs laid, diagnosis can generally be made using only one or two  fecal smears . [ 31 ]
The diagnosis is usually incidental when the host passes a worm in the stool or vomit. The eggs can be seen in a smear of fresh feces examined on a glass slide under a microscope and there are various techniques to concentrate them first or increase their visibility, such as the ether sedimentation method or the  Kato technique . The eggs have a characteristic shape: they are oval with a thick, mamillated shell (covered with rounded mounds or lumps), measuring  35–50 micrometer in diameter and 40–70 in length. During pulmonary disease, larvae may be found in fluids aspirated from the lungs. White blood cell counts may demonstrate peripheral  eosinophilia ; this is common in many parasitic infections and is not specific to ascariasis. On X-ray, 15–35 cm long filling defects, sometimes with a whirled appearance (bolus of worms). [ citation needed ]


Prevention is by improved access to sanitation which includes the use of properly functioning and clean toilets by all community members as one important aspect. [ 1 ]  Handwashing with soap may be protective; however, there is no evidence it affects the severity of the disease. [ 8 ]  Eliminating the use of untreated human faeces as  fertilizer  is also important. [ citation needed ]


In areas where more than 20% of the population is affected treating everyone is recommended. [ 1 ]  This has a cost of about 2 to 3 cents per person per treatment. [ 1 ]  This is known as  mass drug administration  and is often carried out among school-age children. [ 32 ]  For this purpose, broad-spectrum  benzimidazoles  such as  mebendazole  and  albendazole  are the drugs of choice recommended by  WHO . [ 33 ]


Medications that are used to kill roundworms are called  ascaricides . Those recommended by the World Health Organization for ascariasis are:  albendazole ,  mebendazole ,  levamisole  and  pyrantel pamoate . [ 2 ]  Single-dose of albendazole, mebendazole, and  ivermectin  are effective against ascariasis. They are effective at removing parasites and eggs from the intestines. [ 34 ]  Other effective agents include  tribendimidine  and  nitazoxanide . [ 2 ]  Pyrantel pamoate may induce intestinal obstruction in a heavy worm load. Albendazole is contraindicated during pregnancy and children under two years of age.  Thiabendazole  may cause migration of the worm into the  esophagus , so it is usually combined with  piperazine . [ citation needed ]


Piperazine is a flaccid paralyzing agent that blocks the response of  Ascaris  muscle to acetylcholine, which immobilizes the worm. It prevents migration when treatment is accomplished with weak drugs such as thiabendazole. If used by itself, it causes the worm to be passed out in the feces and may be used when worms have caused blockage of the intestine or the biliary duct. [ citation needed ]


Corticosteroids  can treat some of the symptoms, such as inflammation. [ citation needed ]


In some cases with severe infestation, the worms may cause  bowel obstruction , requiring emergency surgery. [ 38 ]  The bowel obstruction may be due to the number of worms in the bowel or  twisting of the bowel . [ 38 ]  During the surgery the worms may be manually removed. [ 38 ]


It is rare for infections to be life-threatening. [ 1 ]


Ascariasis is  common  in tropical regions as well as subtropical and regions that lack proper sanitation. It is rare to find traces of the infection in developed or urban regions. [ 39 ]


Roughly 0.8–1.3 billion individuals are infected with this intestinal worm, primarily in Africa and Asia. [ 1 ] [ 2 ] [ 11 ]  About 120 to 220 million of these cases are symptomatic. [ 1 ]


As of 2010, ascariasis caused about 2,700 directly attributable deaths, down from 3,400 in 1990. [ 12 ]  The indirectly attributable deaths due to the malnutrition link may be much higher. [ citation needed ]


Mouse and pig animal models are used to study  Ascaris  infection. [ 40 ] [ 41 ]


Ascariasis is more common in young animals than mature ones, with signs including unthriftiness, potbelly, rough hair coat, and slow growth. [ 42 ]


In pigs, the infection is caused by  Ascaris suum .  It is characterized by poor weight gain, leading to financial losses for the farmer. [ 1 ]


In horses and other equines, the equine roundworm is  Parascaris equorum . [ citation needed ]


Kings of England Richard III [ 43 ]  and Henry VIII [ 44 ]  both had ascariasis.


Blastocystosis  refers to a medical condition caused by infection with  Blastocystis .   Blastocystis  is a protozoal, single-celled parasite that inhabits the gastrointestinal tracts of humans and other animals.  Many different types of  Blastocystis  exist, and they can infect humans, farm animals, birds, rodents, amphibians, reptiles, fish, and even cockroaches. Blastocystosis has been found to be a possible risk factor for development of  irritable bowel syndrome . [ 1 ]


Researchers have published conflicting reports concerning whether  Blastocystis  causes symptoms in humans, with one of the earliest reports in 1916. [ 2 ]   The incidence of reports associated with symptoms began to increase in 1984, [ 3 ]  with physicians from Saudi Arabia reporting symptoms in humans [ 4 ]  and US physicians reporting symptoms in individuals with travel to less developed countries. [ 5 ]   A lively debate ensued in the early 1990s, with some physicians objecting to publication of reports that  Blastocystis  caused disease. [ 6 ] [ 7 ] [ 8 ] [ 9 ]   Some researchers believe the debate has been resolved by finding of multiple species of  Blastocystis  that can infect humans, with some causing symptoms and others being harmless (see Genetics and Symptoms). [ citation needed ]


A few of most commonly reported symptoms are:


Some less commonly reported symptoms include:


Researchers have sought to develop models to understand the variety of symptoms seen in humans.  Some patients do not have symptoms, while others report severe diarrhea and fatigue. [ citation needed ]


A number of researchers have investigated the possibility that some species of  Blastocystis  are more virulent than others. An Italian researcher reported differences in the protein profiles of isolates associated with chronic and acute infection. [ 19 ]   A research team from Malaysia reported that isolates from symptomatic patients produced large amoeboid forms that were not present in isolates from asymptomatic patients. [ 20 ]   The development of a classification system for  Blastocystis  in 2007 produced a series of studies investigating this possibility. [ citation needed ]


The studies that followed generally found that no specific "pathogenic" or nonpathogenic species of  Blastocystis  exists. [ 21 ] [ 22 ]  One study investigated the subtypes found in patients with irritable bowel syndrome (IBS),  inflammatory bowel disease  (IBD), and chronic diarrhea, and found the subtypes in these diseases were similar (subtypes 2 and 3), and have also been found in asymptomatic carriers. The researchers concluded that host factors, such as age and genetics, may play the dominant role in determining the symptoms seen in the disease. [ 23 ]


Blastocystis colonisation is positively associated with  IBS  and is a possible risk factor for developing IBS. [ 1 ]  A study of IBS patients in the Middle East showed a "significantly increased" immune reaction in IBS patients to  Blastocystis , even when the organism could not be identified in stool samples. [ 24 ]


The following reports have linked  Blastocystis  infection to  inflammatory bowel disease :


Humans contract  Blastocystis  infection by drinking water or eating food contaminated with  feces  from an infected human or animal. [ 29 ]   Blastocystis  infection can be spread from animals to humans, from humans to other humans, from humans to animals, and from animals to animals. [ 30 ] [ 31 ]  Risk factors for infection have been reported as following:


Research studies have suggested the following items are  not  risk factors for contracting  Blastocystis  infection:


Pathogenesis refers to the mechanism by which an organism causes disease.  The following disease-causing mechanisms have been reported in studies of  Blastocystis  infection:


Diagnosis is performed by determining if the infection is present, and then making a decision as to whether the infection is responsible for the symptoms.  Diagnostic methods in clinical use have been reported to be of poor quality and more reliable methods have been reported in research papers. [ 30 ] [ 59 ] [ 60 ] [ 61 ] [ 62 ]


For identification of infection, the only method clinically available in most areas is the ova and parasite (O&P) exam, which identifies the presence of the organism by microscopic examination of a chemically preserved stool specimen.  This method is sometimes called direct microscopy.  In the United States, pathologists are required to report the presence of  Blastocystis  when found during an O&P exam, so a special test does not have to be ordered. Direct microscopy is inexpensive, as the same test can identify a variety of gastrointestinal infections, such as  Giardia ,  Entamoeba histolytica , and  Cryptosporidium .  However, one laboratory director noted that pathologists using conventional microscopes failed to identify many  Blastocystis  infections, and indicated the necessity for special microscopic equipment for identification. [ 9 ]   The following table shows the sensitivity of Direct Microscopy in detecting  Blastocystis  when compared to stool culture, a more sensitive technique.  Stool culture was considered by some researchers to be the most reliable technique, but a recent study found stool culture only detected 83% of individuals infected when compared to  polymerase chain reaction  (PCR) testing. [ 62 ]


Reasons given for the failure of Direct Microscopy include: (1) Variable Shedding: The quantity of  Blastocystis  organisms varies substantially from day to day in infected humans and animals; [ 63 ]   (2) Appearance: Some forms of  Blastocystis  resemble fat cells or white blood cells, [ 62 ]  making it difficult to distinguish the organism from other cells in the stool sample; (3) Large number of morphological forms:  Blastocystis  cells can assume a variety of shapes, some have been described in detail only recently, so it is possible that additional forms exist but have not been identified. [ 62 ]


Several methods have been cited in literature for determination of the significance of the finding of  Blastocystis :


The following diagnostic methods are not routinely available to patients.  Researchers have reported that they are more reliable at detecting infection, and in some cases can provide the physician with information to help determine whether  Blastocystis  infection is the cause of the patient's symptoms: [ citation needed ]


Serum antibody testing : A 1993 research study performed by the  NIH  with United States patients suggested that it was possible to distinguish symptomatic and asymptomatic infection with  Blastocystis  using serum antibody testing. [ 67 ]   The study used blood samples to measure the patient's immune reaction to chemicals present on the surface of the  Blastocystis  cell.  It found that patients diagnosed with symptomatic  Blastocystis  infection exhibited a much higher immune response than controls who had  Blastocystis  infection but no symptoms.  The study was repeated in 2003 at  Ain Shams University  in Egypt with Egyptian patients with equivalent results. [ 59 ]


Fecal antibody testing : A 2003 study at Ain Shams University in Egypt indicated that patients symptomatically infected could be distinguished with a fecal antibody test. [ 59 ]  The study compared patients diagnosed with symptomatic  Blastocystis  infection to controls who had  Blastocystis  infection but no symptoms.  In the group with symptoms, IgA antibodies to  Blastocystis  were detected in fecal specimens that were not present in the healthy control group.


Stool culture :  Culturing has been shown to be a more reliable method of identifying infection.  In 2006, researchers reported the ability to distinguish between disease causing and non-disease causing isolates of  Blastocystis  using stool culture. [ 68 ]   Blastocystis  cultured from patients who were sick and diagnosed with  Blastocystis  infection produced large, highly adhesive amoeboid forms in culture.  These cells were absent in  Blastocystis  cultures from healthy controls.  Subsequent genetic analysis showed the  Blastocystis  from healthy controls was genetically distinct from that found in patients with symptoms.  Protozoal culture is unavailable in most countries due to the cost and lack of trained staff able to perform protozoal culture.


Genetic analysis of isolates : Researchers have used techniques which allow the DNA of  Blastocystis  to be isolated from fecal specimens. [ 30 ] [ 62 ]  This method has been reported to be more reliable at detecting  Blastocystis  in symptomatic patients than stool culture. [ 62 ]   This method also allows the species group of  Blastocystis  to be identified.  Research is continuing into which species groups are associated with symptomatic (see Genetics and Symptoms) blastocystosis. [ citation needed ]


Immuno-fluorescence (IFA) stain : An IFA stain causes  Blastocystis  cells to glow when viewed under a microscope, making the diagnostic method more reliable.  IFA stains are in use for  Giardia  and  Cryptosporidium  for both diagnostic purposes and water quality testing.  A 1991 paper from the  NIH  described the laboratory development of one such stain. [ 3 ]    However, no company currently offers this stain commercially. [ citation needed ]


Reports conflict regarding whether  Blastocystis  causes disease in humans. These reports resulted in a brief debate in medical journals in the early 1990s between some physicians in the United States who believed that  Blastocystis  was harmless, and physicians in the United States and overseas who believed it could cause disease. [ citation needed ]


At the time, it was common practice to identify all  Blastocystis  from humans as  Blastocystis hominis , while  Blastocystis  from animals was identified differently (e.g.  Blastocystis ratti  from rats).  Research performed since then has shown that the concept of  Blastocystis hominis  as a unique species of  Blastocystis  infecting humans is not supported by microbiological findings.  Although one species group associated with primates was found, it was also discovered that humans can acquire infection from any one of nine species groups of  Blastocystis  which are also carried by cattle, pigs, rodents, chickens, pheasants, monkeys, dogs, and other animals. [ 30 ] [ 31 ] [ 69 ]  Research has suggested that some types produce few or no symptoms, while others produce illness and intestinal inflammation. [ 68 ] [ 20 ]   Researchers have suggested conflicting reports may be due to the practice of naming all  Blastocystis  from humans  Blastocystis hominis [ 31 ]  and have proposed discontinuing the use of that term. [ 31 ]


A standard naming system for  Blastocystis  organisms from humans and animals has been proposed which names  Blastocystis  isolates according to the genetic identity of the  Blastocystis  organism rather than the host. [ 31 ]   The naming system used identifies all isolates as  Blastocystis  sp. subtype  nn  where nn is a number from 1 to 9 indicating the species group of the  Blastocystis  organism.  The identification of the species can not be performed with a microscope at this time, because the different species look alike.  Identification requires equipment for genetic analysis that is common in microbiology laboratories, but not available to most physicians.  Some new scientific papers have begun using the standard naming system. [ 70 ]


There is a lack of scientific study to support the efficacy of any particular treatment. [ 71 ]  An additional review published in 2009 made a similar conclusion, noting that because the diagnostics in use have been unreliable, it has been impossible to determine whether a drug has eradicated the infection, or just made the patient feel better. [ 72 ]   Historical reports, such as one from 1916, note difficulty associated with eradication of  Blastocystis  from patients, describing it as "an infection that is hard to get rid of." [ 2 ]


A 1999  in vitro  study from Pakistan found 40% of isolates are resistant to common antiprotozoal drugs. [ 73 ]  A study of isolates from patients diagnosed with IBS found 40% of isolates resistant to  metronidazole  and 32% resistant to  furazolidone . [ 74 ]  Drugs reported in studies to be effective in eradicating  Blastocystis  infection have included  metronidazole , [ 4 ] [ 75 ]   trimethoprim , [ 76 ]   TMP-SMX  (only trimethoprim is active with  sulphamethoxazole  demonstrating no activity), [ 75 ] [ 76 ]   tetracycline , [ 76 ]   doxycycline ,  nitazoxanide , [ 77 ]   pentamidine , [ 78 ]   paromomycin [ 79 ]  and  iodoquinol . [ 80 ]  Iodoquinol has been found to be less effective in practice than in-vitro. [ 81 ] [ 82 ]   Miconazole  and  quinacrine  have been reported as effective agents against  Blastocystis  growth in-vitro. [ 76 ] [ 83 ]   Rifaximin , [ 84 ]  and  albendazole  have shown promise as has  ivermectin  which demonstrated high effectiveness against blastocystis hominis isolates in an in vitro study. [ 85 ]  There is also evidence that the probiotic yeast  Saccharomyces boulardii , [ 79 ]  and the plant  Mallotus oppositifolius [ 86 ]  may be effective against  Blastocystis  infections.


Physicians have described the successful use of a variety of discontinued antiprotozoals in treatment of  Blastocystis  infection.   Emetine  was reported as successful in cases in early 20th century with British soldiers who contracted  Blastocystis  infection while serving in Egypt. [ 2 ]   In vitro  testing showed  emetine  was more effective than  metronidazole  or  furazolidone . [ 87 ]  Emetine is available in the United States through special arrangement with the  Center for Disease Control .  Clioquinol  (Entero-vioform) was noted as successful in treatment of  Blastocystis  infection but removed from the market following an adverse event in Japan. [ 3 ]   Stovarsol  and Narsenol, two arsenic-based antiprotozoals, were reported to be effective against the infection. [ 3 ]  Carbarsone was available as an anti-infective compound in the United States as late as 1991, and was suggested as a possible treatment. [ 3 ]  The reduction in the availability of antiprotozoal drugs has been noted as a complicating factor in treatment of other protozoal infections. [ 88 ]   For example, in  Australia , production of  diloxanide furoate  ended in 2003,  paromomycin  is available under special access provisions, and the availability of  iodoquinol  is limited. [ 89 ]


Like other protozoal infections, the prevalence of  Blastocystis  infection varies depending on the area investigated and the population selected.  A number of different species groups of  Blastocystis  infect humans, [ 69 ]  with some being reported to cause disease while others do not. [ 68 ] [ 20 ]   To date, surveys have not distinguished between different types of  Blastocystis   in humans, so the significance of findings may be difficult to evaluate.  Developing countries have been reported to have higher incidences, but recent studies suggest that symptomatic infection with  Blastocystis  may be prevalent in certain industrialized countries, as well. [ citation needed ]


Experimental infection in immunocompetent and immunocompromised mice has produced intestinal inflammation, altered bowel habits, lethargy, and death. [ 26 ] [ 27 ] [ 28 ]   Chronic diarrhea has been reported in non-human higher primates. [ 96 ]


While many enteric protists are the subject of research,  Blastocystis  is unusual in that basic questions concerning how it should be diagnosed and treated and how it causes disease remain unsettled.  The following groups have ongoing research programs directed at these questions:


Singh


treatment


Botulism  is a rare and potentially fatal  illness  caused by  botulinum toxin , which is produced by the bacterium  Clostridium botulinum . The disease begins with weakness, blurred vision,  feeling tired , and trouble speaking. This may then be followed by weakness of the arms, chest muscles, and legs. Vomiting, swelling of the abdomen, and diarrhea may also occur. The disease does not usually affect  consciousness  or cause a  fever .


Botulism can occur in several ways. The  bacterial spores  which cause it are common in both soil and water and are very resistant. They produce the  botulinum toxin  when exposed to low oxygen levels and certain temperatures. Foodborne botulism happens when food containing the toxin is eaten. Infant botulism instead happens when the bacterium develops in the  intestines  and releases the toxin. This typically only occurs in children less than one year old, as protective mechanisms against development of the bacterium develop after that age. Wound botulism is found most often among those who  inject street drugs . In this situation, spores enter a wound, and in the absence of oxygen, release the toxin. The disease is not passed directly between people. Its diagnosis is confirmed by finding the toxin or bacteria in the person in question.


Prevention is primarily by proper food preparation. The toxin, though not the spores, is destroyed by heating it to more than 85 °C (185 °F) for longer than five minutes. The clostridial spores can be destroyed in an autoclave with moist heat (120°C/ 250°F for at least 15 minutes) or dry heat (160°C for 2 hours) or by irradiation. The spores of group I strains are inactivated by heating at 121°C (250°F) for 3 minutes during commercial canning. Spores of group II strains are less heat-resistant, and they are often damaged by 90°C (194°F) for 10 minutes, 85°C for 52 minutes, or 80°C for 270 minutes; however, these treatments may not be sufficient in some foods. [ 1 ]   Honey  can contain the organism, and for this reason, honey should not be fed to children under 12 months. Treatment is with an  antitoxin . In those who lose their ability to breathe on their own,  mechanical ventilation  may be necessary for months.  Antibiotics  may be used for wound botulism. Death occurs in 5 to 10% of people. Botulism also affects many other animals. The word is from  Latin   botulus , meaning 'sausage'.


The muscle weakness of botulism characteristically starts in the muscles supplied by the  cranial nerves —a group of twelve nerves that control  eye movements , the  facial muscles  and the muscles controlling  chewing  and  swallowing .  Double vision ,  drooping of both eyelids , loss of facial expression and swallowing problems may therefore occur. In addition to affecting the  voluntary muscles , it can also cause  disruptions in the autonomic nervous system . This is experienced as  a dry mouth and throat  (due to decreased production of saliva),  postural hypotension  (decreased blood pressure on standing, with resultant lightheadedness and risk of blackouts), and eventually  constipation  (due to decreased  forward movement of intestinal contents ). [ 2 ]  Some of the toxins (B and E) also precipitate  nausea ,  vomiting , [ 2 ]  and  difficulty with talking . The weakness then spreads to the arms (starting in the shoulders and proceeding to the forearms) and legs (again from the thighs down to the feet). [ 2 ]


Severe botulism leads to reduced movement of the  muscles of respiration , and hence problems with  gas exchange . This may be experienced as  dyspnea  (difficulty breathing), but when severe can lead to  respiratory failure , due to the buildup of unexhaled  carbon dioxide  and its resultant depressant effect on the brain. This may lead to respiratory compromise and death if untreated. [ 2 ]


Clinicians frequently think of the symptoms of botulism in terms of a classic triad:  bulbar palsy  and descending paralysis, lack of fever, and clear senses and mental status ("clear sensorium"). [ 3 ]


Infant botulism (also referred to as  floppy baby syndrome ) was first recognized in 1976, and is the most common form of botulism in the United States. Infants are susceptible to infant botulism in the first year of life, with more than 90% of cases occurring in infants younger than six months. [ 4 ]  Infant botulism results from the ingestion of the  C. botulinum  spores, and subsequent colonization of the small intestine. The infant gut may be colonized when the composition of the  intestinal microflora  (normal flora) is insufficient to competitively inhibit the growth of  C. botulinum  and levels of bile acids (which normally inhibit  clostridial  growth) are lower than later in life. [ 5 ]


The growth of the spores releases  botulinum toxin , which is then absorbed into the bloodstream and taken throughout the body, causing paralysis by blocking the release of  acetylcholine  at the  neuromuscular junction . Typical symptoms of infant botulism include constipation, lethargy, weakness, difficulty feeding, and an altered cry, often progressing to a complete descending  flaccid paralysis . Although constipation is usually the first symptom of infant botulism, it is commonly overlooked. [ 6 ]


Honey  is a known dietary reservoir of  C. botulinum  spores and has been linked to infant botulism. For this reason, honey is not recommended for infants less than one year of age. [ 5 ]  Most cases of infant botulism, however, are thought to be caused by acquiring the spores from the natural environment.  Clostridium botulinum  is a ubiquitous soil-dwelling bacterium. Many infant botulism patients have been demonstrated to live near a construction site or an area of soil disturbance. [ 7 ]


Infant botulism has been reported in 49 of 50 US states (all save for Rhode Island), [ 4 ]  and cases have been recognized in 26 countries on five continents. [ 8 ]


Infant botulism has no long-term side effects. [ citation needed ]


Botulism can result in death due to  respiratory  failure. However, in the past 50 years, the proportion of patients with botulism who die has fallen from about 50% to 7% due to improved supportive care. A patient with severe botulism may require  mechanical ventilation  (breathing support through a ventilator) as well as intensive medical and nursing care, sometimes for several months. The person may require rehabilitation therapy after leaving the hospital. [ 9 ]


Clostridium botulinum  is an  anaerobic ,  Gram-positive , spore-forming rod.  Botulinum toxin  is one of the most powerful known toxins: about one  microgram  is lethal to humans when inhaled. [ 10 ]  It acts by blocking  nerve  function ( neuromuscular blockade ) through inhibition of the excitatory  neurotransmitter   acetylcholine 's release from the  presynaptic  membrane of  neuromuscular junctions  in the  somatic nervous system . This causes paralysis. Advanced botulism can cause  respiratory failure  by paralysing the muscles of the chest; this can progress to  respiratory arrest . [ 11 ]  Furthermore, acetylcholine release from the presynaptic membranes of  muscarinic  nerve synapses is blocked. This can lead to a variety of autonomic signs and symptoms described above. [ citation needed ]


In all cases, illness is caused by the botulinum toxin which the bacterium  C. botulinum  produces in anaerobic conditions and not by the bacterium itself. The pattern of damage occurs because the toxin affects nerves that fire (depolarize) at a higher frequency first. [ 12 ]


Mechanisms of entry into the human body for botulinum toxin are described below. [ citation needed ]


The most common form in Western countries is infant botulism. This occurs in infants who are  colonized  with the bacterium in the small intestine during the early stages of their lives. The bacterium then produces the toxin, which is absorbed into the bloodstream. The consumption of  honey  during the first year of life has been identified as a risk factor for infant botulism; it is a factor in a fifth of all cases. [ 2 ]  The adult form of infant botulism is termed  adult intestinal toxemia , and is exceedingly rare. [ 2 ]


Toxin that is produced by the bacterium in containers of food that have been improperly preserved is the most common cause of food-borne botulism. Fish that has been pickled without the salinity or acidity of brine that contains  acetic acid  and high  sodium  levels, as well as smoked fish stored at too high a temperature, presents a risk, as does improperly canned food. [ citation needed ]


Food-borne botulism results from contaminated food in which  C. botulinum  spores have been allowed to germinate in low-oxygen conditions. This typically occurs in improperly prepared home-canned food substances and fermented dishes without adequate salt or acidity. [ 13 ]  Given that multiple people often consume food from the same source, it is common for more than a single person to be affected simultaneously. Symptoms usually appear 12–36 hours after eating, but can also appear within 6 hours to 10 days. [ 14 ]


No withdrawal periods have been established for cows affected by Botulism. Lactating cows injected with various doses of Botulinum toxin C have not resulted in detectable Botulinum  neurotoxin  in milk produced. [ 15 ]  Using  mouse bioassays  and  immunostick ELISA tests , botulinum toxin was detected in whole blood and serum but not in milk samples, suggesting that botulinum type C toxin does not enter milk in detectable concentrations. [ 16 ]  Cooking and pasteurization denatures botulinum toxin but does not necessarily eliminate spores. Botulinum spores or toxins can find their way into the dairy production chain from the environment. [ 17 ]  Despite the low risk of milk and meat contamination, the protocol for fatal bovine botulism cases appears to be incineration of carcasses and withholding any potentially contaminated milk from human consumption. It is also advised that raw milk from affected cows should not be consumed by humans or fed to calves. [ 18 ]


There have been several reports of botulism from pruno wine made of food scraps in prison. [ 19 ] [ 20 ] [ 21 ]  In a Mississippi prison in 2016, prisoners illegally brewed alcohol that led to 31 cases of botulism. The research study done on these cases found the symptoms of mild botulism matched the symptoms severe botulism though the outcomes and progression of the disease were different. [ 22 ]


Wound botulism results from the contamination of a wound with the bacteria, which then secrete the toxin into the bloodstream. This has become more common in  intravenous drug users  since the 1990s, especially people using  black tar heroin  and those  injecting heroin into the skin  rather than the veins. [ 2 ]  Wound botulism can also come from a minor wound that is not properly cleaned out; the skin grows over the wound thus trapping the spore in an anaerobic environment and creating botulism. One example was a person who cut their ankle while using a weed eater; as the wound healed over, it trapped a blade of grass and spec of soil under the skin that lead to severe botulism requiring hospitalization and rehabilitation for months. Wound botulism accounts for 29% of cases. [ citation needed ]


Isolated cases of botulism have been described after  inhalation  by laboratory workers. [ 23 ]


Symptoms of botulism may occur away from the injection site of  botulinum toxin . [ 24 ]  This may include loss of strength, blurred vision, change of voice, or trouble breathing which can result in death. [ 24 ]  Onset can be hours to weeks after an injection. [ 24 ]  This generally only occurs with inappropriate strengths of botulinum toxin for cosmetic use or due to the larger doses used to treat movement disorders. [ 2 ]  However, there are cases where an off-label use of botulinum toxin resulted in severe botulism and death. [ 25 ]  Following a 2008 review the FDA added these concerns as a  boxed warning . [ 26 ]  An international grassroots effort led by NeverTox to assemble the people experiencing Iatrogenic Botulism Poisoning (IBP) and provide education and emotional support serves 39,000 people through a Facebook group who are suffering from adverse events from botulinum toxin injections.  [ 27 ]


Prior to the boxed warning labels that included a disclaimer that botulinum toxin injections could cause botulism, there were a series of lawsuits against the pharmaceutical firms that manufactured injectable botulinum toxin. A Hollywood producer's wife brought a lawsuit after experiencing debilitating adverse events from migraine treatment.  [ 28 ]  A lawsuit on behalf of a 3-year-old boy who was permanently disabled by a botulinum toxin injection was settled in court during the trial.  [ 29 ]  The family of a 7-year-old boy treated with botulinum toxin injections for leg spasms sued after the boy almost died. [ 30 ]  Several families of people who died after treatments with botulinum toxin injections brought lawsuits. [ 31 ]   [ 32 ]   [ 33 ] [ 34 ]  One lawsuit prevailed for the plaintiff who was awarded compensation of $18 million; the plaintiff was a physician who was diagnosed with botulism by thirteen neurologists at the NIH. [ 35 ]  Deposition video from that lawsuit quotes a pharmaceutical executive stating that "Botox doesn't cause botulism." [ 36 ]


The toxin is the protein  botulinum toxin  produced under anaerobic conditions (where there is no oxygen) [ 37 ]  by the bacterium  Clostridium botulinum . [ 38 ]


Clostridium botulinum  is a large anaerobic Gram-positive bacillus that forms subterminal  endospores . [ 39 ]


There are eight serological varieties of the bacterium denoted by the letters A to H. The toxin from all of these acts in the same way and produces similar symptoms: the motor nerve endings are prevented from releasing acetylcholine, causing flaccid paralysis and symptoms of blurred vision, ptosis, nausea, vomiting, diarrhea or constipation, cramps, and respiratory difficulty. [ citation needed ]


Botulinum toxin is broken into eight neurotoxins (labeled as types A, B, C [C1, C2], D, E, F, and G), which are  antigenically  and  serologically  distinct but structurally similar. Human botulism is caused mainly by types A, B, E, and (rarely) F. Types C and D cause toxicity only in other animals. [ 40 ]


In October 2013, scientists released news of the discovery of type H, the first new botulism neurotoxin found in forty years. However, further studies showed type H to be a chimeric toxin composed of parts of types F and A (FA). [ 41 ]


Some types produce a characteristic putrefactive smell and digest meat (types A and some of B and F); these are said to be  proteolytic ; type E and some types of B, C, D and F are nonproteolytic and can go undetected because there is no strong odor associated with them. [ 39 ]


When the bacteria are under stress, they develop spores, which are inert. Their natural habitats are in the soil, in the silt that comprises the bottom sediment of streams, lakes, and coastal waters and ocean, while some types are natural inhabitants of the intestinal tracts of mammals (e.g., horses, cattle, humans), and are present in their excreta. The spores can survive in their inert form for many years. [ 42 ]


Toxin is produced by the bacteria when environmental conditions are favourable for the spores to replicate and grow, but the gene that encodes for the toxin protein is actually carried by a virus or  phage  that infects the bacteria. Little is known about the natural factors that control phage infection and replication within the bacteria. [ 43 ]


The spores require warm temperatures, a protein source, an anaerobic environment, and moisture in order to become active and produce toxin. In the wild, decomposing vegetation and invertebrates combined with warm temperatures can provide ideal conditions for the botulism bacteria to activate and produce toxin that may affect feeding birds and other animals. Spores are not killed by boiling, but botulism is uncommon because special, rarely obtained conditions are necessary for botulinum toxin production from C. botulinum spores, including an anaerobic, low-salt, low-acid, low-sugar environment at ambient temperatures. [ 44 ]


Botulinum inhibits the release within the nervous system of  acetylcholine , a neurotransmitter, responsible for communication between motor neurons and muscle cells. All forms of botulism lead to  paralysis  that typically starts with the muscles of the face and then spreads towards the limbs. [ 2 ]  In severe forms, botulism leads to paralysis of the breathing muscles and causes  respiratory failure . In light of this life-threatening complication, all suspected cases of botulism are treated as  medical emergencies , and public health officials are usually involved to identify the source and take steps to prevent further cases from occurring. [ 2 ]


Botulinum toxin A and E specifically cleave the SNAP-25, whereas serotype B, D, F and G cut synaptobrevin. Serotype C cleaves both SNAP-25 and syntaxin. This causes blockade of neurotransmitter  acetylcholine  release, [ 45 ]  ultimately leading to paralysis.


For botulism in babies, diagnosis should be made on signs and symptoms. Confirmation of the diagnosis is made by testing of a  stool  or  enema  specimen with the mouse  bioassay .


In people whose history and physical examination suggest botulism, these clues are often not enough to allow a diagnosis. Other diseases such as  Guillain–Barré syndrome ,  stroke , and  myasthenia gravis  can appear similar to botulism, and special tests may be needed to exclude these other conditions. These tests may include a  brain scan ,  cerebrospinal fluid  examination, nerve conduction test ( electromyography , or EMG), and an  edrophonium  chloride (Tensilon) test for  myasthenia gravis . A definite diagnosis can be made if botulinum toxin is identified in the food, stomach or intestinal contents, vomit or feces. The toxin is occasionally found in the blood in  peracute  cases. Botulinum toxin can be detected by a variety of techniques, including  enzyme-linked immunosorbent assays  (ELISAs),  electrochemiluminescent  (ECL) tests and mouse inoculation or feeding trials. The toxins can be typed with neutralization tests in mice. In toxicoinfectious botulism, the organism can be cultured from tissues. On egg yolk medium, toxin-producing colonies usually display surface iridescence that extends beyond the colony. [ 46 ]


Although the vegetative form of the bacteria is destroyed by boiling, [ 47 ] [ 48 ]  the spore itself is not killed by the temperatures reached with normal sea-level-pressure boiling, leaving it free to grow and again produce the toxin when conditions are right. [ 49 ] [ 50 ] [ 51 ]


A recommended prevention measure for infant botulism is to avoid giving honey to infants less than 12 months of age, as botulinum spores are often present. In older children and adults the normal intestinal bacteria suppress development of  C. botulinum . [ 52 ]


While commercially canned goods are required to undergo a "botulinum cook" in a pressure cooker at 121 °C (250 °F) for 3 minutes, [ citation needed ]  and thus rarely cause botulism, there have been notable exceptions. Two were the 1978 Alaskan salmon outbreak and the 2007  Castleberry's Food Company  outbreak. Foodborne botulism is the rarest form, accounting for only around 15% of cases (US) [ 53 ]  and has more frequently resulted from  home-canned  foods with low acid content, such as  carrot juice ,  asparagus , green  beans ,  beets , and  corn . However, outbreaks of botulism have resulted from more unusual sources. In July 2002, fourteen  Alaskans  ate  muktuk  ( whale meat ) from a  beached whale , and eight of them developed symptoms of botulism, two of them requiring  mechanical ventilation . [ 54 ]


Other, much rarer sources of infection (about every decade in the US [ 53 ] ) include  garlic  or herbs [ 55 ]  stored covered in  oil  without  acidification , [ 56 ]   chili peppers , [ 53 ]  improperly handled baked potatoes wrapped in  aluminum  foil, [ 53 ]  tomatoes, [ 53 ]  and home-canned or  fermented fish .


When canning or preserving food at home, attention should be paid to hygiene, pressure, temperature, refrigeration and storage. When making home preserves, only acidic fruit such as apples, pears, stone fruits and berries should be used. Tropical fruit and tomatoes are low in acidity and must have some acidity added before they are canned. [ 57 ]


Low-acid foods have pH values higher than 4.6. They include red meats, seafood, poultry, milk, and all fresh vegetables except for most tomatoes. Most mixtures of low-acid and acid foods also have pH values above 4.6 unless their recipes include enough lemon juice, citric acid, or vinegar to make them acidic. Acid foods have a pH of 4.6 or lower. They include fruits, pickles, sauerkraut, jams, jellies, marmalades, and fruit butters. [ 58 ]


Although tomatoes usually are considered an acid food, some are now known to have pH values slightly above 4.6. Figs also have pH values slightly above 4.6. Therefore, if they are to be canned as acid foods, these products must be acidified to a pH of 4.6 or lower with lemon juice or citric acid. Properly acidified tomatoes and figs are acid foods and can be safely processed in a boiling-water canner. [ 58 ]


Oils infused with fresh garlic or herbs should be acidified and refrigerated. Potatoes which have been baked while wrapped in aluminum foil should be kept hot until served or refrigerated. Because the botulism toxin is destroyed by high temperatures, home-canned foods are best boiled for 10 minutes before eating. [ 59 ]  Metal cans containing food in which bacteria are growing may bulge outwards due to gas production from bacterial growth or the food inside may be foamy or have a bad odor; cans with any of these signs should be discarded. [ 60 ] [ 61 ]


Any container of food which has been heat-treated and then assumed to be airtight which shows signs of not being so, e.g., metal cans with pinprick holes from rust or mechanical damage, should be discarded. Contamination of a canned food solely with  C. botulinum  may not cause any visual defects to the container, such as bulging. Only assurance of sufficient thermal processing during production, and absence of a route for subsequent contamination, should be used as indicators of food safety.


The addition of  nitrites  and  nitrates  to processed meats such as ham, bacon, and sausages reduces growth and toxin production of  C. botulinum . [ 62 ] [ 63 ]


Vaccines  are under development, but they have side effects. [ 64 ] [ clarification needed ]  As of 2017 work to develop a better vaccine was being carried out, but the US FDA had not approved any vaccine against botulism. [ 65 ] [ 66 ]


Botulism is generally treated with botulism  antitoxin  and supportive care. [ 64 ]


Supportive care for botulism includes monitoring of respiratory function. Respiratory failure due to  paralysis  may require  mechanical ventilation  for 2 to 8 weeks, plus intensive medical and nursing care. After this time, paralysis generally improves as new  neuromuscular connections  are formed. [ 67 ]


In some abdominal cases, physicians may try to remove contaminated food still in the digestive tract by inducing vomiting or using  enemas . Wounds should be treated, usually surgically, to remove the source of the toxin-producing bacteria. [ 68 ]


Botulinum antitoxin consists of  antibodies  that neutralize botulinum toxin in the  circulatory system  by  passive immunization . [ 69 ]  This prevents additional toxin from binding to the neuromuscular junction, but does not reverse any already inflicted paralysis. [ 69 ]


In adults, a trivalent antitoxin containing antibodies raised against botulinum toxin types A, B, and E is used most commonly; however, a  heptavalent botulism antitoxin  has also been developed and was approved by the U.S.  FDA  in 2013. [ 11 ] [ 70 ]  In infants, horse-derived antitoxin is sometimes avoided for fear of infants developing  serum sickness  or lasting  hypersensitivity  to horse-derived proteins. [ 71 ]  To avoid this, a human-derived antitoxin has been developed and approved by the U.S. FDA in 2003 for the treatment of infant botulism. [ 72 ]  This human-derived antitoxin has been shown to be both safe and effective for the treatment of infant botulism. [ 72 ] [ 73 ]  However, the danger of equine-derived antitoxin to infants has not been clearly established, and one study showed the equine-derived antitoxin to be both safe and effective for the treatment of infant botulism. [ 71 ]


Trivalent (A,B,E) botulinum antitoxin is derived from equine sources utilizing whole  antibodies  (Fab and Fc portions). In the United States, this antitoxin is available from the local health department via the  CDC . The second antitoxin,  heptavalent (A,B,C,D,E,F,G) botulinum antitoxin , is derived from "despeciated" equine  IgG  antibodies which have had the Fc portion cleaved off leaving the F(ab')2 portions. This less immunogenic antitoxin is effective against all known strains of botulism where not contraindicated. [ 74 ]


The paralysis caused by botulism can persist for two to eight weeks, during which supportive care and ventilation may be necessary to keep the patient alive. [ 67 ]  Botulism can be fatal in five to ten percent of people who are affected. [ 64 ]  However, if left untreated, botulism is fatal in 40 to 50 percent of cases. [ 73 ]


Infant botulism typically has no long-term side effects but can be complicated by treatment-associated adverse events. The  case fatality  rate is less than two percent for hospitalized babies. [ 75 ]


Globally, botulism is fairly rare, [ 64 ]  with approximately 1,000 identified cases yearly. [ 76 ]


In the United States an average of 145 cases are reported each year. Of these, roughly 65% are infant botulism, 20% are wound botulism, and 15% are foodborne. [ 77 ]  Infant botulism is predominantly sporadic and not associated with epidemics, but great geographic variability exists. From 1974 to 1996, for example, 47% of all infant botulism cases reported in the U.S. occurred in California. [ 77 ]


Between 1990 and 2000, the  Centers for Disease Control and Prevention  reported 263 individual foodborne cases from 160 botulism events in the United States with a case-fatality rate of 4%. Thirty-nine percent (103 cases and 58 events) occurred in Alaska, all of which were attributable to traditional Alaskan aboriginal foods. In the lower 49 states, home-canned food was implicated in 70 events (~69%) with canned asparagus being the most frequent cause. Two restaurant-associated outbreaks affected 25 people. The median number of cases per year was 23 (range 17–43), the median number of events per year was 14 (range 9–24). The highest incidence rates occurred in Alaska, Idaho, Washington, and Oregon. All other states had an incidence rate of 1 case per ten million people or less. [ 78 ]


The number of cases of food borne and infant botulism has changed little in recent years, but wound botulism has increased because of the use of  black tar heroin , especially in  California . [ 79 ]


All data regarding botulism antitoxin releases and laboratory confirmation of cases in the US are recorded annually by the Centers for Disease Control and Prevention and published on their website. [ 77 ]


The largest recorded outbreak of foodborne botulism in the United Kingdom occurred in June 1989. A total of 27 patients were affected; one patient died. Twenty-five of the patients had eaten one brand of hazelnut yogurt in the week before the onset of symptoms. Control measures included the cessation of all yogurt production by the implicated producer, the withdrawal of the firm's yogurts from sale, the recall of cans of the hazelnut conserve, and advice to the general public to avoid the consumption of all hazelnut yogurts. [ 86 ]


From 1958 to 1983 there were 986 outbreaks of botulism in China involving 4,377 people with 548 deaths. [ 87 ]


After the  Chinese Communist Revolution  in 1949, a mysterious plague (named  Qapqal disease ) was noticed to be affecting several  Sibe villages  in  Qapqal Xibe Autonomous County . It was endemic with distinctive epidemic patterns, yet the underlying cause remained unknown for a long period of time. [ 88 ]  It caused a number of deaths and forced some people to leave the place. [ 89 ]


In 1958, a team of experts were sent to the area by the Ministry of Health to investigate the cases. The epidemic survey conducted proved that the disease was primarily type A botulism, [ 90 ]  with several cases of type B. [ 88 ]  The team also discovered that the source of the botulinum was local fermented grain and beans, as well as a raw meat food called  mi song hu hu . [ 89 ]  They promoted the improvement of fermentation techniques among local residents, and thus eliminated the disease.


From 1985 to 2005 there were outbreaks causing 91 confirmed cases of foodborne botulism in  Canada , 85% of which were in  Inuit  communities, especially  Nunavik , as well as   First Nations  of the coast of  British Columbia , following consumption of traditionally prepared marine mammal and fish products. [ 91 ]


In 2017, there were 70 cases of botulism with 8 deaths in Ukraine. The previous year there were 115 cases with 12 deaths. Most cases were the result of dried fish, a common local  drinking snack . [ 92 ]


In 2020, several cases of botulism were reported in  Vietnam . All of them were related to a product containing contaminated vegetarian  pâté . Some patients were put on life support. [ 93 ] [ 94 ]


Botulism can occur in many  vertebrates  and  invertebrates . Botulism has been reported in such species as rats, mice, chicken, frogs, toads, goldfish,  aplysia , squid, crayfish,  drosophila  and leeches. [ 95 ]


Death from botulism is common in waterfowl; an estimated 10,000 to 100,000 birds die of botulism annually. The disease is commonly called "limberneck". In some large outbreaks, a million or more birds may die. Ducks appear to be affected most often. An  enzootic  form of duck botulism in the Western US and Canada is known as "western duck sickness". [ 96 ]  Botulism also affects commercially raised poultry. In chickens, the mortality rate varies from a few birds to 40% of the flock.


Botulism seems to be relatively uncommon in domestic mammals; however, in some parts of the world, epidemics with up to 65% mortality are seen in cattle. The prognosis is poor in large animals that are recumbent.


In cattle, the symptoms may include drooling, restlessness, incoordination, urine retention,  dysphagia , and sternal recumbency. Laterally recumbent animals are usually very close to death. In sheep, the symptoms may include drooling, a serous nasal discharge, stiffness, and incoordination. Abdominal respiration may be observed and the tail may switch on the side. As the disease progresses, the limbs may become paralyzed and death may occur. Phosphorus-deficient cattle, especially in southern Africa, are inclined to ingest bones and carrion containing clostridial toxins and consequently develop  lame sickness  or  lamsiekte .


The clinical signs in horses are similar to cattle. The muscle paralysis is progressive; it usually begins at the hindquarters and gradually moves to the front limbs, neck, and head. Death generally occurs 24 to 72 hours after initial symptoms and results from respiratory paralysis. Some foals are found dead without other clinical signs.


Clostridium botulinum  type C toxin has been incriminated as the cause of  grass sickness , a condition in horses which occurs in rainy and hot summers in  Northern Europe . The main symptom is  pharynx  paralysis. [ 97 ]


Domestic dogs  may develop systemic toxemia after consuming  C. botulinum  type C exotoxin or spores within bird carcasses or other infected meat [ 98 ]  but are generally resistant to the more severe effects of  C. botulinum  type C. Symptoms include flaccid muscle paralysis, which can lead to death due to cardiac and respiratory arrest. [ 99 ]


Pigs are relatively resistant to botulism. Reported symptoms include anorexia, refusal to drink, vomiting, pupillary dilation, and muscle paralysis. [ 100 ]


In poultry and wild birds,  flaccid paralysis  is usually seen in the legs, wings, neck and eyelids. Broiler chickens with the toxicoinfectious form may also have diarrhea with excess  urates .


One of the main routes of exposure for botulism is through the consumption of food contaminated with  C. botulinum . Food-borne botulism can be prevented in domestic animals through careful inspection of the feed, purchasing high quality feed from reliable sources, and ensuring proper storage. Poultry litter and animal carcasses are places in which  C. botulinum  spores are able to germinate so it is advised to avoid spreading poultry litter or any carcass containing materials on fields producing feed materials due to their potential for supporting  C. botulinum  growth. [ 101 ]  Additionally, water sources should be checked for dead or dying animals, and fields should be checked for animal remains prior to mowing for hay or silage. Correcting any dietary deficiencies can also prevent animals from consuming contaminated materials such as bones or carcasses. [ 102 ]  Raw materials used for silage or feed mixed on site should be checked for any sign of mold or rotten appearance. Acidification of animal feed can reduce, but will not eliminate, the risk of toxin formation, especially in carcasses that remain whole. [ 103 ]


Vaccines have been developed for use in animals to prevent botulism. The availability and approval of these vaccines varies depending on the location, with places experiencing more cases generally having more vaccines available and routine vaccination is more common. [ 103 ]


A variety of vaccines have been developed for the prevention of botulism in livestock. Most initial vaccinations require multiple doses at intervals from 2–6 weeks, however, some newer vaccines require only one shot. This mainly depends on the type of vaccine and manufacturers recommendations. All vaccines require annual boosters to maintain immunity. Many of these vaccines can be used on multiple species including cattle, sheep, and goats with some labeled for use in horses and mules as well as separate vaccines for mink. Additionally, vaccination during an outbreak is as beneficial as therapeutic treatment in cattle, and this method is also used in horses and pheasants. [ 103 ]


The use of region specific toxoids to immunize animals has been shown to be effective. Toxoid types C and D used to immunize cattle is a useful vaccination method in South Africa and Australia. Toxoid has also been shown to be an appropriate method of immunizing minks and pheasants. In endemic areas, for example Kentucky, vaccination with type B toxoid appears to be effective. [ 102 ]


Based on CIA research in  Fort Detrick  on  biological warfare ,  anthrax  and botulism were widely regarded as the two most effective options. [ 104 ]  During the 1950s, a highly lethal strain was discovered during the biological warfare program. [ 104 ]  The  CIA  continued to hold 5 grams of  Clostridium botulinum , even after  Nixon's ban on biological warfare  in 1969. [ 104 ]  During the  Gulf War , when the United States were concerned with a potential biowarfare attack, the efforts around botulism turned to prevention. [ 104 ]  However, the only way to make antitoxin in America until the 1990s was by drawing antibodies from a single horse named  First Flight , raising much concern from Pentagon health officials. [ 104 ] [ 105 ]


Iraq has historically possessed many types of germs, including botulism. [ 104 ]  The  American Type Culture Collection  sold 5 variants of botulinum to the  University of Baghdad  in May 1986. [ 104 ]  1991 CIA reports also show Iraqis filled shells, warheads, and bombs with biological agents like botulinum (though none have been deployed). [ 104 ]  The Iraqi air force used the code name "tea" to refer to botulinum, and it was also referred to as bioweapon "A." [ 104 ]


A Japanese cult called  Aum Shinrikyo  created laboratories that produced biological weapons, specifically botulinum,  anthrax , and  Q fever . [ 104 ]  From 1990 to 1995, the cult staged numerous unsuccessful bioterrorism attacks on civilians. [ 104 ]  They sprayed botulinum toxin from a truck in downtown Tokyo and in the Narita airport, but there are no reported cases of botulism as a result. [ 104 ]


Capillaria philippinensis  is a  parasitic   nematode  which causes  intestinal capillariasis .  This sometimes fatal disease was first discovered in Northern  Luzon , Philippines, in 1964.  Cases have also been reported from China, Egypt, Indonesia, Iran, Japan, Korea, Lao PDR, Taiwan and Thailand. [ 1 ]   Cases diagnosed in Italy and Spain were believed to be acquired abroad, with one case possibly contracted in Colombia. [ 2 ]  The natural life cycle of  C. philippinensis  is believed to involve fish as  intermediate hosts , and fish-eating birds as definitive hosts.  Humans acquire  C. philippinensis  by eating small species of infested fish whole and raw.


Between the first case reported in 1964 and the end of 1967, more than 1000 cases were documented in and around Northern Luzon particularly at Tagudin, Ilocos Sur, including 77 deaths.   Witch doctors  were hired by the locals to  exorcise  the curse placed on them by the river god, which they believed was responsible for this sudden disaster. [ 3 ]


In 1968, the cause was identified as  Capillaria philippinensis . [ 4 ]   Adult  C. philippinensis  are very small, with males measuring 1.5–3.9 mm long and 23–28 μm maximum width, while adult females are 2.3–5.3 mm long and 29–47 μm maximum width.  Eggs measure 36–45 μm long and 20 μm wide, and are described as peanut-shaped with a striated shell.


This species has been transferred to the genus  Aonchotheca , as  Aonchotheca philippinensis , [ 5 ]  and to the genus  Paracapillaria , as  Paracapillaria philippinensis . [ 6 ]  However, this species is almost universally referred to as  Capillaria philippinensis  in the current medical literature.


The complete life cycle of  C. philippinensis  has been demonstrated in experimental studies, and may be either indirect (involving an intermediate host) or direct (complete in one host). [ 7 ]


While the natural host range is not known, experimental infestations of several fishes, including  Cyprinus carpio ,  Puntius gonionotus ,  Rasbora borapetensis ,  Eleotris melanosoma ,  Ambassis  commersoni  and  Apogon  sp., with  C. philippinensis  eggs yielded infective larvae.  Experimental infestations with larvae of several birds, including  Amaurornis phoenicurus ,  Ardeola bacchus ,  Nycticorax nycticorax ,  Bubulcus ibis ,  Ixobrychus sinensis ,  Gallinula chloropus , and  Rostratula benghalensis , yielded mature adults.


Direct life cycle.  Researchers also found that feeding just a few dozen larvae from the intestines of fish to Mongolian gerbils ( Meriones unguiculatus ) or monkeys ( Macaca  sp.) led to infestations with thousands of adult worms through " autoinfection ".  Autoinfection is when the offspring produced by adults can reinfest the same host, allowing the infestation to multiply within a single host animal.  Both  oviparous  (egg-laying) and larviparous (giving birth to active larvae) adult female  C. philippinensis  were found in Mongolian gerbils and some birds. The experimentally infested monkeys never developed any clinical symptoms, even during prolonged, active infestations. Of several rodents tested, only Mongolian gerbils developed severe symptoms due to infestation and died.


Although  C. philippinensis  infections are rare, it can serve as an indicator that one is being exposed to raw or undercooked fish. Early diagnosis of the parasite is beneficial so the number of worms in an infected person would not increase. [ 8 ]


This parasite can be diagnosed by taking a tissue  biopsy  from the small intestine or by examining stool samples through a microscope. [ 9 ]   In a heavily infected person, it is best to examine their feces because it will show an abundance of adult worms and eggs. When looking at the eggs of  C. philippinensis , one must be able to distinguish it from the eggs of  Trichuris trichiura .  C. philippinensis  eggs have nonprotruding polar plugs and are slightly smaller than  T. trichiura  eggs. [ 10 ]


C. philippinensis  infections should be treated with 200 mg of mebendazole. This drug is taken twice a day for 20 days or until all symptoms subside and there are no longer eggs present in the stool samples of the patient. Another drug that may be used is albendazole 400 mg, which is taken orally every day for at least 10 days. [ 11 ]


Clostridioides difficile  infection [ 5 ]  ( CDI  or  C-diff ), also known as  Clostridium difficile  infection , is a symptomatic  infection  due to the  spore -forming bacterium  Clostridioides difficile . [ 6 ]  Symptoms include watery  diarrhea , fever, nausea, and  abdominal pain . [ 1 ]  It makes up about 20% of cases of  antibiotic-associated diarrhea . [ 1 ]   Antibiotics can contribute to detrimental changes in  gut microbiota ; specifically, they decrease short-chain fatty acid absorption which results in osmotic, or watery, diarrhea. [ 7 ]  Complications may include  pseudomembranous colitis ,  toxic megacolon ,  perforation of the colon , and  sepsis . [ 1 ]


Clostridioides difficile  infection is spread by bacterial spores found within  feces . [ 1 ]  Surfaces may become contaminated with the spores with further spread occurring via the hands of healthcare workers. [ 1 ]  Risk factors for infection include  antibiotic  or  proton pump inhibitor  use, hospitalization, hypoalbuminemia, [ 8 ]  other health problems, and older age. [ 1 ]  Diagnosis is by  stool culture  or testing for the bacteria's  DNA  or  toxins . [ 1 ]  If a person tests positive but has no symptoms, the condition is known as  C. difficile   colonization  rather than an infection. [ 1 ]


Prevention efforts include  terminal room cleaning  in hospitals, limiting antibiotic use, and  handwashing  campaigns in hospitals. [ 2 ]   Alcohol based hand sanitizer  does not appear effective. [ 2 ]  Discontinuation of antibiotics may result in resolution of symptoms within three days in about 20% of those infected. [ 1 ]


The antibiotics  metronidazole ,  vancomycin , or  fidaxomicin , will cure the infection. [ 1 ] [ 3 ]  Retesting after treatment, as long as the symptoms have resolved, is not recommended, as a person may often remain colonized. [ 1 ]  Recurrences have been reported in up to 25% of people. [ 9 ]  Some tentative evidence indicates  fecal microbiota transplantation  and  probiotics  may decrease the risk of recurrence. [ 2 ] [ 10 ]


C. difficile  infections occur in all areas of the world. [ 11 ]  About 453,000 cases occurred in the United States in 2011, resulting in 29,000 deaths. [ 2 ] [ 4 ]  Global rates of disease increased between 2001 and 2016. [ 2 ] [ 11 ]   C. difficile  infections occur more often in women than men. [ 2 ]  The bacterium was discovered in 1935 and found to be disease-causing in 1978. [ 11 ]  Attributable costs for  Clostridioides difficile  infection in hospitalized adults range from
$4500 to $15,000. [ 12 ]  In the United States,  healthcare-associated infections  increase the cost of care by US$1.5 billion each year. [ 13 ]  Although  C. difficile  is a common healthcare-associated infection, at most 30% of infections are transmitted within hospitals. [ 14 ]  The majority of infections are acquired outside of hospitals, where medications and a recent history of diarrheal illnesses (e.g.  laxative abuse  or food poisoning due to  salmonellosis ) are thought to drive the risk of colonization. [ 15 ]


Signs and symptoms of CDI range from mild diarrhea to severe life-threatening  inflammation of the colon . [ 16 ]


In adults, a  clinical prediction rule  found the best  signs  to be significant diarrhea ("new onset of more than three partially formed or watery stools per 24-hour period"), recent antibiotic exposure, abdominal pain, fever (up to 40.5 °C or 105 °F), and a distinctive foul odor to the stool resembling horse manure. [ 17 ]  In a hospital population, prior antibiotic treatment plus diarrhea or abdominal pain had a  sensitivity  of 86% and a  specificity  of 45%. [ 18 ]  In this study with a prevalence of positive cytotoxin assays of 14%, the  positive predictive value  was 18% and the  negative predictive value  was 94%. [ citation needed ]


In children, the most prevalent symptom of a CDI is watery diarrhea with at least three bowel movements a day for two or more days, which may be accompanied by fever, loss of appetite, nausea, and/or abdominal pain. [ 19 ]  Those with a severe infection also may develop serious inflammation of the colon and have little or no diarrhea. [ citation needed ]


Infection with  C. difficile   bacteria  is responsible for  C. difficile  diarrhea.


Clostridia are  anaerobic   motile   bacteria , ubiquitous in nature, and especially prevalent in soil. Under the microscope, they appear as long, irregular (often drumstick- or spindle-shaped) cells with a bulge at their terminal ends. Under  gram staining ,  C. difficile  cells are  gram-positive  and show optimum growth on  blood agar  at human body temperatures in the absence of  oxygen . When stressed, the bacteria produce  spores  that are able to tolerate extreme conditions that the active bacteria cannot tolerate. [ 20 ]


C. difficile  may colonize the human  colon  without symptom; approximately 2–5% of the adult population are carriers, although it varies considerably with  demographics . [ 20 ]  The risk of colonization has been linked to a history of unrelated diarrheal illnesses (e.g. laxative abuse and  food poisoning  due to Salmonellosis or  Vibrio cholerae  infection). [ 15 ]


Pathogenic  C. difficile  strains produce multiple  toxins . [ 21 ]  The most well-characterized are  enterotoxin  ( Clostridium difficile  toxin A ) and  cytotoxin  ( Clostridium difficile  toxin B ), both of which may produce  diarrhea  and  inflammation  in infected people, although their relative contributions have been debated. [ 20 ]  Toxins A and B are glucosyltransferases that target and inactivate the  Rho family of GTPases . Toxin B (cytotoxin) induces  actin  depolymerization by a mechanism correlated with a decrease in the  ADP-ribosylation  of the low molecular mass GTP-binding Rho proteins. [ 22 ]  Another toxin,  binary toxin , also has been described, but its role in disease is not fully understood. [ 23 ]


Antibiotic treatment of CDIs may be difficult, due both to  antibiotic resistance  and physiological factors of the bacteria (spore formation, protective effects of the pseudomembrane). [ 20 ]  The emergence of a new and highly toxic strain of  C. difficile  that is resistant to  fluoroquinolone  antibiotics such as  ciprofloxacin  and  levofloxacin , said to be causing geographically dispersed outbreaks in North America, was reported in 2005. [ 24 ]  The U.S.  Centers for Disease Control and Prevention   in Atlanta warned of the emergence of an epidemic strain with increased virulence, antibiotic resistance, or both. [ 25 ]


C. difficile  is transmitted from person to person by the  fecal-oral route . The organism forms heat-resistant spores that are not killed by alcohol-based hand cleansers or routine surface cleaning. Thus, these spores survive in clinical environments for long periods. Because of this, the bacteria may be cultured from almost any surface. Once spores are ingested, their acid-resistance allows them to pass through the stomach unscathed. Upon exposure to  bile acids , they germinate and multiply into vegetative cells in the colon.  The presence of the bile acid  deoxycholic acid  in the intestinal environment can promote induction of  C. difficle   biofilm  formation. [ 26 ]  People without a history of gastrointestinal disturbances due to antibiotic use or diarrheal illness are less likely to become colonized by  C. difficile . [ 15 ]


In 2005, molecular analysis led to the identification of the  C. difficile  strain type characterized as group BI by  restriction endonuclease  analysis, as North American pulse-field-type NAP1 by  pulsed-field gel electrophoresis   and as  ribotype  027; the differing terminology reflects the predominant techniques used for epidemiological typing. This strain is referred to as  C. difficile  BI/NAP1/027. [ 27 ]


C. difficile  colitis is associated most strongly with the use of these antibiotics:  fluoroquinolones ,  cephalosporins , and  clindamycin . [ 28 ]


Some research suggests the routine  use of antibiotics in the raising of livestock  is contributing to outbreaks of bacterial infections such as  C. difficile . [ 29 ]


People are most often  infected in hospitals ,  nursing homes , [ 30 ]  or other medical institutions, although infection outside medical settings is increasing. Individuals can develop the infection if they touch objects or surfaces that are contaminated with feces and then touch their mouth or mucous membranes. Healthcare workers could possibly spread the bacteria or contaminate surfaces through hand contact. [ 31 ]  The rate of  C. difficile  acquisition is estimated to be 13% in those with hospital stays of up to two weeks, and 50% with stays longer than four weeks. [ 32 ]


Long-term hospitalization or residence in a nursing home within the previous year are independent risk factors for increased  colonization . [ 33 ]


Increasing rates of community-acquired CDI are associated with the use of medication to suppress  gastric acid  production:  H2-receptor antagonists  increased the risk 1.5-fold, and  proton pump inhibitors  by 1.7 with once-daily use and 2.4 with more than once-daily use. [ 34 ] [ 35 ]  Increased risk in recurrent CDI is also found with gastric acid repression use in observational studies, with a rate of 22.1%, compared to patients without gastric acid repression has a rate of 17.3% of recurrent CDI. [ 36 ]


People with a recent history of diarrheal illness are at increased risk of becoming colonized by  C. difficile  when exposed to spores, including laxative abuse and gastrointestinal pathogens. [ 15 ]   Disturbances that increase intestinal motility are thought to transiently elevate the concentration of available dietary sugars, allowing  C. difficile  to proliferate and gain a foothold in the gut. [ 37 ]  Although not all colonization events lead to disease, asymptomatic carriers remain colonized for years at a time. [ 15 ]  During this time, the abundance of  C. difficile  varies considerably day-to-day, causing periods of increased shedding that could substantially contribute to community-acquired infection rates. [ 15 ]


As a result of suppression of healthy bacteria, via a loss of bacterial food source, prolonged use of an  elemental diet  increases the risk of developing  C. difficile  infection. [ 38 ]  Low serum albumin levels is a risk factor for the development of  C. difficile  infection and when infected for severe disease. [ 39 ] [ 40 ]  The protective effects of serum albumin may be related to the capability of this protein to bind  C. difficile  toxin A and toxin B, thus impairing entry into enterocytes. [ 40 ]


Chronic kidney disease  (CKD) has been identified as a risk factor in the development of a  C. difficile  infection. [ 41 ] [ 42 ]  Patients with CKD have a higher risk of both initial and recurring infection, as well as a higher chance of severe infection, than those without CKD. [ 43 ]  Patients with Inflammatory Bowel Disease are also at higher risk for infection and a recent study suggests they may have intermittent  C. difficile  infection masked by IBD symptoms, and testing should be considered in patients with changes in disease activity. [ 44 ]


The use of systemic antibiotics, including broad-spectrum penicillins/cephalosporins, fluoroquinolones, and clindamycin, causes the normal microbiota of the bowel to be altered. In particular, when the  antibiotic  kills off other competing bacteria in the intestine, any bacteria remaining will have less competition for space and nutrients. The net effect is to permit more extensive growth than normal of certain bacteria.  C. difficile  is one such type of bacterium. In addition to proliferating in the bowel,  C. difficile  also produces  toxins . Without either toxin A or toxin B,  C. difficile  may colonize the gut, but is unlikely to cause pseudomembranous colitis. [ 45 ]  The colitis associated with severe infection is part of an inflammatory reaction, with the "pseudomembrane" formed by a viscous collection of inflammatory cells,  fibrin , and necrotic cells. [ 20 ]


Prior to the advent of tests to detect  C. difficile  toxins, the diagnosis most often was made by  colonoscopy  or  sigmoidoscopy . The appearance of "pseudomembranes" on the mucosa of the  colon  or  rectum  is highly suggestive, but not diagnostic of the condition. [ 46 ]  The pseudomembranes are composed of an exudate made of inflammatory debris,  white blood cells . Although colonoscopy and sigmoidoscopy are still employed, now stool testing for the presence of  C. difficile  toxins is frequently the first-line diagnostic approach. Usually, only two toxins are tested for—toxin A and toxin B—but the organism produces several others. This test is not 100% accurate, with a considerable false-negative rate even with repeat testing. [ 47 ]


CDI may be classified in non-severe CDI, severe CDI and fulminant CDI depending on creatinine and white blood count parameters. [ 48 ]