In 2022, a study conducted by Elisa Barroeta-Echegaray and colleagues concluded that  Giardia duodenalis  secretes  enolase  as a monomer during the interaction, or attachment, of trophozoites with intestinal epithelial cells. This interaction was shown to activate  plasminogen  and induce  necroptotic damage  in intestinal epithelial cells. The researchers demonstrated that blocking the enolase inhibited trophozoite attachment to intestinal epithelial cells. Furthermore, enolase was shown to enhance plasmin activity, leading to significant cell damage characterized by vacuolization and intercellular separation. Enolase also induced  necroptosis  in epithelial cells via  tumor necrosis factor α (TNF-α)  and  apoptosis-inducing factor  (AIF), independent of  caspase-3  activity. These findings suggest that Giardia enolase is a critical  virulence factor  in host-pathogen interactions. [ 5 ]


The first likely description of  Giardia  was in 1681 by  Antonie van Leeuwenhoek , who in a letter to  Robert Hooke , described "animalcules" resembling  Giardia  trophozoites in his stool. [ 14 ] [ 46 ]  The next known description of  Giardia  wasn't until 1859, when Czech physician  Vilém Lambl  published a description of the trophozoite stages he saw in the stool of a pediatric patient. Lambl termed the organism  Cercomonas intestinalis . [ 47 ]  In 1888,  Raphaël Blanchard  renamed the parasite  Lamblia intestinalis  in Lambl's honor. [ 47 ]  In 1915,  Charles Stiles  renamed the organism  Giardia lamblia  in honor of both Lambl and Professor  Alfred Mathieu Giard  of Paris. [ 47 ] [ 48 ]  In 1921,  Charles E. Simon  published a detailed description of the parasite's morphology. [ 14 ]


Halzoun  ( Arabic :حلزون) is the local name of a  buccopharyngeal   infection  occurring in  Lebanon , probably caused by  pentastomida larvae  of  Linguatula serrata  (dog tongue worm) which wander into the  throat  of the human host after ingestion of infected raw liver or lymph nodes from sheep or goats. [ 1 ]  The word Halzoun means " Snail " in Arabic.


Halzoun is considered to be a form of infection with  Fasciola , whereby ingestion of infected raw sheep and goat livers may result in the attachment of adult living worms by their suckers to the pharyngeal mucosa causing  edema  of the  soft palate ,  pharynx  and  larynx . This edema is accompanied by  dyspnea  (shortness of breath) and occasionally  asphyxia . [ citation needed ]


This article related to  parasites  is a  stub . You can help Wikipedia by  expanding it .


Helminthiasis , also known as  worm infection , is any  macroparasitic  disease of humans and other animals in which a part of the body is infected with  parasitic   worms , known as  helminths . There are numerous species of these  parasites , which are broadly classified into  tapeworms ,  flukes , and  roundworms . They often live in the  gastrointestinal tract  of their  hosts , but they may also burrow into other  organs , where they induce physiological damage.


Soil-transmitted helminthiasis  and  schistosomiasis  are the most important helminthiases, and are among the  neglected tropical diseases . [ 1 ]  These group of helminthiases have been targeted under the joint action of the world's leading  pharmaceutical companies  and  non-governmental organizations  through a project launched in 2012 called the  London Declaration on Neglected Tropical Diseases , which aimed to control or eradicate certain neglected tropical diseases by 2020. [ 2 ]


Helminthiasis has been found to result in poor birth outcome, poor cognitive development, poor school and work performance, poor socioeconomic development, and poverty. [ 3 ] [ 4 ]  Chronic illness,  malnutrition , and  anemia  are further examples of secondary effects. [ 5 ]


Soil-transmitted helminthiases are responsible for parasitic infections in as much as a quarter of the human population worldwide. [ 6 ]  One well-known example of soil-transmitted helminthiases is  ascariasis .


Of all the known helminth species, the most important helminths with respect to understanding their transmission pathways, their control, inactivation and enumeration in samples of human excreta from dried feces,  faecal sludge ,  wastewater , and  sewage sludge  are: [ 7 ]


Helminthiases are classified as follows (the disease names end with "-sis" and the causative worms are in brackets):


The signs and symptoms of helminthiasis depend on a number of factors including: the site of the infestation within the body; the type of worm involved; the number of worms and their volume; the type of  damage  the infesting worms cause; and, the immunological response of the body. Where the burden of parasites in the body is light, there may be no symptoms. [ citation needed ]


Certain worms may cause particular constellations of symptoms. For instance,  taeniasis  can lead to  seizures  due to  neurocysticercosis . [ 8 ]


In extreme cases of  intestinal  infestation, the mass and volume of the worms may cause the outer layers of the intestinal wall, such as the muscular layer, to tear. This may lead to  peritonitis ,  volvulus , and  gangrene  of the intestine. [ 9 ]


As pathogens in the body, helminths induce an  immune  response. Immune-mediated  inflammatory  changes occur in the skin,  lung ,  liver , intestine,  central nervous system , and eyes. Signs of the body's immune response may include  eosinophilia ,  edema , and  arthritis . [ 10 ]  An example of the immune response is the  hypersensitivity  reaction that may lead to  anaphylaxis . Another example is the migration of  Ascaris  larvae through the  bronchi  of the lungs causing  asthma . [ 11 ]


In humans,  T helper cells  and  eosinophils  respond to helminth infestation. It is well established that T helper 2 cells are the central players of protective immunity to helminths, [ 12 ]  while the roles for B cells and antibodies are context-dependent. [ 13 ]  Inflammation leads to encapsulation of egg deposits throughout the body. Helminths excrete into the intestine toxic substances after they feed. These substances then enter the circulatory and lymphatic systems of the host body. [ citation needed ]


Chronic immune responses to helminthiasis may lead to increased susceptibility to  other infections  such as  tuberculosis ,  HIV , and  malaria . [ 14 ] [ 15 ] [ 16 ]  There is conflicting information about whether deworming reduces HIV progression and viral load and increases  CD4  counts in  antiretroviral  naive and experienced individuals, although the most recent Cochrane review found some evidence that this approach might have favorable effects. [ 17 ] [ 18 ]  Helminth infection also lowers the immune responses to vaccination for other diseases such as  BCG ,  measles , and  Hepatitis B . [ 19 ]


Chronic helminthiasis may cause severe  morbidity . [ 20 ]  Helminthiasis has been found to result in poor birth outcome, poor cognitive development, poor school and work performance, decreased productivity, poor socioeconomic development, and poverty. [ 3 ] [ 4 ] [ 5 ]


Helminthiasis may cause chronic illness through malnutrition including  vitamin deficiencies ,  stunted growth ,  anemia , and  protein-energy malnutrition . Worms compete directly with their hosts for nutrients, but the magnitude of this effect is likely minimal as the nutritional requirements of worms is relatively small. [ 21 ] [ 22 ] [ 23 ]  In pigs and humans,  Ascaris  has been linked to  lactose intolerance  and  vitamin A ,  amino acid , and fat  malabsorption . [ 3 ]  Impaired nutrient uptake may result from direct damage to the intestinal mucosal wall or from more subtle changes such as chemical imbalances and changes in gut flora. [ 24 ]  Alternatively, the worms’ release of  protease inhibitors  to defend against the body's digestive processes may impair the breakdown of other nutrients. [ 21 ] [ 23 ]  In addition, worm induced diarrhoea may shorten gut transit time, thus reducing absorption of nutrients. [ 3 ]


Malnutrition due to worms can give rise to  anorexia . [ 22 ]  A study of 459 children in  Zanzibar  revealed spontaneous increases in appetite after  deworming . [ 25 ]  Anorexia might be a result of the body's immune response and the stress of combating infection. [ 23 ]  Specifically, some of the  cytokines  released in the immune response to worm infestation have been linked to anorexia in animals. [ 21 ]


Helminths may cause  iron-deficiency anemia . This is most severe in heavy  hookworm infections , as  Necator americanus  and  Ancylostoma duodenale  feed directly on the blood of their hosts. Although the daily consumption of an individual worm (0.02–0.07 ml and 0.14–0.26 ml respectively) is small, the collective consumption under heavy infection can be clinically significant. [ 3 ] [ 23 ]  Intestinal  whipworm  may also cause anemia. Anemia has also been associated with reduced stamina for physical labor, a decline in the ability to learn new information, and apathy, irritability, and fatigue. [ 3 ]  A study of the effect of deworming and iron supplementation in 47 students from the  Democratic Republic of the Congo  found that the intervention improved cognitive function. [ 26 ]  Another study found that in 159  Jamaican  schoolchildren, deworming led to better auditory  short-term memory  and scanning and retrieval of  long-term memory  over a period of nine-weeks. [ 27 ]


Malnutrition due to helminths may affect cognitive function leading to low educational performance, decreased concentration and difficulty with abstract cognitive tasks. Iron deficiency in infants and preschoolers is associated with "lower scores ... on tests of mental and motor development ... [as well as] increased fearfulness, inattentiveness, and decreased social responsiveness". [ 21 ]  Studies in the Philippines and Indonesia found a significant correlation between helminthiasis and decreased memory and fluency. [ 28 ] [ 29 ]  Large parasite burdens, particularly severe hookworm infections, are also associated with  absenteeism , under-enrollment, and attrition in school children. [ 21 ]


Helminths are transmitted to the  final host  in several ways. The most common infection is through  ingestion  of contaminated vegetables, drinking water, and raw or undercooked meat. Contaminated food may contain eggs of nematodes such as  Ascaris ,  Enterobius , and  Trichuris ; cestodes such as  Taenia ,  Hymenolepis , and  Echinococcus ; and trematodes such as  Fasciola . Raw or undercooked meats are the major sources of  Taenia  (pork, beef and venison),  Trichinella  (pork and bear),  Diphyllobothrium  (fish),  Clonorchis  (fish), and  Paragonimus  (crustaceans). Schistosomes and nematodes such as hookworms ( Ancylostoma  and  Necator ) and  Strongyloides  can penetrate the skin directly. [ 20 ]


The roundworm,  Dracunculus  has a complex mode of transmission: it is acquired from drinking infested water or eating frogs and fish that contain (had eaten) infected crustaceans ( copepods ); and can also be transmitted from infected pets (cats and dogs). [ 30 ]  Roundworms such as  Brugia ,  Wuchereria and   Onchocerca  are directly  transmitted by mosquitoes . [ 31 ] [ 32 ]  In the developing world, the use of contaminated water is a major risk factor for infection. [ 33 ]  Infection can also take place through the practice of  geophagy , which is not uncommon in parts of  sub-Saharan Africa . Soil is eaten, for example, by children or pregnant women to counteract a real or perceived deficiency of minerals in their diet. [ 34 ]


Specific helminths can be identified through  microscopic  examination of their eggs (ova) found in faecal samples. The number of eggs is measured in units of  eggs per gram . [ 35 ]  However, it does not quantify  mixed infections , and in practice, is inaccurate for quantifying the eggs of schistosomes and soil-transmitted helminths. [ 36 ]  Sophisticated tests such as  serological assays ,  antigen tests , and  molecular diagnosis  are also available; [ 35 ] [ 37 ]  however, they are time-consuming, expensive and not always reliable. [ 38 ]


Disrupting the cycle of the worm will prevent infestation and re-infestation. Prevention of infection can largely be achieved by addressing the issues of  WASH —water,  sanitation  and  hygiene . [ 39 ] [ 40 ] [ 41 ]  The reduction of  open defecation  is particularly called for, [ 42 ] [ 43 ]  as is stopping the use of  human waste  as  fertilizer . [ 6 ]


Further preventive measures include adherence to appropriate  food hygiene , wearing of shoes, regular  deworming  of pets, and the proper disposal of their feces. [ 3 ]


Scientists are also searching for a vaccine against helminths, such as a  hookworm vaccine . [ 44 ]


Broad-spectrum  benzimidazoles  (such as  albendazole  and  mebendazole ) are the first line treatment of intestinal  roundworm  and  tapeworm  infections. Macrocyclic lactones (such as  ivermectin ) are effective against adult and migrating larval stages of nematodes.  Praziquantel  is the drug of choice for schistosomiasis, taeniasis, and most types of food-borne trematodiases.  Oxamniquine  is also widely used in mass deworming programmes.  Pyrantel  is commonly used for veterinary nematodiasis. [ 45 ] [ 46 ]   Artemisinins  and derivatives are proving to be candidates as drugs of choice for trematodiasis. [ 47 ]


In  regions where helminthiasis is common , mass deworming treatments may be performed, particularly among school-age children, who are a high-risk group. [ 48 ] [ 49 ]  Most of these initiatives are undertaken by the  World Health Organization  (WHO) with positive outcomes in many regions. [ 50 ] [ 51 ]  Deworming programs can improve school attendance by 25 percent. [ 52 ]  Although deworming improves the health of an individual, outcomes from  mass deworming  campaigns, such as reduced deaths or increases in cognitive ability, nutritional benefits, physical growth, and performance, are uncertain or not apparent. [ 53 ] [ 54 ] [ 55 ] [ 56 ]


If complications of helminthiasis, such as  intestinal obstruction  occur, emergency surgery may be required. [ 9 ] [ 57 ]  Patients who require non-emergency surgery, for instance for removal of worms from the  biliary tree , can be pre-treated with the anthelmintic drug albendazole. [ 9 ]


Areas with the highest prevalence of helminthiasis are  tropical  and  subtropical  areas including sub-Saharan Africa, central and east Asia, and the Americas. [ citation needed ]


Some types of helminthiases are classified as  neglected tropical diseases . [ 1 ] [ 58 ]  They include:


The soil-transmitted helminths ( A. lumbricoides ,  T. trichiura ,  N. americanus ,  A. duodenale) ,  schistosomes , and  filarial worms  collectively infect more than a quarter of the human population worldwide at any one time, far surpassing HIV and malaria together. [ 35 ] [ 37 ]   Schistosomiasis  is the second most prevalent parasitic disease of humans after malaria. [ 59 ]


In 2014–15, the WHO estimated that approximately 2 billion people were infected with soil-transmitted helminthiases, [ 6 ]  249 million with schistosomiasis, [ 60 ]  56 million people with food-borne trematodiasis, [ 61 ]  120 million with lymphatic filariasis, [ 62 ]  37 million people with onchocerciasis, [ 63 ]  and 1 million people with echinococcosis. [ 64 ]  Another source estimated a much higher figure of 3.5 billion infected with one or more soil-transmitted helminths. [ 65 ] [ 66 ]


In 2014, only 148 people were reported to have  dracunculiasis  because of a successful eradication campaign for that particular helminth, which is easier to eradicate than other helminths as it is transmitted only by drinking contaminated water. [ 67 ]


Because of their high mobility and lower standards of hygiene, school-age children are particularly vulnerable to helminthiasis. [ 68 ]  Most children from developing nations will have at least one infestation. Multi-species infections are very common. [ 69 ]


The most common intestinal parasites in the United States are  Enterobius vermicularis ,  Giardia lamblia ,  Ancylostoma duodenale ,  Necator americanus , and  Entamoeba histolytica . [ 70 ]


In a developing country like Bangladesh, the most common species are round worm ( Ascaris lumbricoides ), whipworm (Tricurias tricuras) and hookworm
(Ancylostoma duodenalis).  [ 71 ]


Even in areas of high prevalence, the frequency and severity of infection is not uniform within communities or families. [ 72 ]  A small proportion of community members harbour the majority of worms, and this depends on age. The maximum worm burden is at five to ten years of age, declining rapidly thereafter. [ 73 ]  Individual predisposition to helminthiasis for people with the same sanitation infrastructure and hygiene behavior is thought to result from differing  immunocompetence ,  nutritional status , and  genetic factors . [ 72 ]  Because individuals are predisposed to a high or a low worm burden, the burden reacquired after successful treatment is proportional to that before treatment. [ 72 ]


It is estimated that intestinal nematode infections cause 5 million  disability-adjusted life years  (DALYS) to be lost, of which hookworm infections account for more than 3 million DALYS and ascaris infections more than 1 million. [ 74 ]  There are also signs of progress: The  Global Burden of Disease Study  published in 2015 estimates a 46 percent (59 percent when age standardised) reduction in  years lived with disability  (YLD) for the 13-year time period from 1990 to 2013 for all intestinal/nematode infections, and even a 74 percent (80 percent when age standardised) reduction in YLD from ascariasis. [ 75 ]


As many as 135,000 die annually from soil transmitted helminthiasis. [ 3 ] [ 37 ] [ 76 ]


The 1990–2013  Global Burden of Disease Study  estimated 5,500 direct deaths from schistosomiasis, [ 77 ]  while more than 200,000 people were estimated in 2013 to die annually from causes related to schistosomiasis. [ 78 ]  Another 20 million have severe consequences from the disease. [ 79 ]  It is the most deadly of the neglected tropical diseases. [ 80 ]


807 to 1,121 [ 81 ]


604–795 [ 81 ]


576–740 (hookworm in general) [ 89 ]


(210 "affected" [ 90 ] )


200,000 indirect deaths from "causes related to" Schistosomiasis [ 78 ]


(all types of  Taenia : 40 to 60 [ 94 ] )


Hookworm infection  is an infection by a type of  intestinal parasite  known as a  hookworm . [ 1 ] [ 5 ]  Initially, itching and a rash may occur at the site of infection. Those only affected by a few worms may show no symptoms. Those infected by many worms may experience  abdominal pain , diarrhea, weight loss, and  tiredness . The mental and physical development of children may be affected.  Anemia  may result. [ 1 ]


Two common hookworm infections in humans are  ancylostomiasis  and  necatoriasis , caused by the species  Ancylostoma duodenale  and  Necator americanus  respectively. Hookworm eggs are deposited in the stools of infected people. If these end up in the environment, they can hatch into  larvae  (immature worms), which can then penetrate the skin. One type can also be spread through contaminated food. Risk factors include walking  barefoot  in warm climates, where  sanitation  is poor. Diagnosis is by examination of a  stool sample  with a  microscope . [ 1 ]


The risk of infection can be reduced on an individual level by not walking barefoot in areas where the disease is common. At a population level, decreasing  outdoor defecation , not using raw feces as  fertilizer , and  mass deworming  are effective. [ 1 ]  Treatment is typically with the medications  albendazole  or  mebendazole  for one to three days.  Iron supplements  may be needed in those with anemia. [ 3 ]


Hookworms infected about 428 million people in 2015. [ 4 ]  Heavy infections can occur in both children and adults, but are less common in adults. [ 2 ]  They are rarely fatal. [ 6 ]  Hookworm infection is a  soil-transmitted helminthiasis  and classified as a  neglected tropical disease . [ 7 ]


No symptoms or signs are specific to hookworm infection, but they give rise to a combination of intestinal  inflammation  and progressive  iron-deficiency anemia  and  protein deficiency . Coughing, chest pain, wheezing, and fever sometimes result from severe infection. Epigastric pains, indigestion, nausea,  vomiting ,  constipation , and  diarrhea  can occur early or in later stages, as well, although gastrointestinal symptoms tend to improve with time. Signs of advanced severe infection are those of anemia and protein deficiency, including  emaciation ,  cardiac failure , and abdominal distension with  ascites . [ citation needed ]


Larval  invasion of the  skin  (mostly in the Americas) can produce a skin disease called  cutaneous larva migrans  also known as creeping eruption. The hosts of these worms are not human and the larvae can only penetrate the upper five layers of the skin, where they give rise to intense, local  itching , usually on the foot or lower leg, known as  ground itch . This infection is due to larvae from the  A. braziliense  hookworm. The larvae migrate in tortuous tunnels between the  stratum basale  and  stratum corneum  of the skin, causing  serpiginous  vesicular  lesions . With the advancing movement of the larvae, the rear portions of the lesions become dry and crusty. The lesions are typically intensely itchy. [ 8 ]


The incubation period can vary between a few weeks to many months and is largely dependent on the number of hookworm parasites an individual is infected with. [ 9 ]


Hookworm infections in humans include  ancylostomiasis  and  necatoriasis . Ancylostomiasis is caused by  Ancylostoma duodenale ,  which is the more common type found in the  Middle East ,  North Africa ,  India , and (formerly) in  southern Europe . Necatoriasis is caused by  Necator americanus ,  the more common type in  the Americas ,  sub-Saharan Africa ,  Southeast Asia ,  China , and  Indonesia . [ citation needed ]


Other animals such as  birds ,  dogs , and  cats  may also be affected.  A. tubaeforme  infects cats,  A. caninum  infects dogs, and  A. braziliense  and  Uncinaria stenocephala  infect both cats and dogs. Some of these infections can be  transmitted to humans . [ 10 ]


A. duodenale  worms are grayish-white or pinkish with the head slightly bent in relation to the rest of the body. This bend forms a definitive hook shape at the anterior end for which hookworms are named. They possess well-developed mouths with two pairs of teeth. While males measure approximately one centimeter by 0.5 millimeter, the females are often longer and stouter. Additionally, males can be distinguished from females based on the presence of a prominent posterior copulatory bursa. [ 11 ]


N. americanus  is very similar in morphology to  A. duodenale .  N. americanus  is generally smaller than  A. duodenale  with males usually 5 to 9 mm long and females about 1 cm long. Whereas  A. duodenale  possesses two pairs of teeth,  N. americanus  possesses a pair of cutting plates in the buccal capsule. Additionally, the hook shape is much more defined in  Necator  than in  Ancylostoma . [ 11 ]


The hookworm thrives in warm soil where temperatures are over 18 °C (64 °F). They exist primarily in  sandy  or  loamy  soil and cannot live in  clay  or muck.  Rainfall  averages must be more than 1,000 mm (39 in) a year for them to survive. Only if these conditions exist can the eggs hatch. Infective larvae of  N. americanus  can survive at higher temperatures, whereas those of  A. duodenale  are better adapted to cooler climates. Generally, they live for only a few weeks at most under natural conditions and die almost immediately on exposure to direct sunlight or  desiccation . [ citation needed ]


Infection of the host is by the larvae, not the eggs. While  A. duodenale  can be ingested, the usual method of infection is through the skin; this is commonly caused by walking  barefoot  through areas contaminated with fecal matter. The larvae can penetrate the skin of the foot, and once inside the body, they migrate through the  vascular system  to the  lungs , and from there up the  trachea , and are swallowed. They then pass down the  esophagus  and enter the digestive system, finishing their journey in the  intestine , where the larvae mature into adult worms. [ 12 ] [ 13 ]


Once in the host gut,  Necator  tends to cause a prolonged infection, generally 1 to 5 years (many worms die within a year or two of infection), though some adult worms have been recorded to live for 15 years or more.  Ancylostoma  adults are short-lived, surviving on average for only about 6 months. However, the infection can be prolonged because dormant larvae can be "recruited" sequentially from tissue "stores" over many years, to replace expired adult worms. This can give rise to seasonal fluctuations in infection prevalence and intensity (apart from normal seasonal variations in transmission). [ citation needed ]


They mate inside the host, females laying from 10,000 to 30,000 eggs per day and some 15 to 56 million eggs during their adult lifetimes, which pass out in feces. Because 5 to 7 weeks are needed for adult worms to mature, mate, and produce eggs, in the early stages of very heavy infection, acute symptoms might occur without any eggs being detected in the patient's feces. This can make diagnosis very difficult. [ citation needed ]


N. americanus  and  A. duodenale  eggs can be found in warm, moist soil where they eventually hatch into first-stage larvae, or L1. L1, the feeding noninfective rhabditoform stage, will feed on soil microbes and eventually molt into second-stage larvae, L2, which is also in the rhabditoform stage. It will feed for about 7 days and then molt into the third-stage larvae, or L3. This is the filariform stage of the parasite, that is, the nonfeeding infective form of the larvae. The L3 larvae are extremely motile and seek higher ground to increase their chances of penetrating the skin of a human host. The L3 larvae can survive up to 2 weeks without finding a host. While  N. americanus  larvae only infect through penetration of the skin,  A. duodenale  can infect both through penetration and orally. After the L3 larvae have successfully entered the host, they then travel through the subcutaneous venules and lymphatic vessels of the human host. Eventually, the L3 larvae enter the lungs through the pulmonary capillaries and break out into the alveoli. They then travel up the trachea to be coughed and swallowed by the host. After being swallowed, the L3 larvae are then found in the small intestine, where they molt into the L4, or adult worm stage. The entire process from skin penetration to adult development takes about 5–9 weeks. The female adult worms release eggs ( N. americanus  about 9,000–10,000 eggs/day and  A. duodenale  25,000–30,000 eggs/day), which are passed in the feces of the human host. These eggs hatch in the environment within several days and the cycle starts anew. [ 12 ] [ 14 ] [ 15 ]


Hookworm infection is generally considered to be asymptomatic, but as Norman Stoll described in 1962, it is an extremely dangerous infection because its damage is "silent and insidious." [ 16 ]  An individual may experience general symptoms soon after infection. Ground-itch, which is an allergic reaction at the site of parasitic penetration and entry, is common in patients infected with  N. americanus . [ 11 ]  Additionally, cough and  pneumonitis  may result as the larvae begin to break into the  alveoli  and travel up the trachea. Then once the larvae reach the small intestine of the host and begin to mature, the infected individual will experience diarrhea and other gastrointestinal discomfort. [ 11 ]  However, the "silent and insidious" symptoms referred to by Stoll are related to chronic, heavy-intensity hookworm infections. Major morbidity associated with hookworm infection is caused by intestinal blood loss, iron deficiency anemia, and protein malnutrition. [ 14 ]  They result mainly from adult hookworms in the small intestine ingesting blood, rupturing  erythrocytes , and degrading  hemoglobin  in the host. [ 12 ]  This long-term blood loss can manifest itself physically through facial and peripheral  edema ;  eosinophilia  and pica/ geophagy  caused by iron deficiency anemia are also experienced by some hookworm-infected patients. [ 11 ]  Recently, more attention has been given to other important outcomes of hookworm infection that play a large role in public health. It is now widely accepted that children who have chronic hookworm infection can experience growth retardation as well as intellectual and cognitive impairments. [ 12 ] [ 17 ]  Additionally, recent research has focused on the potential of adverse maternal-fetal outcomes when the mother is infected with hookworm during pregnancy. [ citation needed ]


The disease was linked to nematode worms ( Ankylostoma duodenalis ) from one-third to half an inch long in the intestine chiefly through the labours of  Theodor Bilharz  and  Griesinger  in Egypt (1854). [ 18 ]


The symptoms can be linked to inflammation in the gut stimulated by feeding hookworms, such as nausea, abdominal pain and intermittent diarrhea, and to progressive anemia in prolonged disease:  capricious  appetite,  pica / geophagy  (or dirt-eating), obstinate constipation followed by  diarrhea ,  palpitations , thready pulse, coldness of the skin, pallor of the mucous membranes, fatigue and weakness, shortness of breath and in cases running a fatal course,  dysentery ,  hemorrhages  and  edema . [ 18 ]  The worms suck  blood  and damage the  mucosa . However, the blood loss in the stools is not visibly apparent. [ citation needed ]


Blood tests in early infection often show a rise in numbers of eosinophils, a type of white blood cell that is preferentially stimulated by worm infections in tissues (large numbers of eosinophils are also present in the local inflammatory response). Falling blood hemoglobin levels will be seen in cases of prolonged infection with anemia. [ citation needed ]


In contrast to most intestinal  helminthiases , where the heaviest parasitic loads tend to occur in children, hookworm prevalence and intensity can be higher among adult males. The explanation for this is that hookworm infection tends to be occupational so that coworkers and other close groups maintain a high prevalence of infection among themselves by contaminating their work environment. However, in most endemic areas, adult women are the most severely affected by anemia, mainly because they have much higher physiological needs for iron (menstruation, repeated pregnancy). An interesting consequence of this in the case of  Ancylostoma duodenale  infection is translactational transmission of infection: the skin-invasive larvae of this species do not all immediately pass through the lungs and on into the gut, but spread around the body via the circulation, to become dormant inside muscle fibers. In a pregnant woman, after childbirth some or all of these larvae are stimulated to re-enter the circulation (presumably by sudden hormonal changes), then to pass into the mammary glands, so that the newborn baby can receive a large dose of infective larvae through its mother's milk. This accounts for otherwise inexplicable cases of very heavy, even fatal, hookworm infections in children a month or so of age, in places such as China, India, and northern Australia.
An identical phenomenon is much more commonly seen with  Ancylostoma caninum  infections in dogs, where the newborn pups can even die of hemorrhaging from their intestines caused by massive numbers of feeding hookworms. This also reflects the close evolutionary link between the human and canine parasites, which probably have a common ancestor dating back to when humans and dogs first started living closely together.
Filariform larvae are the infective stage of the parasite: infection occurs when larvae in soil penetrate the skin, or when they are ingested through contaminated food and water following skin penetration. [ citation needed ]


Diagnosis depends on finding characteristic worm eggs on microscopic examination of the stools, although this is not possible in early infection. Early signs of infection in most dogs include limbular limping and anal itching. The eggs are oval or elliptical, measuring 60 by 40 μm, colorless, not  bile  stained, and with a thin transparent  hyaline  shell membrane. When released by the worm in the intestine, the egg contains an unsegmented  ovum . During its passage down the intestine, the ovum develops and thus the eggs passed in feces have a segmented ovum, usually with 4 to 8  blastomeres .
As the eggs of both  Ancylostoma  and  Necator  (and most other hookworm species) are indistinguishable, to identify the genus, they must be cultured in the lab to allow larvae to hatch out. If the fecal sample is left for a day or more under tropical conditions, the larvae will have hatched out, so eggs might no longer be evident. In such a case, it is essential to distinguish hookworms from  Strongyloides  larvae, as infection with the latter has more serious implications and requires different management. The larvae of the two hookworm species can also be distinguished microscopically, although this would not be done routinely, but usually for research purposes. Adult worms are rarely seen (except via endoscopy, surgery or autopsy), but if found, would allow definitive identification of the species. Classification can be performed based on the length of the buccal cavity, the space between the oral opening and the esophagus: hookworm rhabditoform larvae have long buccal cavities whereas  Strongyloides  rhabditoform larvae have short buccal cavities. [ 11 ]


Recent research has focused on the development of DNA-based tools for diagnosis of infection, specific identification of hookworm, and analysis of genetic variability within hookworm populations. [ 19 ]  Because hookworm eggs are often indistinguishable from other parasitic eggs,  PCR  assays could serve as a molecular approach for accurate diagnosis of hookworm in the feces. [ 19 ] [ 20 ]


The infective larvae develop and survive in an environment of damp dirt, particularly sandy and loamy soil. They cannot survive in clay or muck. The main lines of precaution are those dictated by good  hygiene  behaviors:


Moxidectin  is available in the United States as ( imidacloprid  + moxidectin) topical solution for dogs and cats. It utilizes moxidectin for control and prevention of roundworms, hookworms,  heartworms , and  whipworms .


Most of these public health concerns have focused on children who are infected with hookworm. This focus on children is largely due to the large body of evidence that has demonstrated strong associations between hookworm infection and impaired learning, increased absences from school, and decreased future economic productivity. [ 12 ]  In 2001, the 54th World Health Assembly passed a resolution demanding member states to attain a minimum target of regular deworming of at least 75% of all at-risk school children by the year 2010. [ 21 ]  A 2008 World Health Organization publication reported on these efforts to treat at-risk school children. Some of the interesting statistics were as follows: 1) only 9 out of 130 endemic countries were able to reach the 75% target goal; and 2) less than 77 million school-aged children (of the total 878 million at risk) were reached, which means that only 8.78% of at-risk children are being treated for hookworm infection. [ 22 ]


School-based  mass deworming  programs have been the most popular strategy to address the issue of hookworm infection in children. School-based programs are extremely cost-effective as schools already have an available, extensive, and sustained infrastructure with a skilled workforce that has a close relationship with the community. [ 21 ]  With little training from a local health system, teachers can easily administer the drugs which often cost less than US$0.50 per child per year. [ 23 ]


Recently, many people have questioned if the school-based programs are necessarily the most effective approach. An important concern with school-based programs is that they often do not reach children who do not attend school, thus ignoring a large number of at-risk children. A 2008 study by Massa  et al.  continued the debate regarding school-based programs. They examined the effects of community-directed treatments versus school-based treatments in the Tanga Region of Tanzania. A major conclusion was that the mean infection intensity of hookworm was significantly lower in the villages employing the community-directed treatment approach than the school-based approach. The community-directed treatment model used in this specific study allowed villagers to take control of the child's treatment by having villagers select their own community drug distributors to administer the antihelminthic drugs. Additionally, villagers organized and implemented their own methods for distributing the drugs to all children. [ 24 ]  The positive results associated with this new model highlight the need for large-scale community involvement in deworming campaigns. [ citation needed ]


Many mass deworming programs also combine their efforts with public health education. These health education programs often stress important preventative techniques such as: washing your hands before eating and staying away from water/areas contaminated by human feces. These programs may also stress that shoes must be worn, however, these come with their own health risks and may not be effective. [ 25 ]  Shoe wearing patterns in towns and villages across the globe are determined by cultural beliefs, and the levels of education within that society. The wearing of shoes will prevent the entry of hookworm infections from the surrounding soils into tender skin regions; such as areas between the toes. [ 26 ]


Historical examples, such as the hookworm campaigns in Mississippi and Florida from 1943 to 1947 have shown that the primary cause of hookworm infection is poor sanitation, which can be solved by building and maintaining  toilets . But while these may seem like simple tasks, they raise important public health challenges. Most infected populations are from poverty-stricken areas with very poor sanitation. Thus, it is most likely that at-risk children do not have access to  clean water  to  wash their hands  and live in environments with no proper sanitation infrastructure. Health education, therefore, must address preventive measures in ways that are both feasible and sustainable in the context of resource-limited settings. [ citation needed ]


Evaluation of numerous public health interventions has generally shown that improvement in each individual component ordinarily attributed to poverty (for example, sanitation, health education, and underlying nutrition status) often has minimal impact on transmission. For example, one study found that the introduction of latrines into a resource-limited community only reduced the prevalence of hookworm infection by four percent. [ 27 ]  However, another study in Salvador, Brazil found that improved  drainage  and  sewerage  had a  significant impact  on the prevalence of hookworm infection but no impact at all on the intensity of hookworm infection. [ 28 ]  This seems to suggest that environmental control alone has a limited but incomplete effect on the transmission of hookworms. It is imperative, therefore, that more research is performed to understand the efficacy and sustainability of integrated programs that combine numerous preventive methods including education, sanitation, and treatment.


The most common treatments for hookworm are  benzimidazoles , specifically  albendazole  and  mebendazole . BZAs kill adult worms by binding to the nematode's β- tubulin  and subsequently inhibiting  microtubule  polymerization within the parasite. [ 14 ]  In certain circumstances,  levamisole  and  pyrantel pamoate  may be used. [ 12 ]  A 2008 review found that the efficacy of single-dose treatments for hookworm infections were as follows: 72% for albendazole, 15% for mebendazole, and 31% for pyrantel pamoate. [ 29 ]  This substantiates prior claims that albendazole is much more effective than mebendazole for hookworm infections. Also of note is that the World Health Organization does recommend anthelmintic treatment in pregnant women after the first trimester. [ 14 ]  It is also recommended that if the patient also has anemia that  ferrous sulfate  (200 mg) be administered three times daily at the same time as anthelmintic treatment; this should be continued until hemoglobin values return to normal which could take up to 3 months. [ 11 ]


Hookworm infection can be treated with local  cryotherapy  when the hookworm is still in the skin. [ 30 ]


Albendazole is effective both in the intestinal stage and during the stage the parasite is still migrating under the skin. [ 30 ]


In the case of anemia,  iron  supplementation can cause relief symptoms of  iron-deficiency anemia . However, as red blood cell levels are restored, a shortage of other essentials such as  folic acid  or  vitamin B 12  may develop, so these might also be supplemented.


During the 1910s, common treatments for hookworm included  thymol ,  2-naphthol ,  chloroform ,  gasoline , and  eucalyptus oil . [ 31 ]  By the 1940s, the treatment of choice used  tetrachloroethylene , [ 32 ]  given as 3 to 4 cc in the fasting state, followed by 30 to 45 g of  sodium sulfate . Tetrachloroethylene was reported to have a cure rate of 80 percent for Necator infections, but 25 percent in Ancylostoma infections, and often produced mild intoxication in the patient.


Other important issues related to the treatment of hookworm are reinfection and drug resistance. It has been shown that reinfection after treatment can be extremely high. Some studies even show that 80% of pretreatment hookworm infection rates can be seen in treated communities within 30–36 months. [ 14 ]  While reinfection may occur, it is still recommended that regular treatments be conducted as it will minimize the occurrence of chronic outcomes. There are also increasing concerns about the issue of drug resistance. Drug resistance has appeared in front-line anthelmintics used for livestock nematodes. Generally, human nematodes are less likely to develop resistance due to longer reproducing times, less frequent treatment, and more targeted treatment. Nonetheless, the global community must be careful to maintain the effectiveness of current anthelmintic as no new anthelmintic drugs are in the late-stage development. [ 14 ]


It is estimated that between 576 and 740 million individuals are infected with hookworm. [ 33 ] [ 14 ]  Of these infected individuals, about 80 million are severely affected. [ 19 ]  The major cause of hookworm infection is  N. americanus  which is found in the Americas, sub-Saharan Africa, and Asia. [ 12 ]   A. duodenale  is found in more scattered focal environments, namely Europe and the Mediterranean. Most infected individuals are concentrated in sub-Saharan Africa and East Asia/the Pacific Islands with each region having estimates of 198 million and 149 million infected individuals, respectively. Other affected regions include: South Asia (50 million), Latin America and the Caribbean (50 million), South Asia (59 million), and Middle East/North Africa (10 million). [ 14 ]  A majority of these infected individuals live in poverty-stricken areas with poor sanitation. Hookworm infection is most concentrated among the world's poorest who live on less than $2 a day. [ 12 ]


While hookworm infection may not directly lead to mortality, its effects on morbidity demand immediate attention. When considering  disability-adjusted life years  (DALYs), neglected tropical diseases, including hookworm infection, rank among diarrheal diseases,  ischemic heart disease ,  malaria , and  tuberculosis  as one of the most important health problems of the developing world.


It has been estimated that as many as 22.1 million  DALYs  have been lost due to hookworm infection. Recently, there has been increasing interest to address the public health concerns associated with hookworm infection. For example, the  Bill & Melinda Gates Foundation  recently donated US$34 million to fight Neglected Tropical Diseases including hookworm infection. [ 34 ]  Former US President Clinton also announced a mega-commitment at the Clinton Global Initiative (CGI) 2008 Annual Meeting to de-worm 10 million children. [ 35 ]


Many of the numbers regarding the prevalence of hookworm infection are estimates as there is no international surveillance mechanism currently in place to determine prevalence and global distribution. [ 12 ]  Some prevalence rates have been measured through survey data in endemic regions around the world. The following are some of the most recent findings on prevalence rates in regions endemic with hookworm.


Darjeeling ,  Hooghly District ,  West Bengal , India  (Pal  et al.  2007) [ 36 ]


Xiulongkan  Village,  Hainan Province , China  (Gandhi  et al.  2001) [ 37 ]


Hòa Bình , Northwest Vietnam  (Verle  et al.  2003) [ 38 ]


Minas Gerais , Brazil  (Fleming  et al.  2006) [ 39 ]


KwaZulu-Natal , South Africa  (Mabaso  et al.  2004) [ 40 ]


Lowndes County, Alabama ,  United States   [ 41 ] [ 42 ]


There have also been technological developments that may facilitate more accurate mapping of hookworm prevalence. Some researchers have begun to use geographical information systems (GIS) and  remote sensing  (RS) to examine helminth ecology and epidemiology. Brooker  et al.  utilized this technology to create helminth distribution maps of sub-Saharan Africa. By relating satellite-derived environmental data with prevalence data from school-based surveys, they were able to create detailed prevalence maps. The study focused on a wide range of helminths, but interesting conclusions about hookworm specifically were found. As compared to other helminths, hookworms can survive in much hotter conditions and were highly prevalent throughout the upper end of the thermal range. [ 43 ]


Improved molecular diagnostic tools are another technological advancement that could help improve existing prevalence statistics. Recent research has focused on the development of a DNA-based tool that can be used for diagnosis of infection, specific identification of hookworm, and analysis of genetic variability in hookworm populations. Again this can serve as a major tool for different public health measures against hookworm infection. Most research regarding diagnostic tools is now focused on the creation of a rapid and cost-effective assay for the specific diagnosis of hookworm infection. Many are hopeful that its development can be achieved within the next five years. [ when? ] [ 19 ]


The symptoms now attributed to hookworm appear in  papyrus  papers of ancient  Egypt  ( c.  1500 BC ), described as a derangement characterized by anemia.  Avicenna , a Persian physician of the eleventh century, discovered the worm in several of his patients and related it to their disease. In later times, the condition was noticeably prevalent in the mining industry in  England ,  France ,  Germany ,  Belgium ,  North Queensland , and elsewhere. [ 18 ]


Italian physician  Angelo Dubini  was the modern-day discoverer of the worm in 1838 after an  autopsy  of a peasant woman. Dubini published details in 1843 and identified the species as  A. duodenale . [ 44 ]  Working in the Egyptian medical system in 1852 German physician  Theodor Bilharz , drawing upon the work of colleague  Wilhelm Griesinger , found these worms during autopsies and went a step further in linking them to local endemic occurrences of  chlorosis , which would probably be called  iron-deficiency anemia  today.


A breakthrough came 25 years later following a  diarrhea  and  anemia  epidemic that took place among  Italian  workmen employed on the  Gotthard Rail Tunnel . [ 18 ]  In an 1880 paper, physicians  Camillo Bozzolo ,  Edoardo Perroncito , and  Luigi Pagliani  correctly hypothesized that hookworm was linked to the fact that workers had to defecate inside the 15 km tunnel, and that many wore worn-out shoes. [ 45 ]  The work environment often contained standing water, sometimes knee-deep, and the larvae were capable of surviving several weeks in the water, allowing them to infect many of the workers. In 1897, it was established that the skin was the principal avenue of infection and the  biological life cycle  of the hookworm was clarified.


In 1899, American zoologist  Charles Wardell Stiles  identified progressive  pernicious anemia  seen in the southern United States as being caused by the hookworm  A. duodenale . Testing in the 1900s revealed very heavy infestations in school-age children. In  Puerto Rico , Dr. Bailey K. Ashford, a US Army physician, organized and conducted a parasite treatment campaign, which cured approximately 300,000 people (one-third of the Puerto Rican population) and reduced the death rate from this anemia by 90 percent during the years 1903–04.


On October 26, 1909, the Rockefeller Sanitary Commission for the Eradication of Hookworm Disease was organized as a result of a gift of US$1 million from  John D. Rockefeller , Sr. The five-year program was a remarkable success and a great contribution to the United States' public health, instilling public education, medication, field work and modern government health departments in eleven southern states. [ 46 ]
The hookworm exhibit was a prominent part of the 1910 Mississippi State Fair.


The commission found that an average of 40% of school-aged children were infected with hookworm. Areas with higher levels of hookworm infection prior to the eradication program experienced greater increases in school enrollment, attendance, and literacy after the intervention. Econometric studies have shown that this effect cannot be explained by a variety of alternative factors, including differential trends across areas, changing crop prices, shifts in certain educational and health policies, and the effect of malaria eradication. [ 47 ]  No significant contemporaneous results were found for adults who should have benefited less from the intervention owing to their substantially lower (prior) infection rates. The program nearly eradicated hookworm and would flourish afterward with new funding as the  Rockefeller Foundation   International Health Division . [ 48 ]


The RF's hookworm campaign in Mexico showed how science and politics play a role in developing health policies. It brought together government officials, health officials, public health workers, Rockefeller officials, and the community. This campaign was launched to eradicate hookworms in Mexico. Although the campaign did not focus on long-term treatments, it did set the terms of the relationship between Mexico and the Rockefeller Foundation. The scientific knowledge behind this campaign helped shape public health policies, improved public health and built a strong relationship between US and Mexico. [ 49 ]


In the 1920s, hookworm eradication reached the Caribbean and Latin America, where great mortality was reported among people in the  West Indies  towards the end of the 18th century, as well as through descriptions sent from  Brazil  and various other tropical and subtropical regions. [ 18 ]


Treatment in the early 20th century relied on the use of  Epsom salt  to reduce protective mucus, followed by  thymol  to kill the worms. [ 50 ] [ 31 ]  By the 1940s,  tetrachloroethylene  was the leading method. [ 32 ]  It was not until later in the mid-20th century when new organic drug compounds were developed. [ 51 ]


It is estimated that a third of all pregnant women in developing countries are infected with hookworm, 56% of all pregnant women in developing countries experience anemia, and 20% of all maternal deaths are either directly or indirectly related to anemia. Numbers like this have led to an increased interest in the topic of hookworm-related anemia during pregnancy. [ 52 ]  With the understanding that chronic hookworm infection can often lead to anemia, many people are now questioning if the treatment of hookworm could effect change in severe anemia rates and thus also on maternal and child health as well. Most evidence suggests that the contribution of hookworm to maternal anemia merits that all women of child-bearing age living in endemic areas be subject to periodic anthelmintic treatment. The World Health Organization even recommends that infected pregnant women be treated after their first trimester. [ 14 ]  Regardless of these suggestions, only Madagascar, Nepal, and Sri Lanka have added deworming to their antenatal care programs. [ 53 ]


This lack of deworming of pregnant women is explained by the fact that most individuals still fear that anthelmintic treatment will result in adverse birth outcomes. However, a 2006 study by Gyorkos et al. found that when comparing a group of pregnant women treated with mebendazole with a control placebo group, both illustrated rather similar rates of adverse birth outcomes. The treated group demonstrated 5.6% adverse birth outcomes, while the control group had 6.25% adverse birth outcomes. [ 52 ]  Furthermore, Larocque et al. illustrated that treatment for hookworm infection actually led to positive health results in the infant. This study concluded that treatment with mebendazole plus iron supplements during antenatal care significantly reduced the proportion of very low birth weight infants when compared to a placebo control group. [ 54 ]  Studies so far have validated recommendations to treat infected pregnant women for hookworm infection during pregnancy.


A review found that a single dose of  antihelminthics  (anti-worm drugs) given in the second trimester of pregnancy "may reduce maternal anaemia and worm prevalence when used in settings with a high prevalence of maternal helminthiasis". [ 55 ]


The intensity of hookworm infection as well as the species of hookworm have yet to be studied as they relate to hookworm-related anemia during pregnancy. Additionally, more research must be done in different regions of the world to see if trends noted in completed studies persist. [ citation needed ]


Co-infection with hookworm and  Plasmodium falciparum  is common in Africa. [ 56 ]  Although exact numbers are unknown, preliminary analyses estimate that as many as a quarter of African schoolchildren (17.8–32.1 million children aged 5–14 years) may be coincidentally at-risk of both  P. falciparum  and hookworm. [ 57 ]  While original hypotheses stated that co-infection with multiple parasites would impair the host's immune response to a single parasite and increase susceptibility to clinical disease, studies have yielded contrasting results. For example, one study in Senegal showed that the risk of clinical malaria infection was increased in helminth-infected children in comparison to helminth-free children while other studies have failed to reproduce such results, [ 58 ]  and even among laboratory mouse experiments the effect of helminths on malaria is variable. [ 59 ]


Some hypotheses and studies suggest that helminth infections may protect against cerebral malaria due to the possible modulation of pro-inflammatory and anti-inflammatory cytokine responses. [ 60 ]  Furthermore, the mechanisms underlying this supposed increased susceptibility to disease are unknown. For example, helminth infections cause potent and highly polarized immune response characterized by increased  T-helper cell  type 2 (T h 2)  cytokine  and  Immunoglobulin E  (IgE) production. [ 61 ]  However, the effect of such responses on the human immune response is unknown. Additionally, both malaria and helminth infection can cause anemia, but the effect of co-infection and possible enhancement of anemia is poorly understood. [ 51 ]


The  hygiene hypothesis  states that infants and children who lack exposure to infectious agents are more susceptible to allergic diseases via modulation of immune system development. The theory was first proposed by David P. Strachan who noted that  hay fever  and  eczema  were less common in children who belonged to large families. [ 62 ]  Since then, studies have noted the effect of gastrointestinal worms on the development of allergies in the developing world. For example, a study in Gambia found that the eradication of worms in some villages led to increased skin reactions to allergies among children. [ 63 ]


While annual or semi-annual mass antihelminthic administration is a critical aspect of any public health intervention, many have begun to realize how unsustainable it is due to aspects such as poverty, high rates of re-infection, and diminished efficacy of drugs with repeated use. Current research, therefore, has focused on the development of a vaccine that could be integrated into existing control programs. The goal of vaccine development is not necessarily to create a vaccine with sterilizing immunity or complete protection against immunity. A vaccine that reduces the likelihood of vaccinated individuals developing severe infections and thus reduced blood and nutrient levels could still have a significant impact on the high burden of disease throughout the world.


Current research focuses on targeting two stages in the development of the worm: the larval stage and the adult stage. Research on larval antigens has focused on proteins that are members of the  pathogenesis-related protein  superfamily,  Ancylostoma  Secreted Proteins. [ 64 ]  Although they were first described in  Anyclostoma , these proteins have also been successfully isolated from the secreted product of  N. americanus .  N. americanus  ASP-2 (Na-ASP-2) is currently the leading larval-stage hookworm vaccine candidate. A randomized, double-blind, placebo-controlled study has already been performed; 36 healthy adults without a history of hookworm infection were given three intramuscular injections of three different concentrations of Na-ASP-2 and observed for six months after the final vaccination. [ 65 ]  The vaccine induced significant anti-Na-ASP-2 IgG and cellular immune responses. In addition, it was safe and produced no debilitating side effects. The vaccine is now in a phase one trial; healthy adult volunteers with documented evidence of previous infection in Brazil are being given the same  dose concentration  on the same schedule used in the initial study. [ 64 ]  If this study is successful, the next step would be to conduct a phase two trial to assess the rate and intensity of hookworm infection among vaccinated persons. Because the Na-ASP-2 vaccine only targets the larval stage, it is critical that all subjects enrolled in the study be treated with antihelminthic drugs to eliminate adult worms prior to vaccination.


Adult hookworm antigens have also been identified as potential candidates for vaccines. When adult worms attach to the intestinal mucosa of the human host, erythrocytes are ruptured in the worm's digestive tract which causes the release of free hemoglobin which is subsequently degraded by a proteolytic cascade. Several of these proteins that are responsible for this proteolytic cascade are also essential for the worm's nutrition and survival. [ 66 ]  Therefore, a vaccine that could induce antibodies for these antigens could interfere with the hookworm's digestive pathway and impair the worm's survival. Three proteins have been identified: the aspartic protease-hemoglobinase APR-1, the cysteine protease-hemoglobinase CP-2, and a glutathione S-transferase. [ 67 ] [ 68 ] [ 69 ]  Vaccination with APR-1 and CP-2 led to reduced host blood loss and fecal egg counts in dogs. [ 67 ] [ 68 ]  With APR-1, vaccination even led to reduced worm burden. [ 67 ]  Research is currently stymied at the development of at least one of these antigens as a recombinant protein for testing in clinical trials.


The term "hookworm" is sometimes used to refer to hookworm infection. [ 12 ]  A hookworm is a type of parasitic worm ( helminth ).


Intestinal capillariasis  is a disease in the group of  helminthiasis  diseases caused by the  nematode   Capillaria philippinensis .


Symptoms in infested humans include watery  diarrhea , abdominal pain,  edema , weight loss,  borborygmus  (stomach growling), and depressed levels of  potassium  and  albumin  in the blood.  In humans, the parasites damage the cells of the intestinal wall.  This damage interferes with the absorption of nutrients and the maintenance of a proper  electrolyte  balance.  Untreated  C. philippinensis  infestations are often fatal. [ citation needed ]


Diagnosis usually involves finding the eggs and/or adults of  C. philippinensis  in stool samples. [ citation needed ]


Prevention is as simple as avoiding eating small, whole, uncooked fish.  However, in  C. philippinensis   endemic  areas, such dietary habits are common and have been practiced for many generations. [ citation needed ]


Anthelmintics  such as  mebendazole  and  albendazole  have been reported to eliminate infestation of humans more effectively than  thiabendazole . [ 1 ]


Irritable bowel syndrome  ( IBS ) is a  functional gastrointestinal disorder  characterized by a group of symptoms that commonly include  abdominal pain , abdominal bloating and changes in the consistency of  bowel movements . [ 1 ]  These symptoms may occur over a long time, sometimes for years. [ 2 ]  IBS can negatively affect  quality of life  and may result in missed school or work or reduced productivity at work. [ 13 ]  Disorders such as  anxiety ,  major depression , and  myalgic encephalomyelitis/chronic fatigue syndrome  (ME/CFS) are common among people with IBS. [ 1 ] [ 14 ] [ note 1 ] [ 15 ]


The cause of IBS is not known but multiple factors have been proposed to lead to the condition. [ 2 ]  Theories include combinations of " gut–brain axis " problems, alterations in  gut motility , visceral hypersensitivity, infections including  small intestinal bacterial overgrowth ,  neurotransmitters , genetic factors, and  food sensitivity . [ 2 ]  Onset may be triggered by a  stressful  life event, [ 16 ]  or an  intestinal infection . [ 17 ]  In the latter case, it is called  post-infectious irritable bowel syndrome . [ 17 ]


Diagnosis is based on symptoms in the absence of worrisome features and once other potential conditions have been ruled out. [ 7 ]  Worrisome or "alarm" features include onset at greater than 50 years of age, weight loss,  blood in the stool , or a family history of  inflammatory bowel disease . [ 7 ]  Other conditions that may present similarly include  celiac disease ,  microscopic colitis , inflammatory bowel disease,  bile acid malabsorption , and  colon cancer . [ 7 ]


Treatment of IBS is carried out to improve symptoms. This may include dietary changes, medication,  probiotics , and  counseling . [ 9 ] [ 18 ]  Dietary measures include increasing  soluble fiber  intake, or a  diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols  (FODMAPs). The "low FODMAP" diet is meant for short to medium term use and is not intended as a life-long therapy. [ 7 ] [ 19 ] [ 20 ]  The medication  loperamide  may be used to help with diarrhea while  laxatives  may be used to help with constipation. [ 7 ]  There is strong clinical-trial evidence for the use of  antidepressants , often in lower doses than that used for depression or anxiety, even in patients without comorbid mood disorder.  Tricyclic antidepressants  such as  amitriptyline  or  nortriptyline  and medications from the  selective serotonin reuptake inhibitor  (SSRI) group may improve overall symptoms and reduce pain. [ 7 ]   Patient education  and a good  doctor–patient relationship  are an important part of care. [ 7 ] [ 21 ]


About 10–15% of people in the  developed world  are believed to be affected by IBS. [ 1 ] [ 11 ]  The prevalence varies according to country (from 1.1% to 45.0%) and criteria used to define IBS; however the average global prevalence is 11.2%. [ 12 ]  It is more common in  South America  and less common in  Southeast Asia . [ 7 ]  In the  Western world , it is twice as common in women as men and typically occurs before age 45. [ 1 ]  However, women in  East Asia  are not more likely than their male counterparts to have IBS, indicating much lower rates among East Asian women. [ 22 ]  Similarly, men from South America, South Asia and Africa are just as likely to have IBS as women in those regions, if not more so. [ 23 ]  The condition appears to become less common with age. [ 7 ]  IBS does not affect life expectancy or lead to other serious diseases. [ 10 ]  The first description of the condition was in 1820, while the current term  irritable bowel syndrome  came into use in 1944. [ 24 ]


The primary symptoms of IBS are  abdominal pain  or discomfort in association with frequent diarrhea or constipation and a change in bowel habits. [ 25 ]  Symptoms usually are experienced as acute attacks that subside within one day, but recurrent attacks are likely. [ 26 ]  There may also be urgency for bowel movements, a feeling of incomplete evacuation ( tenesmus ) or bloating. [ 27 ]  In some cases, the symptoms are relieved by  bowel movements . [ 21 ]


People with IBS, more commonly than others, have  gastroesophageal reflux , symptoms relating to the  genitourinary system ,  fibromyalgia ,  headache ,  backache , and psychiatric symptoms such as depression, sleep disorders, [ 28 ]  and  anxiety . [ 14 ] [ 27 ]  About a third of adults who have IBS also report  sexual dysfunction , typically in the form of a reduction in  libido . [ 29 ]


While the causes of IBS are still unknown, it is believed that the entire  gut–brain axis  is affected. [ 30 ] [ 31 ]  Recent findings suggest that an allergy triggered peripheral immune mechanism may underlie the symptoms associated with abdominal pain in patients with irritable bowel syndrome. [ 32 ]  IBS is more prevalent in obese patients. [ 33 ]


People who are younger than 50, women, and those with a family history of the condition are more likely to develop IBS. [ 34 ]  Further risk factors are  anxiety ,  depression , and  stress . [ 35 ]  The risk of developing IBS increases six-fold after having a gastrointestinal infection ( gastroenteritis ). [ 34 ]  This is also called  post-infectious IBS . The risk of developing IBS following an infection is further increased in those who also had a prolonged fever during the illness. [ 36 ]  Antibiotic use also appears to increase the risk of developing IBS. [ 37 ]  Genetic defects in  innate immunity  and  epithelial  homeostasis increase the risk of developing both post-infectious as well as other forms of IBS. [ 38 ]


The role of the brain–gut axis in IBS has been suggested since the 1990s [ 4 ]  and childhood physical and psychological abuse is often associated with the development of IBS. [ 6 ]  It is believed that psychological stress may trigger IBS in predisposed individuals. [ 3 ]


Given the high levels of anxiety experienced by people with IBS and the overlap with conditions such as  fibromyalgia  and  chronic fatigue syndrome , a potential explanation for IBS involves a disruption of the stress system. The stress response in the body involves the  hypothalamic–pituitary–adrenal axis  (HPA) and the  sympathetic nervous system , both of which have been shown to operate abnormally in people with IBS. Psychiatric illness or anxiety precedes IBS symptoms in two-thirds of people with IBS, and psychological traits predispose previously healthy people to developing IBS after gastroenteritis. [ 39 ] [ 40 ]  Individuals with IBS also report high rates of sleep disturbances such as trouble falling asleep and frequent arousal throughout the night. [ 41 ]


Approximately 10 percent of IBS cases are triggered by an acute  gastroenteritis  infection. [ 42 ]  The  CdtB toxin  is produced by bacteria causing gastroenteritis and the host may develop an  autoimmunity  when host antibodies to CdtB cross-react with  vinculin . [ 43 ]  Genetic defects relating to the  innate immune system  and epithelial barrier as well as high stress and anxiety levels appear to increase the risk of developing post-infectious IBS. Post-infectious IBS usually manifests itself as the diarrhea-predominant subtype. Evidence has demonstrated that the release of high levels of proinflammatory cytokines during acute enteric infection causes increased  gut permeability  leading to  translocation  of the  commensal  bacteria across the  epithelial  barrier; this in turn can result in significant damage to local tissues, which can develop into chronic gut abnormalities in sensitive individuals. However, increased gut permeability is strongly associated with IBS regardless of whether IBS was initiated by an infection or not. [ 38 ]  A link between  small intestinal bacterial overgrowth  and  tropical sprue  has been proposed to be involved as a cause of post-infectious IBS. [ 44 ]


Small intestinal bacterial overgrowth  (SIBO) occurs with greater frequency in people who have been diagnosed with IBS compared to healthy controls. [ 45 ]  SIBO is most common in diarrhea-predominant IBS but also occurs in constipation-predominant IBS more frequently than healthy controls. Symptoms of SIBO include bloating, abdominal pain, diarrhea or constipation among others. IBS may be the result of the immune system interacting abnormally with gut microbiota resulting in an abnormal  cytokine  signalling profile. [ 46 ]


Certain bacteria are found in lower or higher abundance when compared with healthy individuals. Generally  Bacteroidota ,  Bacillota , and  Pseudomonadota  are increased and  Actinomycetota ,  Bifidobacteria , and  Lactobacillus  are decreased. Within the human gut, there are common phyla found. The most common is Bacillota. This includes  Lactobacillus , which is found to have a decrease in people with IBS, and  Streptococcus , which is shown to have an increase in abundance. Within this phylum, species in the class  Clostridia  are shown to have an increase, specifically  Ruminococcus  and  Dorea . The family  Lachnospiraceae  presents an increase in IBS-D patients. The second most common phylum is Bacteroidota. In people with IBS, the Bacteroidota phylum has been shown to have an overall decrease, but an increase in the genus  Bacteroides . IBS-D shows a decrease for the phylum Actinomycetota and an increase in Pseudomonadota, specifically in the family  Enterobacteriaceae . [ 47 ]


Alterations of  gut microbiota  ( dysbiosis ) are associated with the intestinal manifestations of IBS, but also with the psychiatric morbidity that coexists in up to 80% of people with IBS. [ 48 ]


Protozoal  infections can cause symptoms that mirror specific IBS subtypes, [ 51 ]  e.g., infection by certain substypes of  Blastocystis hominis  ( blastocystosis ). [ 52 ] [ 53 ]  Many people regard these organisms as incidental findings, and unrelated to symptoms of IBS.


Blastocystis and  Dientamoeba fragilis  colonisation occurs more commonly in IBS affected individuals but their role in the condition is unclear. [ 54 ]


Vitamin D deficiency  is more common in individuals affected by IBS. [ 55 ] [ 56 ]  Vitamin D is involved in regulating triggers for IBS including the gut microbiome, inflammatory processes and immune responses, as well as psychosocial factors. [ 57 ]


SCN5A   mutations  are found in a small number of people who have IBS, particularly the constipation-predominant variant (IBS-C). [ 58 ] [ 59 ]  The resulting defect leads to disruption in bowel function, by affecting the  Nav1.5  channel, in smooth muscle of the colon and  pacemaker cells . [ 60 ] [ 61 ] [ 62 ]


Genetic, environmental, and psychological factors seem to be important in the development of IBS. The condition also has a genetic component even though there is a predominant influence of environmental factors. [ 63 ]


Dysregulated brain-gut axis, abnormal  serotonin / 5-hydroxytryptamine  (5-HT) metabolism, and high density of mucosal  nerve fibers  in the intestines have been implicated in the mechanisms of IBS. A number of  5-HT receptor  subtypes were involved in the IBS symptoms, including  5-HT 3 ,  5-HT 4 , and  5-HT 7  receptors. High levels of 5-HT 7  receptor-expressing mucosal nerve fibers were observed in the colon of IBS patients. A role of  5-HT7 receptor  in intestinal  hyperalgesia  was demonstrated in mouse models with  visceral hypersensitivity , of which a novel 5-HT 7  receptor antagonist administered by mouth reduced intestinal pain levels. [ 64 ]


Abnormalities occur in the gut flora of individuals who have IBS, such as reduced diversity, a decrease in bacteria belonging to the phylum  Bacteroidota , and an increase in those belonging to the phylum  Bacillota . [ 48 ]  The changes in gut flora are most profound in individuals who have diarrhoea-predominant IBS. Antibodies against common components (namely  flagellin ) of the commensal gut flora are a common occurrence in IBS affected individuals. [ 65 ]


Chronic low-grade inflammation commonly occurs in IBS affected individuals with abnormalities found including increased  enterochromaffin cells ,  intraepithelial lymphocytes , and  mast cells  resulting in chronic immune-mediated inflammation of the gut mucosa. [ 30 ] [ 66 ]  IBS has been reported in greater quantities in multigenerational families with IBS than in the regular population. [ 67 ]  It is believed that psychological stress can induce increased inflammation and thereby cause IBS to develop in predisposed individuals. [ 3 ]


No specific laboratory or imaging tests can diagnose irritable bowel syndrome. Diagnosis should be based on symptoms, the exclusion of worrisome features, and the performance of specific investigations to rule out organic diseases that may present similar symptoms. [ 7 ] [ 68 ]


The recommendations for physicians are to minimize the use of medical investigations. [ 69 ]  The  Rome criteria  are typically used for diagnosis. They allow the diagnosis to be based only on symptoms, but no criteria based solely on symptoms is sufficiently accurate to diagnose IBS. [ 70 ] [ 71 ]  Worrisome features include onset at greater than 50 years of age, weight loss,  blood in the stool ,  iron-deficiency anemia , or a family history of  colon cancer ,  celiac disease , or  inflammatory bowel disease . [ 7 ]  The criteria for selecting tests and investigations also depends on the level of available medical resources. [ 72 ]


The Rome IV criteria for diagnosing IBS include recurrent abdominal pain, on average, at least one day/week in the last three months, associated with additional stool- or defecation-related criteria. [ 73 ]  The algorithm may include additional tests to guard against misdiagnosis of other diseases as IBS.  Such "red flag" symptoms that may indicate other diseases as well include weight loss, gastrointestinal bleeding, anemia, or nocturnal symptoms. However, red flag conditions may not always contribute to accuracy in diagnosis; for instance, as many as 31% of people with IBS have blood in their stool, many possibly from  hemorrhoidal  bleeding. [ 74 ]


Investigations are performed to exclude other conditions: [ citation needed ]


Colon cancer ,  inflammatory bowel disease ,  thyroid  disorders ( hyperthyroidism  or  hypothyroidism ), and  giardiasis  can all feature abnormal defecation and abdominal pain. Less common causes of this symptom profile are  carcinoid syndrome ,  microscopic colitis ,  bacterial overgrowth , and  eosinophilic gastroenteritis ; IBS is, however, a common presentation, and testing for these conditions would yield low numbers of positive results, so it is considered difficult to justify the expense. [ 75 ]  Conditions that may present similarly include celiac disease,  bile acid malabsorption , colon cancer, and  dyssynergic defecation . [ 7 ]


Ruling out parasitic infections,  lactose intolerance , small intestinal bacterial overgrowth, and celiac disease is recommended before a diagnosis of IBS is made. [ 68 ]  An  upper endoscopy  with  small bowel   biopsies  is necessary to identify the presence of celiac disease. [ 76 ]  An ileocolonoscopy with biopsies is useful to exclude  Crohn's disease  and  ulcerative colitis  (Inflammatory bowel disease). [ 76 ]


Some people, managed for years for IBS, may have  non-celiac gluten sensitivity  (NCGS). [ 8 ]  Gastrointestinal symptoms of IBS are clinically indistinguishable from those of NCGS, but the presence of any of the following non-intestinal manifestations suggest a possible NCGS:  headache  or  migraine , "foggy mind",  chronic fatigue , [ 77 ]   fibromyalgia , [ 78 ] [ 79 ] [ 80 ]  joint and muscle pain, [ 77 ] [ 78 ] [ 81 ]  leg or arm  numbness , [ 77 ] [ 78 ] [ 81 ]   tingling  of the extremities, [ 77 ] [ 81 ]  dermatitis ( eczema  or  skin rash ), [ 77 ] [ 81 ]   atopic disorders , [ 77 ]   allergy  to one or more inhalants, foods or metals [ 77 ] [ 78 ]  (such as  mites ,  graminaceae ,  parietaria , cat or dog hair/dander,  shellfish , or  nickel [ 78 ] ),  depression , [ 77 ] [ 78 ] [ 81 ]   anxiety , [ 78 ]   anemia , [ 77 ] [ 81 ]   iron-deficiency anemia ,  folate deficiency ,  asthma ,  rhinitis ,  eating disorders , [ 78 ]   neuropsychiatric disorders  (such as  schizophrenia , [ 81 ] [ 82 ]   autism , [ 78 ] [ 81 ] [ 82 ]   peripheral neuropathy , [ 81 ] [ 82 ]   ataxia , [ 82 ]   attention deficit hyperactivity disorder [ 77 ] ) or  autoimmune diseases . [ 77 ]  An improvement with a  gluten-free diet  of immune-mediated symptoms, including autoimmune diseases, once having reasonably ruled out  celiac disease  and  wheat allergy , is another way to realize a differential diagnosis. [ 77 ]


People with IBS are at increased risk of being given inappropriate surgeries such as  appendectomy ,  cholecystectomy , and  hysterectomy  due to being misdiagnosed as other medical conditions. [ 83 ]  Some common examples of misdiagnosis include  infectious diseases ,  coeliac disease , [ 84 ]   Helicobacter pylori , [ 85 ] [ 86 ]   parasites  (non- protozoal ). [ 51 ] [ 87 ] [ 88 ]  The American College of Gastroenterology recommends all people with symptoms of IBS be tested for coeliac disease. [ 89 ]


Bile acid malabsorption  is also sometimes missed in people with diarrhea-predominant IBS.  SeHCAT  tests suggest around 30% of people with D-IBS have this condition, and most respond to  bile acid sequestrants . [ 90 ]


Several medical conditions, or  comorbidities , appear with greater frequency in people with IBS.


IBS can be classified as  diarrhea -predominant (IBS-D),  constipation -predominant (IBS-C), with mixed/alternating stool pattern (IBS-M/IBS-A) or pain-predominant. [ 104 ]  In some individuals, IBS may have an acute onset and develop after an  infectious  illness characterized by two or more of: fever, vomiting, diarrhea, or positive  stool culture . This post-infective syndrome has consequently been termed "post-infectious IBS" (IBS-PI). [ 105 ] [ 106 ] [ 107 ] [ 108 ]


A number of treatments have been found to be effective, including fiber,  talk therapy ,  antispasmodic  and  antidepressant  medication, and peppermint oil. [ 109 ] [ 110 ] [ 111 ]


FODMAPs  are short-chain carbohydrates that are poorly absorbed in the small intestine. A 2018 systematic review found that although there is evidence of improved IBS symptoms with a  low-FODMAP diet , the evidence is of very low quality. [ 112 ]  Symptoms most likely to improve on this type of diet include urgency,  flatulence ,  bloating , [ 113 ]  abdominal pain, and altered stool output. One national guideline advises a low FODMAP diet for managing IBS when other dietary and lifestyle measures have been unsuccessful. [ 114 ]  The diet restricts various carbohydrates which are poorly absorbed in the  small intestine , as well as  fructose  and  lactose , which are similarly poorly absorbed in those with intolerances to them. Reduction of fructose and  fructan  has been shown to reduce IBS symptoms in a dose-dependent manner in people with  fructose malabsorption  and IBS. [ 115 ]


FODMAPs are fermentable  oligo- ,  di- ,  monosaccharides  and  polyols , which are poorly absorbed in the small intestine and subsequently fermented by the bacteria in the distal small and proximal  large intestine . This is a normal phenomenon, common to everyone. The resultant production of gas potentially results in bloating and flatulence. [ 116 ]  Although FODMAPs can produce certain digestive discomfort in some people, not only do they not cause intestinal inflammation, but they help avoid it, because they produce beneficial alterations in the intestinal flora that contribute to maintaining the good health of the colon. [ 117 ] [ 118 ] [ 119 ]  FODMAPs are not the cause of irritable bowel syndrome nor other  functional gastrointestinal disorders , but rather a person develops symptoms when the underlying bowel response is exaggerated or abnormal. [ 116 ]


A  low-FODMAP diet  consists of restricting them from the diet. They are globally trimmed, rather than individually, which is more successful than for example restricting only fructose and fructans, which are also FODMAPs, as is recommended for those with fructose malabsorption. [ 116 ]


A low-FODMAP diet might help to improve short-term digestive symptoms in adults with irritable bowel syndrome, [ 120 ] [ 114 ] [ 121 ] [ 20 ]  but its long-term follow-up can have negative effects because it causes a detrimental impact on the  gut microbiota  and  metabolome . [ 122 ] [ 114 ] [ 20 ] [ 123 ]  It should only be used for short periods of time and under the advice of a specialist. [ 124 ]   A low-FODMAP diet is highly restrictive in various groups of nutrients and can be impractical to follow in the long-term. [ 125 ]  More studies are needed to assess the true impact of this diet on health. [ 114 ] [ 20 ]


In addition, the use of a low-FODMAP diet without verifying the diagnosis of IBS may result in misdiagnosis of other conditions such as celiac disease. [ 126 ]  Since the consumption of  gluten  is suppressed or reduced with a low-FODMAP diet, the improvement of the digestive symptoms with this diet may not be related to the withdrawal of the FODMAPs, but of gluten, indicating the presence of unrecognized celiac disease, avoiding its diagnosis and correct treatment, with the consequent risk of several serious health complications, including various types of cancer. [ 126 ] [ 127 ]


Soluble  fiber  supplementation (e.g.,  psyllium/ispagula husk ) may be effective in improving symptoms. [ 19 ]  However soluble fiber does not appear to reduce pain. [ 128 ]  It acts as a bulking agent, and for many people with IBS-D, allows for a more consistent stool. For people with IBS-C, it seems to allow for a softer, moister, more easily passable stool. [ citation needed ]


However, insoluble fiber (e.g.,  bran ) is not effective for IBS. [ 129 ] [ 130 ]  In some people, insoluble fiber supplementation may aggravate symptoms. [ 131 ] [ 132 ]


Fiber might be beneficial in those who have a predominance of constipation. In people who have IBS-C, soluble fiber can reduce overall symptoms but will not reduce pain. The research supporting dietary fiber contains conflicting small studies complicated by the heterogeneity of types of fiber and doses used. [ 128 ]


Physical activity  can have beneficial effects on irritable bowel syndrome. [ 133 ]  In light of this, the latest British Society of Gastroenterology guidelines on the management of IBS have stated that all patients with IBS should be advised to take regular exercise (strong recommendation, weak certainty evidence), [ 134 ]  whereas the  American College of Gastroenterology  guidelines have suggested with a lower certainty of evidence. [ 135 ]   Physical activity  could significantly improve people’s adherence and, consequently, lead to a significant clinical benefit for symptoms of irritable bowel syndrome. [ 133 ]


Medications that may be useful include antispasmodics such as  dicyclomine  and  antidepressants . [ 136 ]  Both H1- antihistamines  and  mast cell stabilizers  have shown efficacy in reducing pain associated with  visceral hypersensitivity  in IBS. [ 30 ]


A number of  5-HT3 antagonists  or 5-HT4 agonists were proposed clinically to treat diarrhea-predominant IBS and constipation-predominant IBS, respectively. However, severe side effects have resulted in its withdrawal by food and drug administration and are now prescribed under emergency investigational drug protocol. [ 137 ]  Other 5-HT receptor subtypes, such as  5-HT7 receptor , have yet to be developed.


For people who do not adequately respond to dietary fiber, osmotic  laxatives  such as  polyethylene glycol ,  sorbitol , and  lactulose  can help avoid "cathartic colon" which has been associated with stimulant laxatives. [ 138 ]   Lubiprostone  is a gastrointestinal agent used for the treatment of constipation-predominant IBS. [ 139 ]


The use of  antispasmodic  drugs (e.g.,  anticholinergics  such as  hyoscyamine  or  dicyclomine ) may help people who have cramps or diarrhea. A meta-analysis by the  Cochrane Collaboration  concludes that one out of seven people benefit from treatment with antispasmodics. [ 136 ]  Antispasmodics can be divided into two groups: neurotropics and musculotropics. Musculotropics, such as  mebeverine , act directly at the smooth muscle of the gastrointestinal tract, relieving spasm without affecting normal gut motility. [ citation needed ]  Since this action is not mediated by the autonomic nervous system, the usual anticholinergic side effects are absent. [ 140 ]  The antispasmodic  otilonium  may also be useful. [ 141 ]


Proton-pump inhibitors  (PPIs) used to suppress stomach acid production may cause  small intestinal bacterial overgrowth  (SIBO) leading to IBS symptoms. [ 142 ]  Discontinuation of PPIs in selected individuals has been recommended as it may lead to an improvement or resolution of IBS symptoms. [ 143 ]


Evidence is conflicting about the benefit of  antidepressants  in IBS. Some meta-analyses have found a benefit, while others have not. [ 144 ]  There is good evidence that low doses of  tricyclic antidepressants  (TCAs) can be effective for IBS. [ 136 ] [ 145 ]  With TCAs, about one in three people improve. [ 146 ]


However, the evidence is less robust for the effectiveness of other antidepressant classes such as  selective serotonin reuptake inhibitor  antidepressants (SSRIs). Because of their serotonergic effect, SSRIs have been studied in IBS, especially for people who are constipation predominant. As of 2015, the evidence indicates that SSRIs do not help. [ 147 ]  Antidepressants are not effective for IBS in people with depression, possibly because lower doses of antidepressants than the doses used to treat depression are required for relief of IBS. [ 148 ]


Magnesium aluminum silicates  and  alverine citrate  drugs can be effective for IBS. [ 149 ] [ 132 ]


Rifaximin  may be useful as a treatment for IBS symptoms, including abdominal bloating and flatulence, although relief of  abdominal distension  is delayed. [ 3 ] [ 150 ]  It is especially useful where small intestinal bacterial overgrowth is involved. [ 3 ]


In individuals with IBS and low levels of  vitamin D , supplementation is recommended. Some evidence suggests that vitamin D supplementation may improve symptoms of IBS, but further research is needed before it can be recommended as a specific treatment for IBS. [ 55 ] [ 56 ]


There is inconsistent evidence from studies with poor methodological quality that psychological therapies can be effective in the treatment of IBS. [ 148 ]  Preliminary research shows that psychotherapeutic interventions are correlated with reductions in both  autonomic nervous system  dysregulation and gastrointestinal symptoms. [ 41 ]  Reducing stress may also reduce the frequency and severity of IBS symptoms. Techniques that may be helpful include regular exercise, such as swimming, walking, or running. [ 151 ]


Probiotics  can be beneficial in the treatment of IBS; taking 10 billion to 100 billion beneficial bacteria per day is recommended for beneficial results. However, further research is needed on individual strains of beneficial bacteria for more refined recommendations. [ 150 ] [ 152 ]  Probiotics have positive effects such as enhancing the  intestinal mucosal barrier , providing a physical barrier,  bacteriocin  production (resulting in reduced numbers of pathogenic and gas-producing bacteria), reducing intestinal permeability and bacterial translocation, and regulating the immune system both locally and systemically among other beneficial effects. [ 83 ]  Probiotics may also have positive effects on the  gut–brain axis  by their positive effects countering the effects of stress on gut immunity and gut function. [ 153 ]


A number of probiotics have been found to be effective, including  Lactobacillus plantarum , [ 83 ]  and  Bifidobacteria  infantis ; [ 154 ]  but one review found only  Bifidobacteria infantis  showed efficacy. [ 155 ]   B. infantis  may have effects beyond the gut via it causing a reduction of proinflammatory cytokine activity and elevation of blood  tryptophan  levels, which may cause an improvement in symptoms of depression. [ 156 ]  Some  yogurt  is made using probiotics that may help ease symptoms of IBS. [ 157 ]  A probiotic yeast called  Saccharomyces boulardii  has some evidence of effectiveness in the treatment of irritable bowel syndrome. [ 158 ]


Certain probiotics have different effects on certain symptoms of IBS. For example,  Bifidobacterium breve ,  B. longum,  and  Lactobacillus acidophilus  have been found to alleviate abdominal pain.  B. breve, B. infantis, L. casei , or  L. plantarum  species alleviated  distension  symptoms.  B. breve, B. infantis, L. casei, L. plantarum, B. longum, L. acidophilus, L. bulgaricus , and  Streptococcus salivarius  ssp.  thermophilus  have all been found to affect flatulence levels. Most clinical studies show probiotics do not improve straining, sense of incomplete evacuation, stool consistency, fecal urgency, or stool frequency, although a few clinical studies did find some benefit of probiotic therapy. The evidence is conflicting for whether probiotics improve overall quality of life scores. [ 159 ]


Probiotics may exert their beneficial effects on IBS symptoms via preserving the gut microbiota, normalisation of cytokine blood levels, improving the intestinal transit time, decreasing small intestine permeability, and by treating  small intestinal bacterial overgrowth  of fermenting bacteria. [ 159 ]  A  fecal transplant  does not appear useful as of 2019. [ 160 ]


Peppermint oil  appears useful. [ 161 ]  In a meta-analysis it was found to be superior to placebo for improvement of IBS symptoms, at least in the short term. [ 111 ]  An earlier meta-analysis suggested the results of peppermint oil were tentative as the number of people studied was small and blinding of those receiving treatment was unclear. [ 109 ]  Safety during pregnancy has not been established, however, and caution is required not to chew or break the  enteric coating ; otherwise,  gastroesophageal reflux  may occur as a result of  lower esophageal sphincter  relaxation. Occasionally, nausea and perianal burning occur as side effects. [ 130 ]   Iberogast , a multi-herbal extract, was found to be superior in efficacy to placebo. [ 162 ]   A comprehensive meta-analysis using twelve random trials resulted that the use of peppermint oil is an effective therapy for adults with irritable bowel syndrome. [ 163 ]


Research into  cannabinoids  as treatment for IBS is limited. GI propulsion, secretion, and inflammation in the gut are all modulated by the  ECS  (Endocannabinoid system), providing a rationale for cannabinoids as treatment candidates for IBS. [ 164 ]


Only limited evidence exists for the effectiveness of other herbal remedies for IBS. As with all herbs, it is wise to be aware of possible drug interactions and adverse effects. [ 130 ]


There are no benefits of  acupuncture  compared to placebo for IBS symptom severity or IBS-related quality of life. [ 165 ]


The prevalence of IBS varies by country and by age range examined. The bar graph at right shows the percentage of the population reporting symptoms of IBS in studies from various geographic regions (see table below for references). The following table contains a list of studies performed in different countries that measured the prevalence of IBS and IBS-like symptoms:


10.5% [ 169 ]


Wilson, 2004


In  Western countries , women are around two to three times more likely to be diagnosed with IBS and four to five times more likely to seek specialty care for it than men. [ 174 ]  However, women in East Asian countries are not more likely than men to have irritable bowel syndrome, and there are conflicting reports about the female predominance of the disease in Africa and other parts of Asia. [ 175 ]  People diagnosed with IBS are usually younger than 45 years old. [ 1 ]  Studies of females with IBS show symptom severity often fluctuates with the menstrual cycle, suggesting hormonal differences may play a role. [ 176 ]  Endorsement of gender-related traits has been associated with quality of life and psychological adjustment in IBS. [ 177 ]  The increase in gastrointestinal symptoms during menses or early menopause may be related to declining or low estrogen and progesterone, suggesting that estrogen withdrawal may play a role in IBS. [ 178 ]  Gender differences in healthcare-seeking may also play a role. [ 179 ]  Gender differences in trait anxiety may contribute to lower pain thresholds in women, putting them at greater risk for a number of chronic pain disorders. [ 180 ]  Finally, sexual trauma is a major risk factor for IBS, as are other forms of abuse. [ 181 ]  Because women are at higher risk of sexual abuse than men, sex-related risk of abuse may contribute to the higher rate of IBS in women. [ 182 ]


The concept of an "irritable bowel" was introduced by  P. W. Brown , first in  The Journal of the Kansas Medical Society  in 1947 [ 183 ]  and later in the  Rocky Mountain Medical Journal  in 1950. [ 184 ]   The term was used to categorize people who developed symptoms of diarrhea, abdominal pain, and constipation, but where no well-recognized infective cause could be found.  Early theories suggested the irritable bowel was caused by a psychosomatic or mental disorder. [ 185 ]


The aggregate cost of irritable bowel syndrome in the United States has been estimated at $1.7–10 billion in direct medical costs, with an additional $20 billion in indirect costs, for a total of $21.7–30 billion. [ 13 ]  A study by a managed care company comparing medical costs for people with IBS to non-IBS controls identified a 49% annual increase in medical costs associated with a diagnosis of IBS. [ 186 ]  People with IBS incurred average annual direct costs of $5,049 and $406 in out-of-pocket expenses in 2007. [ 187 ]  A study of workers with IBS found that they reported a 34.6% loss in productivity, corresponding to 13.8 hours lost per 40 hour week. [ 188 ]  A study of employer-related health costs from a Fortune 100 company conducted with data from the 1990s found people with IBS incurred US$4527 in claims costs vs. $3276 for controls. [ 189 ]  A study on Medicaid costs conducted in 2003 by the  University of Georgia College of Pharmacy  and  Novartis  found IBS was associated in an increase of $962 in Medicaid costs in California, and $2191 in North Carolina.  People with IBS had higher costs for physician visits, outpatients visits, and prescription drugs.  The study suggested the costs associated with IBS were comparable to those found for people with asthma. [ 190 ]


Individuals with IBS have been found to have decreased diversity and numbers of  Bacteroidota  microbiota. Preliminary research into the effectiveness of  fecal microbiota transplant  in the treatment of IBS has been very favourable with a 'cure' rate of between 36 percent and 60 percent with remission of core IBS symptoms persisting at 9 and 19 months follow up. [ 191 ] [ 192 ]  Treatment with probiotic strains of bacteria has shown to be effective, though not all strains of microorganisms confer the same benefit and adverse side effects have been documented in a minority of cases. [ 193 ]


There is increasing evidence for the effectiveness of  mesalazine  (5-aminosalicylic acid) in the treatment of IBS. [ 194 ]  Mesalazine is a drug with  anti-inflammatory  properties that has been reported to significantly reduce immune mediated inflammation in the gut of IBS affected individuals with mesalazine therapy resulting in improved IBS symptoms as well as feelings of general wellness in IBS affected people. It has also been observed that mesalazine therapy helps to normalise the gut flora which is often abnormal in people who have IBS. The therapeutic benefits of mesalazine may be the result of improvements to the  epithelial  barrier function. [ 195 ]  Treatment based on "abnormally" high IgG antibodies cannot be recommended. [ 196 ]


Differences in visceral sensitivity and intestinal physiology have been noted in IBS. Mucosal barrier reinforcement in response to oral 5-HTP was absent in IBS compared to controls. [ 197 ]  IBS/IBD individuals are less often  HLA  DQ2/8 positive than in upper functional gastrointestinal disease and healthy populations. [ 198 ]


Efficacy of mast cell directed therapies in irritable bowel syndrome is an area of ongoing research. [ 199 ]


A similar syndrome is found in rats ( Rattus  spp.). [ 200 ]  In rats a short-chain fatty acid receptor is involved, a  free fatty acid receptor 2  subtype –   GPR43   – that is expressed in both  enteroendocrine cells  and  mucosal mast cells . [ 200 ]  These cells then respond in an exaggerated way to the IBS rat's own large quantity of  maldigestion  products. [ 200 ]


Isosporiasis , also known as  cystoisosporiasis , is a human intestinal disease caused by the parasite  Cystoisospora belli  (previously known as  Isospora belli ). It is found worldwide, especially in tropical and subtropical areas. Infection often occurs in  immuno-compromised  individuals, notably  AIDS  patients, and outbreaks have been reported in institutionalized groups in the United States. The first documented case was in 1915. It is usually spread indirectly, normally through contaminated food or water (CDC.gov). [ 1 ]


Infection causes acute, non-bloody  diarrhea  with crampy abdominal pain, which can last for weeks and result in  malabsorption  and weight loss. In immunodepressed patients, and in infants and children, the diarrhea can be severe.  Eosinophilia  may be present (differently from other protozoan infections). [ 2 ]


The  coccidian  parasite  Cystoisospora belli  infects the  epithelial  cells of the small intestine, and is the least common of the three intestinal coccidia that infect humans ( Toxoplasma ,  Cryptosporidium , and  Cystoisospora ). [ citation needed ]