Giardiasis
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Giardiasis is a parasitic disease caused by Giardia duodenalis (also known as G. lamblia and G. intestinalis).<ref name="Esch2013">Template:Cite journal</ref> Infected individuals who experience symptoms (about 10% have no symptoms) may have diarrhea, abdominal pain, and weight loss.<ref name=BMJ2016/> Less common symptoms include vomiting and blood in the stool.<ref name=BMJ2016/> Symptoms usually begin one to three weeks after exposure and, without treatment, may last two to six weeks or longer.<ref name=CDCSymptoms/>
Giardiasis usually spreads when Giardia duodenalis cysts within faeces contaminate food or water that is later consumed orally.<ref name=BMJ2016/> The disease can also spread between people and through other animals.<ref name=BMJ2016/> Cysts may survive for nearly three months in cold water.<ref name=BMJ2016/> Giardiasis is diagnosed via stool tests.<ref name=BMJ2016/>
Prevention may be improved through proper hygiene practices.<ref name="BMJ2016" /> Asymptomatic cases often do not need treatment.<ref name="BMJ2016" /> When symptoms are present, treatment is typically provided with either tinidazole or metronidazole.<ref name=BMJ2016/> Infection may cause a person to become lactose intolerant, so it is recommended to temporarily avoid lactose following an infection.<ref name=BMJ2016/> Resistance to treatment may occur in some patients.<ref name=BMJ2016/>
Giardiasis occurs worldwide.<ref name=CDC_Giardiasis/> It is one of the most common parasitic human diseases.<ref name=Esch2013/> Infection rates are as high as 7% in the developed world and 30% in the developing world.<ref name=BMJ2016/> In 2013, there were approximately 280 million people worldwide with symptomatic cases of giardiasis.<ref name=Esch2013/> The World Health Organization classifies giardiasis as a neglected disease.<ref name=BMJ2016>Template:Cite journal</ref> It is popularly known as beaver fever<ref name=NYSDOH>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> in North America.
Signs and symptomsEdit
Symptoms vary from none to severe diarrhoea with poor absorption of nutrients.<ref name=CDC_Giardiasis/> The cause of this wide range in severity of symptoms is not fully known but the intestinal flora of the infected host may play a role.<ref name=Cot2011>Template:Cite journal</ref><ref name=":4">Template:Cite journal</ref> Diarrhoea is less likely to occur in people from developing countries.<ref name=Cot2011 />
Symptoms typically develop 9–15 days after exposure,<ref name="Barry2013" /> but may occur as early as one day.<ref name="CDC_Giardiasis">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The most common and prominent symptom is chronic diarrhoea, which can occur for weeks or months if untreated.<ref name=PD6>Template:Cite book</ref><ref name=Robertson2010>Template:Cite journal</ref> Diarrhoea is often greasy and foul-smelling, with a tendency to float.<ref name=PD6/><ref name=CDCSymptoms>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> This characteristic diarrhoea is often accompanied by several other symptoms, including gas, abdominal cramps, and nausea or vomiting.<ref name="PD6" /><ref name=CDCSymptoms/> Some people also experience symptoms outside of the gastrointestinal tract, such as itchy skin, hives, and swelling of the eyes and joints, although these are less common.<ref name=CDCSymptoms/> Fever occurs in only about 15% of infected people,<ref>Template:Cite book</ref> despite the nickname "beaver fever".<ref name=NYSDOH/>
Prolonged disease is often characterised by diarrhoea and malabsorption of nutrients in the intestine.<ref name=PD6/> This malabsorption causes fatty stools, substantial weight loss, and fatigue.<ref name=PD6/> Additionally, those with giardiasis often have difficulty absorbing lactose, vitamin A, folate, and vitamin B12.<ref name=Robertson2010/><ref name=CDCSymptoms/> In children, prolonged giardiasis can cause failure to thrive and may impair mental development.<ref name="PD6" /><ref name=Robertson2010/> Symptomatic infections are well recognised as causing lactose intolerance,<ref name="pmid2614615">Template:Cite journal</ref> which, though usually temporary, may become permanent.<ref name="pmid1174208">Template:Cite journal</ref><ref name="pmid3430245">Template:Cite journal</ref>
CauseEdit
Template:Multiple image Giardiasis is caused by the protozoan Giardia duodenalis.<ref name=Auer2012/> The infection occurs in many animals, including beavers, other rodents, cows, and sheep.<ref name=Auer2012/> Animals are believed to play a role in keeping infections present in an environment.<ref name=Auer2012/>
G. duodenalis has been sub-classified into eight genetic assemblages (designated A–H).<ref name="Heyworth2016" /> Genotyping of G. duodenalis isolated from various hosts has shown that assemblages A and B infect the largest range of host species, and appear to be the main and possibly only G. duodenalis assemblages that infect humans.<ref name="Heyworth2016">Template:Cite journal Template:Open access</ref><ref>Template:Cite journal</ref>
Risk factorsEdit
According to the United States Centers for Disease Control and Prevention (CDC), people at greatest risk of infection are:<ref name="cdc.gov">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
- People in childcare settings
- People who are in close contact with someone who has the disease
- Travellers within areas that have poor sanitation
- People who have contact with faeces, such as during sexual activity
- Backpackers or campers who drink untreated water from springs, lakes, or rivers
- Swimmers who swallow water from swimming pools, hot tubs, interactive fountains, or untreated recreational water from springs, lakes, or rivers
- People who get their household water from a shallow well
- People with weakened immune systems
- People who have contact with infected animals or animal environments contaminated with faeces
Factors that increase infection risk for people from developed countries include changing nappies/diapers, consuming raw food, owning a dog, and travelling in the developing world.<ref name=BMJ2016/> However, 75% of infections in the United Kingdom are acquired in the UK, not through travel elsewhere.<ref name=BMJ2016/> In the United States, giardiasis occurs more often in summer, which is believed to be due to a greater amount of time spent on outdoor activities and travelling in the wilderness.<ref name=Auer2012/>
TransmissionEdit
Giardiasis is transmitted via the faecal-oral route with the ingestion of cysts.<ref name="Barry2013">Template:Cite journal</ref> Primary routes are personal contact and contaminated water and food.<ref name="Barry2013"/> The cysts can stay infectious for up to three months in cold water.<ref name=Auer2012/>
Many people with Giardia infections have no or few symptoms.<ref name=Gard2001>Template:Cite journal</ref> They may, however, still spread the disease.<ref name=Gard2001/>
PathophysiologyEdit
The life cycle of Giardia consists of a cyst form and a trophozoite form.<ref name=":4" /> The cyst form is infectious and once it has found a host, transforms into the trophozoite form.<ref name=":4" /> This trophozoite attaches to the intestinal wall and replicates within the gut.<ref name=":4" /> As trophozoites continue along the gastrointestinal tract, they convert back to their cyst form which is then excreted with faeces.<ref name="BMJ2016" /> Ingestion of only a few of these cysts is needed to generate infection in another host.<ref name=":6" />
Infection with Giardia results in decreased expression of brush border enzymes, morphological changes to the microvillus, increased intestinal permeability, and programmed cell death of small intestinal epithelial cells.<ref name=":5">Template:Cite journal</ref> Both trophozoites and cysts are contained within the gastrointestinal tract and do not invade beyond it.<ref>Template:Cite journal</ref>
The attachment of trophozoites causes villous flattening and inhibition of enzymes that break down disaccharide sugars in the intestines.<ref name=Cot2011 /><ref name=":5" /> Ultimately, the community of microorganisms that lives in the intestine may overgrow and may be the cause of further symptoms, though this idea has not been fully investigated. The alteration of the villi leads to an inability of nutrient and water absorption from the intestine, resulting in diarrhoea, one of the predominant symptoms.<ref name=":5" /> In the case of asymptomatic giardiasis, there can be malabsorption with or without histological changes to the small intestine. The degree to which malabsorption occurs in symptomatic and asymptomatic cases is highly varied.Template:Citation needed
The species Giardia intestinalis uses enzymes that break down proteins to attack the villi of the brush border and appears to increase crypt cell proliferation and crypt length of crypt cells existing on the sides of the villi. On an immunological level, activated host T lymphocytes attack endothelial cells that have been injured to remove the cell.<ref name=Cot2011 /> This occurs after the disruption of proteins that connect brush border endothelial cells to one another.<ref name=":5" /> The result is increased intestinal permeability.<ref name=":5" />
There appears to be a further increase in programmed enterocyte cell death by Giardia intestinalis, which further damages the intestinal barrier and increases permeability.<ref name=":5" /> There is significant upregulation of the programmed cell death cascade by the parasite, and substantial downregulation of the anti-apoptotic protein Bcl-2 and upregulation of the proapoptotic protein Bax.<ref name=Cot2011 /> These connections suggest a role of caspase-dependent apoptosis in the pathogenesis of giardiasis.<ref name=Cot2011 />
Giardia protects its growth by reducing the formation of the gas nitric oxide by consuming all local arginine, which is the amino acid necessary to make nitric oxide.<ref name=Cot2011 /> Arginine starvation is known to be a cause of programmed cell death, and local removal is a strong apoptotic agent.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Host defenceEdit
Host defence against Giardia consists of natural barriers, production of nitric oxide, and activation of the innate and adaptive immune systems.Template:Citation needed
Natural barriersEdit
Natural barriers defend against the parasite entering the host's body. Natural barriers consist of mucus layers, bile salt, proteases, and lipases. Additionally, peristalsis and the renewal of enterocytes provide further protection against parasites.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
Nitric oxide productionEdit
Nitric oxide does not kill the parasite, but it inhibits the growth of trophozoites as well as excystation and encystation.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
Innate immune systemEdit
Lectin pathway of complementEdit
The lectin pathway of complement is activated by mannose-binding lectin (MBL) which binds to N-acetylglucosamine. N-acetylglucosamine is a ligand for MBL and is present on the surface of Giardia.<ref>Template:Cite journal</ref>
The classical pathway of complementEdit
The classical pathway of complement is activated by antibodies specific against Giardia.Template:Citation needed
Adaptive immune systemEdit
AntibodiesEdit
Antibodies inhibit parasite replication and also induce parasite death via the classical pathway of complement.Template:Citation needed
Infection with Giardia typically results in a strong antibody response against the parasite. While IgG is made in significant amounts, IgA is believed to be more important in parasite control. IgA is the most abundant isotype in intestinal secretions, and it is also the dominant isotype in a mother's milk. Antibodies in a mother's milk protect children against giardiasis (passive immunisation).<ref>Template:Cite journal</ref>
T-cellsEdit
The major aspect of adaptive immune responses is the T-cell response. Giardia is an extracellular pathogen. Therefore CD4+ helper T-cells are primarily responsible for this protective effect.<ref name=":10">Template:Cite journal</ref>
One role of helper T-cells is to promote antibody production and isotype switching. Other roles include cytokine production (Il-4, IL-9) to help recruit other effector cells of the immune response.<ref name=":10" /><ref>Template:Cite journal</ref>
DiagnosisEdit
- "This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0."</ref>
- According to the CDC, the detection of antigens on the surface of organisms in stool specimens is the current test of choice for diagnosis of giardiasis and provides increased sensitivity over more common microscopy techniques.<ref>{{#invoke:citation/CS1|citation
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- A trichrome stain of preserved stool is another method used to detect Giardia.<ref>{{#invoke:citation/CS1|citation
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- Microscopic examination of the stool can be performed for diagnosis.<ref name="BMJ2016" /> This method is not preferred, however, due to inconsistent shedding of trophozoites and cysts in infected hosts.<ref name="BMJ2016" /> Multiple samples over some time, typically one week, must be examined.<ref name="BMJ2016" />
- The Entero-Test uses a gelatin capsule with an attached thread. One end is attached to the inner aspect of the host's cheek, and the capsule is swallowed. Later, the thread is withdrawn and shaken in saline to release trophozoites which can be detected with a microscope. The sensitivity of this test is low, however, and is not routinely used for diagnosis.<ref>Template:Cite journal</ref>
- Immunologic enzyme-linked immunosorbent assay (ELISA) testing may be used for diagnosis.<ref name=":7" /> These tests are capable of a 90% detection rate or more.<ref name=":7">Template:Cite journal</ref>
Although hydrogen breath tests indicate poorer rates of carbohydrate absorption in those asymptomatically infected, such tests are not diagnostic of infection.<ref name="pmid12139217">Template:Cite journal</ref> Serological tests are not helpful in diagnosis.<ref name="BMJ2016" />
PreventionEdit
The CDC recommends hand-washing and avoiding potentially contaminated food and untreated water.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Boiling water contaminated with Giardia effectively kills infectious cysts.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }} Retrieved 24 February 2011</ref> Chemical disinfectants or filters may be used.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Iodine-based disinfectants are preferred over chlorination as the latter is ineffective at destroying cysts.<ref>Template:Citation</ref><ref>Template:Cite journal</ref>
Although the evidence linking the drinking of water in the North American wilderness and giardiasis has been questioned, a number of studies raise concern.<ref>Template:Cite journal</ref> Most if not all CDC verified backcountry giardiasis outbreaks have been attributed to water. Surveillance data (for 2013 and 2014) reports six outbreaks (96 cases) of waterborne giardiasis contracted from rivers, streams or springs<ref>Template:Cite journal</ref> and less than 1% of reported giardiasis cases are associated with outbreaks.<ref>Template:Cite journal</ref>
Person-to-person transmission accounts for the majority of Giardia infections and is usually associated with poor hygiene and sanitation. Giardia is often found on the surface of the ground, in the soil, in undercooked foods, and in water, and on hands that have not been properly cleaned after handling infected faeces.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Water-borne transmission is associated with the ingestion of contaminated water. In the U.S., outbreaks typically occur in small water systems using inadequately treated surface water. Venereal transmission happens through faecal-oral contamination. Additionally, nappy/diaper changing and inadequate handwashing are risk factors for transmission from infected children. Lastly, food-borne epidemics of Giardia have developed through the contamination of food by infected food-handlers.<ref name="pennardt_g">Template:EMedicine</ref>
VaccineEdit
There are no vaccines for humans yet, however, there are several vaccine candidates in development. They are targeting: recombinant proteins, DNA vaccines, variant-specific surface proteins (VSP), cyst wall proteins (CWP), giadins, and enzymes.<ref>Template:Cite journal</ref> Researchers at CONICET have produced an oral vaccine after engineering customised proteins mimicking those expressed on the surface of Giardia trophozoites. The vaccine has proven effective in mice.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
At present, one commercially available vaccine exists – GiardiaVax, made from G. lamblia whole trophozoite lysate. It is a vaccine for veterinary use only in dogs and cats. GiardiaVax should promote the production of specific antibodies.<ref>Template:Cite journal</ref>
TreatmentEdit
Treatment is not always necessary as the infection usually resolves on its own.<ref name=Cot2011 /> However, if the illness is acute or symptoms persist and medications are needed to treat it, a nitroimidazole medication is used such as metronidazole, tinidazole, secnidazole or ornidazole.<ref name="Barry2013"/>
The World Health Organisation and Infectious Disease Society of America recommend metronidazole as first-line therapy.<ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The US CDC lists metronidazole, tinidazole, and nitazoxanide as effective first-line therapies;<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> of these three, only nitazoxanide and tinidazole are approved for the treatment of giardiasis by the US FDA.<ref name="FDA Nitazoxanide">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> A meta-analysis published by the Cochrane Collaboration in 2012 found that compared to the standard of metronidazole, albendazole had equivalent efficacy while having fewer side effects, such as gastrointestinal or neurologic issues.<ref name=":0">Template:Cite journal</ref> Other meta-analyses have reached similar conclusions.<ref name="Solaymani 2010">Template:Cite journal</ref> Both medications need a five to ten-day-long course; albendazole is taken once a day, while metronidazole needs to be taken three times a day. The evidence for comparing metronidazole to other alternatives such as mebendazole, tinidazole, or nitazoxanide was felt to be of very low quality.<ref name=":0" /> While tinidazole has side effects and efficacy similar to those of metronidazole, it is administered with a single dose.<ref name="Gard2001" />
Resistance has been seen clinically to both nitroimidazoles and albendazole, but not nitazoxanide, though nitazoxanide resistance has been induced in research laboratories.<ref name=":6" /><ref name=":1">Template:Cite journal</ref> The exact mechanism of resistance to all of these medications is not well understood.<ref name=":1" /> In the case of nitroimidazole-resistant strains of Giardia, other drugs are available which have shown efficacy in treatment including quinacrine, nitazoxanide, bacitracin zinc, furazolidone and paromomycin.<ref name="Gard2001"/> Mepacrine may also be used for refractory cases.<ref name=":6" />
Probiotics, when given in combination with the standard treatment, have been shown to assist with clearance of Giardia.<ref>Template:Cite journal</ref>
During pregnancy, paromomycin is the preferred treatment drug because of its poor intestinal absorption, resulting in less exposure to the foetus.<ref>Template:Cite journal</ref> Alternatively, metronidazole can be used after the first trimester as there has been wide experience in its use for trichomonas in pregnancy.<ref name="Gard2001"/><ref>Template:Cite journal</ref>
PrognosisEdit
In people with a properly functioning immune system, infection may resolve without medication.<ref name=Cot2011 /> A small portion, however, develop a chronic infection.<ref name=Cot2011 /> People with an impaired immune system are at higher risk of chronic infection.<ref name=Cot2011 /> Medication is an effective cure for nearly all people although there is growing drug-resistance.<ref name="BMJ2016" /><ref name=":3">Template:Cite book</ref><ref name=":6">Template:Cite journal</ref>
Children with chronic giardiasis are at risk for failure to thrive as well as more long-lasting sequelae such as growth stunting.<ref>Template:Cite journal</ref> Up to half of infected people develop a temporary lactose intolerance leading to symptoms that may mimic a chronic infection.<ref name="BMJ2016" /> Some people experience post-infectious irritable bowel syndrome after the infection has cleared.<ref name=Cot2011 /> Giardiasis has also been implicated in the development of food allergies.<ref name=Cot2011 /> This is thought to be due to its effect on intestinal permeability.<ref name=Cot2011 />
EpidemiologyEdit
In some developing countries Giardia is present in 30% of the population.<ref name=Auer2012>Template:Cite book</ref> In the United States it is estimated that it is present in 3–7% of the population.<ref name=Auer2012/> Giardiasis is associated with impaired growth and development in children, particularly influencing a country's economic growth by affecting Disability Adjusted Life Year (DALY) rates.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
The number of reported cases in the United States in 2018 was 15,584.<ref name=":2">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> All states that classify giardiasis as a notifiable disease had cases of giardiasis.<ref name=":2" /> The states of Illinois, Kentucky, Mississippi, North Carolina, Oklahoma, Tennessee, Texas, and Vermont did not notify the Centers for Disease Control and Prevention regarding cases in 2018.<ref name=":2" /> There are seasonal trends associated with giardiasis.<ref>Template:Cite journal</ref> July, August, and September are the months with the highest incidence of giardiasis in the United States.<ref>Template:Cite journal</ref>
In the ECDC's (European Centre for Disease Prevention and Control) annual epidemiological report containing 2014 data, 17,278 confirmed giardiasis cases were reported by 23 of the 31 countries that are members of the EU/EEA.<ref name=":8" /> Germany reported the highest number at 4,011 cases.<ref name=":8" /> Following Germany, the UK reported 3,628 confirmed giardiasis cases. Together, this accounts for 44% of total reported cases.<ref name=":8">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
ResearchEdit
Some intestinal parasitic infections may play a role in irritable bowel syndrome<ref>Template:Cite journal</ref> and other long-term sequelae such as chronic fatigue.<ref>Template:Cite journal</ref><ref>Quote: "for unclear reasons, chronic sequelae, including post-infectious irritable bowel syndrome, chronic fatigue [..], malnutrition [..], cognitive impairment [..], and extra-intestinal manifestations (such as food allergy, urticaria, reactive arthritis, and inflammatory ocular manifestations), can develop and possibly persist beyond detectable parasite shedding". Quoted from: Template:Cite journal</ref> The mechanism of transformation from cyst to trophozoites has not been characterised<ref name=":4" /> but may help develop drug targets for treatment-resistant Giardia. The interaction between Giardia and host immunity, internal flora, and other pathogens is not well understood.<ref name=Cot2011 />In vitro cell cultures have been widely used to study host-parasite interactions, and human enteroids are now being used as non-transformed intestinal epithelial cell infection models for G. intestinalis and other pathogens.<ref>Template:Cite journal</ref>
The main congress about giardiasis is the "International Giardia and Cryptosporidium Conference" (IGCC). A summary of results presented at the most recent edition (2019, in Rouen, France) is available.<ref name="BuretCacciò2020">Template:Cite journal Template:Open access</ref>
Other animalsEdit
In both cats and dogs, giardiasis usually responds to metronidazole and fenbendazole. Metronidazole in pregnant cats can cause developmental malformations.<ref name=":9" /> Many cats dislike the taste of fenbendazole.<ref name=":9">Template:Cite book</ref> Giardiasis has been shown to decrease weight in livestock.<ref name=Cot2011 />