Monday, November 28, 2011

Giardiasis


This week at Infection Landscapes, we continue our series on gut infections by considering a parasite: Giardia lamblia. This is the most significant parasitic cause of diarrhea in the world, and perhaps the third most important contributor to diarrheal disease overall.

The Pathogen. Giardia lamblia (also known as Giardia intestinalis) is a flagellated protozoan parasite. It can infect many different types of animals, including domestic livestock, rodents, household domestic animals like dogs and cats, as well as many sylvan mammals, fish, birds, reptiles and, of course, humans. The parasite has two main forms during the course of its life cycle: the cyst, which is the dormant, yet infectious, stage:



and the trophozoite, which is the motile, feeding, albeit non-infectious, form that inhabits the gut of its host:



The trophozoite targets the villi of the epithelial cells of the small intestine, directly adhering to the epithelium. The parasites attach to the surface of the villi but do not penetrate the cells. During infections with large numbers of organisms, this attachment pattern results in the fusion and flattening of the microvilli, which subsequently results in malabsorption.

The overall life cycle is nicely depicted in this graph by the Centers for Disease Control and Prevention:


As well as in this graph by Mariana Ruiz Villarreal:




Infection is initiated when the cysts are ingested and subsequently excyst in response to environmental stimuli within the host gut tract. The low pH of the stomach is one such important cue. From each quadranucleate cyst, two binucleate trophozoites will emerge during the process of excystation. These trophozoites are morphologically specialized with a concave ventral surface and a ventral disc-shaped organelle to adhere to the epithelial surface of the small intestine. Once emerged, the trophozoites replicate by binary fission. Because an adaptive immune response in the host follows and will eventually clear the parasite, the trophozoites must transform into cysts (encystation) and exit the host in order to survive. These cysts can survive free-living in the environment for long periods of time as long as they do not dry out or freeze. The encysted parasites are also resistant to moderate levels of chlorination. These cysts are highly infectious, demonstrating an infectious dose of only a couple dozen organisms. Given that tens of thousands of cysts are typically present per liter of untreated sewage in the US, and hundreds of thousands to millions of cysts can be present in untreated sewage in the developing world, the importance of good sanitation and water infrastructure for blocking infection is obvious.


The Disease. Up to 50% of infections are asymptomatic. Among those that do experience clinical disease the most common manifestation is diarrhea, with some distinction from that which has been covered in other gut infections at Infection Landscapes. As described above, the adherence of the parasite to the villi of the epithelium disrupts nutrient absorption in the gut. One of the nutrients drastically affected is fat. During active infection fats are not taken up appropriately by the host and are instead digested in part by the natural gut flora of the colon. The excess of fats combined with the excited metabolic state of the gut bacteria and their subsequent metabolic biproducts results in an extraordinarily foul smelling and greasy steatorrhea (high fat content in the stool), in addition to the typical watery diarrhea associated with most of the common gut pathogens. Bloating and excess flatulence are quite common. Frank dysentery can present in clinically apparent giardiasis, but this is rare. With large volume diarrhea, dehydration can also present in acute infections so fluid loss must be monitored. Abdominal pain and fatigue are also common, and weight loss can accompany both acute and chronic infections. Weight loss can be particularly important since it is observed in up to half of the cases. Vomiting can occur in some cases, though this is less common. While diarrhea and steatorrhea are generally transient, repeated or chronic infections with G. lamblia can cause important disruption in growth and development in children because of the malabsorption induced by the parasites in the small intestine. While not typically a killer, because of its high prevalence in children in the developing world, it certainly can be considered a neglected infectious disease and, therefore, an important impediment to children's ability to thrive in geographic regions of poverty.   


The Epidemiology and the Landscape. As described above the infectious stage of the parasite is the cyst. These cysts are transmitted fecal-orally, with waterborne transmission probably the most important route followed closely by foodborne transmission. In addition, direct person to person transmission may also constitute a significant route of transmission, though not as substantial at the population level as the common vehicles of water and food.


The occurrence of giardiasis is quite different between the developing and developed worlds so we will consider these separately as two distinct geographies.


In the developing world, community-based surveys show that greater than 10% of all diarrhea episodes in children may be due to G. lamblia, and approximately one quarter of the people in this part of the world are infected at any given time. In this setting, infection with G. lamblia is associated with the classic risk profile for gut infections in general, i.e. poor sanitation and water infrastructure. These structural deficiencies are the primary reason for the widespread infection with this parasite in resource poor areas. And, while high child mortality doesn't typically attend this infection (unless one is immunocompromised, which is not uncommon in measles-endemic areas), this infection is attended by a fairly high degree of childhood developmental delay due to the extended malabsorption in repeated or chronic disease. So the social cost, while comprising less death, is still high in the developing world. We do not have good country-specific estimates of giardiasis for the whole world. However, based on a wide geographic spectrum of community-based studies and some national surveillance programs, we do know that giardiasis infection is very similar in global distribution to diarrheal disease in general. Moreover, the substantive burden of diarrheal disease as measured by the disability-adjusted life years (DALY) can be applied to giardiasis. The World Health Organization map below depicts the diarrhea-associated global distribution of  DALYs. While the specific numbers do not reflect the DALYs directly attributable to giardiasis, they are proportional and therefore the disparities in the map reflect very similar disparities in giardiasis occurrence and its associated morbidity: 



Age-standardised disability-adjusted life year (DALY) rates from diarrheal diseases by country (per 100,000 inhabitants).
   no data
   less than 500
   500-1000
   1000-1500
   1500-2000
   2000-2500
   2500-3000
   3000-3500
   3500-4000
   4000-4500
   4500-5000
   5000-6000
   more than 6000


In the developed world, the landscape of infection is distinctly different because of the presence of better sanitation and water infrastructure. Rather than the general population of children being at high risk as is the case in the developing world, in the developed world those at greatest risk are specific subgroups that constitute either 1) potentially high transmission networks due to specific behavior and social contacts, such as settings that aggregate small children (e.g., daycare centers) and 2) rural communities whose water sources draw from small surface water with hydrogeographic features that are easily contaminated by either domesticated livestock or sylvan animal reservoirs. Periods of heavy rain can be particularly important in contamination as runoff carries fecal matter into these water sources as it drains the landscape. In addition, individuals who spend significant time in the outdoors due to occupation or recreation may also be at increased risk because of contact with potentially infected water sources. However, while this is often purported, there is very little evidence to support such risk in general, and may be limited to specific bodies of water or to very specific animal-human-water vehicle transmission nidi, for example areas proximal to beaver habitat.


Control and PreventionControl and prevention of giardiasis begins by following the usual guidelines: improving sanitation in resource poor areas and maintaining vigilance in personal hygiene. In most settings in the world where giardiasis is a significant contributor to diarrheal illness, improved infrastructure that can maintain adequate water resources is a first priority in its prevention.








Secondarily, personal hygiene at the individual level, especially in the context of food preparation, can also be very important in preventing the spread of giardiasis: consistent hand washing, boiling water, and thoroughly cooking food are all important in stopping the chain of transmission. Most importantly, since giardiasis is probably the biggest parasitic contributor to global diarrhea overall, and an important contributor to malnutrition, the implementation of these strategies would be an important component to eliminating the global burden of diarrhea as well as delayed development in young children in much of the world. 

23 comments:

  1. This blog is a great source of information which is very useful for me. Thank you very much.

    BEST SOLUTION ON BLOATING.

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  2. I have had direct experience with Giardia as my puppy had this disease when he first started going for walks outside. Our vet told us that, in a place with as dense of a dog-population as Manhattan, basically all of the dogs will get this disease when they are young. However, our vet explicitly told us that this was a "puppy thing" and that once the dog had Giardia once, or at most twice, it would not happen again. In light of what the vet had said, I was surprised to learn that children can get repeated infections, affecting their development. I did some research on reinfection specifically in dogs and found very conflicting information. Therefore, I was wondering, what is the immunogenicity of Giardia? This article seems to imply that healthy adults are less affected, but this could represent immunogenicity or improved hygiene.
    I have also noticed that dog owners are not always as diligent as they should be about cleaning up after their dog, increasing the potential for spread of disease to humans. I was wondering if the human incidence of Giardia coincides with density of the surrounding dog population or with extent of dog contact.

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    1. Thank you for your entry! I couldn't pinpoint where I had heard about this parasite until I read your post. Now, I remember that I've heard about this from a vet because I have a dog and it just occurred to me that this parasite that infects dogs is the same as the one that infects humans! I wonder if the reinfection doesn't have to do with building immunogenicity after infection but with just having better immunity as people (and dogs) get older. Since dogs become "adults" way faster at around 1 year, their immune systems are just better developed versus the long period for humans. Kind of like how we just learned in class about influenza causing GI problems in children but not adults.

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  3. G. lamblia cysts can actually survive for about 2 months in the environment, so this long timeframe obviously poses a problem for transmission control (see Cowan, Talaro - Microbiology, A Systems Approach). I think that this long survival time is actually rare for such pathogenic flagellates as G. lamblia. Thus, this particular characteristic of G. lamblia marks it as a unique parasite. As indicated above, the issue is exasperated by the low dose required for infection. Thus, only a few robust organisms are necessary for transmission. Although hygenic measures are obviously important for the control of this parasite, I wonder about the status of research regarding a human vaccine (unless one is out already - I know that vaccines do exist for certain animals). Maybe it is the case hygenic measures would be far more effective in the long run so that such vaccine research is not even necessary (at least at this point)?

    Interestingly, I just read that G. lamblia was first observed by van Leeuwenhoek in his own feces (again, see Cowan, Talaro - Microbiology, A Systems Approach). I love these reminders that nascent science relied on bold practitioners for success.

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    1. It is interesting to see how a disease is manifested differently based on what part of the world it is located in. It is great that a contrast was made between Giardiasis in the developed and developing world.

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  4. CAN G.LAMBLIA BE RELATED TO HIV/AIDS?

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    1. I don't think Giardia lamblia is related to HIV/AIDs; However, in these individuals with compromised immune systems, an infection with Giardia would be more severe leading to increased probability of inpatient hospitalization management.

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  5. I don't think Giardia lamblia is related to HIV/AIDs; However, in these individuals with compromised immune systems, an infection with Giardia would be more severe leading to increased probability of inpatient hospitalization management.

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  6. In addition to symptoms (diarrhea and foul smelling greasy steatorrhea), diagnosis is made by laboratory testing. This includes the collection of stool specimens (usually three different specimens) which are stained and observed under microscope. Immunoassays are also being used an encouraged, as it gives more sensitivity and specificity. According to the CDC, only molecular testing, such as polymerase chain reaction are used in the identification of Giardia subtypes. (http://www.cdc.gov/parasites/giardia/diagnosis.html)
    One point that I would like to note is that, normally parasitic infections would cause an increase in eosinophils in the blood stream. However, since Giardia does not invade the immune system, but rather adhere to epithelial surface of the small intestines, eosinophils would not be elevated. I am not saying that there would never be eosinophilia, but it is uncommon. There have been rare documented cases of eosinophilia in Giardia lamblia infections.

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    1. This is a great point to make! I never took the time to realize that it is a gut infection that stays completely in the gut rather than using the gut as just as entrance and growth zone. Do you think it is better that it is localized primarily to the gut?

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  7. This is such an intriguing gut infection. I really enjoyed reading about an ailment I haven't even heard of. It was really interesting to see the trophozoites are non infectious, while the cyst version is. It is also amazing that the active yet non infectious form can encyst back into the cyst infectious form. I would like to find more about similar infections.

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  9. This post further proves the importance of proper sanitation, adequate water supplies, and effective preventative measures in avoiding these gut infections. I found that the consumption of tainted water seems to the common denominator among many of the cases - in both the developed and developing countries. Why aren't there more initiatives to create facilities that provide clean water to the people being affected around the world (more so in developing countries)? One facility could go a long way in preventing death and disability due to the diarrheal infections (among others) around the world.

    Secondly, I found it very interesting that 50% of infections are sub-clinical. As such, people need to be more cautious and focus more on prevention rather than treatment.

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    1. Like you have noted, Richard, many of these gut infections seem to arise from insufficient water sanitation measures. And with the sub-clinical rate of 50% for giardiasis, prevention of further infection spread becomes even more important since asymptomatic individuals will not be treated. I agree that there needs to be more effort and resources put into many geographic regions throughout the developing world, but I also think instituting interventions to ensure water boiling and other such behaviors is necessary. For one, it was noted in this post that the cyst stage of giardiasis can live for weeks to months in cool water, so I assume that boiling water may kill the parasite. Secondly, only some dozen organisms are needed for infection, and many more organisms are usually found in water sources throughout the developing world. So while sanitation facilities are essential, I believe it would take many facilities within some communities and significant time before we would see the kind of major declines in rates of giardiasis that we would hope to see.

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  10. I typically think of giardia as the "refrigerator infection" because it can survive at cold temperatures for months. Worldwide, this aspect of the organism's virulence is less important because the fact that it can survive in cold temperatures is usually irrelevant in the endemic areas. It's interesting that for many infections, its "most virulent features" depend on the location where the pathogen is infecting people. For example, giardia's virulence is largely due to its ability to grow in refrigerators in the US, but its virulence is mainly due to its ability to thrive in water and infect at very low dose in Angola. This is an interesting concept to keep in mind in the study of infectious disease epidemiology in general.

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  11. I became very intrigued when the post said, "During infections with large numbers of organisms, this attachment pattern results in the fusion and flattening of the microvilli, which subsequently results in malabsorption." This mechanism is very reminiscent of the mechanism of malabsorption in celiac disease, and I started to wonder if there was any connection between celiac disease and Giardia: perhaps presence of celiac disease offers protection against Giardia because the villi are already flattened, or maybe celiac disease masks Giardia since the symptoms would be there already anyway. I actually found research dating back to 1973 related to this exact topic (found at the link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1648438/) that found that Giardia was found more commonly in patients with less severe villous atrophy due to celiac disease. A more recent study (http://www.ncbi.nlm.nih.gov/pubmed/15233673) suggests that villous atrophy needs to be supplemented with stool sample analysis or Ig markers to make the diagnosis. There is even a case report from 2012 (http://www.ncbi.nlm.nih.gov/pubmed/22617359) in which a patient was diagnosed with celiac disease and Giardia simultaneously but the symptoms resolved following treatment of the Giardia. In the end, I guess my point is that it's interesting to see how similar these mechanisms of disease are, and what this means in a clinical (and public health) context.

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    1. This is a very interesting point, Ben. Giardia is typically known to be a diarrheal disease, however, I did not realize until this article what a huge contributor it is to global malnutrition. All of this is due to, as you mentioned, the interaction of the parasite with the microvilli. It is important for clinicians to keep an open mind to infectious diseases when looking at seeming non-infectious symptoms. Is it an issue with the nervous system or is it Lyme disease? Is it anorexia or a parasitic worm? Is it celiac disease or is it Giardia? Just important questions to consider when diagnosing patients.

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  12. Once again, we have identified another infection more common in overcrowded developing countries that lack sanitary conditions and water quality control. Considering that the cysts from the infectious stage of the parasite can survive free-living in the environment for long periods of time, handling food with poor hygiene or eating produce rinsed in contaminated water can allow the parasite to spread. It was interesting to see that contracting giardiasis from food is not as common since heat kills the parasites. Surprisingly enough, this infection is not only transmitted fecal-orally but also person to person through sexual contact. The Planned Parenthood Advocates of Arizona shared that intestinal parasites like giardiasis can be transmitted through manual or oral contact with the anus.

    Reference:
    http://advocatesaz.org/2012/07/05/sti-awareness-have-you-heard-of-these-10-sexually-transmitted-infections/

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    1. Interesting points! As the most important route of transmission is likely waterborne I would be interested to know if any control efforts have been made to alleviate this mode of transmission in developing countries. Obviously, the best and most equitable prevention method would be restructuring of poor water infrastructure. But if that is not feasible (for economic reasons) it seems like a countrywide water-boil control measure would be at least somewhat beneficial. According to the CDC, both boiling water (rolling boil for 1 minute) and filtration (using a <1 micron filter specific for cyst removal) are both highly effective methods to remove Giardias. Further, disinfection with chlorine dioxide also has a high effectiveness. Thus some sort of prevention measure seems feasible.

      I agree that it is surprising that Giardias can be transmitted via specific types of sexual contact but the same oral-fecal route seems to apply. Similarly, other parasitic infections, such as amebiasis, can be transmitted in the same manner.

      Reference:
      http://www.cdc.gov/healthywater/drinking/travel/backcountry_water_treatment.html

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  13. If this is the main contributor to diarrheal illnesses in the entire world and it can cause developmental delays in children, I would expect there to be more efforts to prevent it. A quarter of people in a specific region being infected at any given time is a lot of sick people. Why is fat the main nutrient that is affected? If they were covering the microvilla, I would think that other nutrients would also have a hard time being absorbed. As I read the sentence about fat absorption, I automatically thought about diet pills. During a seminar about nutrition, health, obesity, etc., the topic of diet pills came out. And apparently one of the few diet pills that works really well blocked fat absorption in the gut, but wasn't popular because of greasy stools. I wonder if the people who created the diet pill thought about blocking fat absorption because of this parasite...

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    1. It's not the main contributor to diarrhea, it's the main parasitic contributor. Still relatively small contribution compared to bacterial and viral sources.

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  15. It is surprising to learn that the cyst form of Giardia can survive weeks to months in cold water but yet the cysts are also vulnerable to freezing. Are the cyst form capable of surviving in warm water as well?

    Because the infection is cleared by the adaptive immune response, I wonder how often doctors still prescribe antiprotozoal medications to assist in the process? Further, would the use of these antibiotics and antiprotozoals for infections such as Giardia contribute to antibiotic resistant pathogens?

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