GIARDIASIS

GIARDIASIS

Current Diagnosis

• Giardiasis is the most common intestinal protozoan infection worldwide.

• Most cases result from exposure to contaminated drinking or recreational water.

• The clinical manifestations range from asymptomatic to chronic diarrhea with malabsorption and weight loss.

• The diagnosis can be established by stool microscopy or by immunoassays of fecal specimens.

• Occasionally, the trophozoites can be found in duodenal specimens when fecal assays are negative.

•   Serologic testing plays no role in the diagnosis.

• Irritable bowel symptoms are very common after successful treatment of giardiasis.

Current Therapy

• The treatment of choice is metronidazole (Flagyl)1  or tinidazole

(Tindamax); tinidazole can be given as a single dose.

• Albendazole (Albenza)1  and nitazoxanide (Alinia) are alternative agents.

• Paromomycin,1  a poorly absorbed aminoglycoside, is commonly recommended during early pregnancy when other agents are avoided.

• True drug resistance has not been documented, but refractory or recurrent cases can be treated by two drugs: a nitroimidazole combined with quinacrine (Atabrine)2  or albendazole.1

1  Not FDA approved for this indication.

2  Not available in the United States.

Background

Giardia lamblia (syn. Giardia intestinalis, Giardia duodenalis) was initially described by Leeuwenhoek in the seventeenth century while doing a microscopic examination of his own diarrheal feces. However, G. lamblia was not widely accepted as a human pathogen until the 1960s, when a number of outbreaks were reported in travelers to endemic areas. The presumed source of infection in these cases was contaminated drinking water. Subsequently, Giardia has become the most commonly identified parasitic cause of diarrhea, and along with Cryptosporidium species is among the most commonly identified parasitic causes of water-borne diarrheal disease.

Organism

Giardia species are members of the diplomonad (two bodies) group of flagellated protozoans. The life cycle consists of the environmentally resistant cyst, which infects its host upon ingestion. It is oval in shape, is about 8 microns × 12 microns in size and contains four nuclei. It excysts into pear-shaped trophozoites in the proximal small intestine that are about 10 to 12 microns by 5 × 7 microns in size. Two symmetrically placed nuclei are in the body of the trophozoites and four pairs of flagella aid with motility. A ventral concave disk uses primarily mechanical means to attach to the intestinal wall of the host. While still in the small intestine, some of the trophozoites then encyst into the cyst form, which is passed in the feces to continue the cycle of infection. The Giardia species are all parasitic and were initially assigned to species on the basis of host of origin. However, in 1952, they were divided into three species [Giardia agilis, amphibians; Giardia muris, rodents; G. duodenalis (G. lamblia), mammals and birds] that could easily be distinguished on the basis of morphologic appearance of the trophozoites. Subsequently, the G. lamblia morphologic group has been divided into additional species based on differences that can be seen at the ultrastructural or molecular level.

Of the organisms that remain assigned to G. lamblia, all are found in mammals, but are divided into eight genotypes or assemblages (A through H) on the basis of molecular differences with varying host specificities. Only Genotypes A and B have been found in humans. It is likely that at least some of these eight genotypes will eventually be assigned to separate species.

Epidemiology

Giardiasis is the most commonly diagnosed human protozoan infection and is one of the most commonly identified forms of gastroenteritis. The majority of cases occur from ingestion of contaminated water or by human-to-human transmission through the fecal–oral route. Thus, the epidemiology of human infections can be understood by examining these mechanisms of transmission. In the United States, the majority of cases are sporadic and occur more often in the summer, probably reflecting infection from recreational water exposure. Infections were more commonly reported in children from ages 1 to 9 years, especially those under 4 years of age. In general, the incidence is higher in the northern states, perhaps because cysts survive longer in cool, moist environments (Figures 1 and 2).

FIGURE 1    Incidence of giardiasis in the United States,  2010. Information is collected through the National Notifiable Diseases Surveillance System (NNDSS). Rates are per 100,000 population. (From Yoder JS, Gargano JW, Wallace RM, Beach MJ, Centers for Disease Control and Prevention. Giardiasis surveillance—United States, 2009–2010. Morb Mortal Wkly Rep Surveill Summ 2012;61:13–23.)†Not a reportable disease in these states.

FIGURE 2    Incidence of giardiasis in the United States (NNDSS).  A, Incidence by age group from 2009 and 2010. B, Incidence by month in 2010. Rates are per 100,000 population. (From Yoder, JS, Gargano, JW, Wallace, RM, Beach, MJ. Centers for Disease Control and Prevention. Giardiasis surveillance—United States, 2009–2010. Morb Mortal Wkly Rep Surveill Summ 2012;61:13–23.)

Direct human-to-human transmission by the fecal oral route also occurs, leading to the higher prevalence found in children in daycare centers. The occasional reports of food-borne transmission most likely occurred because of food being contaminated by infected food handlers.

The greater incidence in children could reflect an increased use of recreational water facilities, daycare exposure, or increased susceptibility to symptomatic disease. The epidemiology of giardiasis in the United States is similar to that found in other developed countries located in temperate regions. However, in developing regions with inadequate availability of purified water, the epidemiology is very different. For example, in a shantytown near Lima, Peru, children were almost universally infected by the age of 2 years, and when treated, they were rapidly reinfected, but there were no symptoms that could clearly be correlated with their infections.

Perhaps an outbreak at a ski resort town in the United States can explain these different epidemiologic patterns. In this water-borne outbreak, tourists were disproportionately affected despite drinking from the same water source as the local residents. The conclusion was that the local residents had repeatedly been exposed to water contaminated by Giardia cysts and were less susceptible to symptomatic disease.

The degree of zoonotic transmission of giardiasis remains controversial. Human acquisition of infection from dogs or cats has not been well documented, and usually the Giardia genotypes found in cats or dogs are distinct from those found in humans (A and B), even in regions where both are endemic. However, Genotypes A and B have sometimes been identified in dogs or other animals, so the question is not totally resolved. On the other hand, beavers have been implicated as a source of contaminated water leading to human infections.

Risk Factors

People with hypogammaglobulinemia, and possibly those with IgA deficiency, are at increased risk for prolonged giardiasis. In animal models, deficiency in cell mediated immunity (CMI) has been associated with increased risk, but in humans the increased risk has not been associated with defects in CMI.

Pathogenesis

Infection is initiated by the ingestion of as few as 10 cysts. After passage through the acidic environment of the stomach, each cyst excysts into two trophozoites in the proximal small intestine.

However, gastric acidity is not required, and people with achlorhydria or who are treated with suppressors of gastric acid remain vulnerable to giardiasis. The trophozoites replicate in the proximal small intestine, where they attach to the intestinal mucosa by their ventral disks. The attachment appears to occur by mechanical means facilitated by the suction generated by the ventral disk and the four pairs of flagella as they provide motility. Although the trophozoites attach to the intestinal wall and leave imprints after separating from the wall, there is no well-documented evidence of invasion, either of the intestinal wall or at extraintestinal sites. Toxins have not been identified as causes of diarrhea. Thus, the current evidence suggests that the symptoms result from the immune response to the trophozoite. The host–parasite interaction leads to enterocyte apoptosis, epithelial barrier disruption, and CD8 lymphocyte activation that leads to microvillous shortening, leading to the malabsorption that is a hallmark of the infection. The trophozoites are coated with a cysteine-rich protein encoded by one of a family of related genes, and expression can be switched from one to another, perhaps contributing to the chronicity of the infection.

Prevention

The strategies for prevention should be determined by the most prevalent risk factors in specific situations. For travelers to endemic regions, the major risk is from the ingestion of contaminated water. Therefore, drinking water should be purified by boiling for one minute or by filtration through a pore size of < 1 micron.

Halogenization with iodine or chlorine requires a prolonged contact time (hours) to inactivate cysts and is not recommended. In daycare centers and for food handlers, the best preventive measure is effective hand washing. In addition, children or workers who are infected should be treated.

Clinical Features

The majority of people with giardiasis are asymptomatic, but the percentages range from rates of diarrhea no higher than background among children in some highly endemic regions to attack rates of nearly 100% in visitors to endemic regions. Symptomatic patients typically present for evaluation only after several days or even weeks of illness because of the subacute onset. The symptoms of giardiasis typically develop after an incubation period of 1 to 2 weeks and consist of diarrhea that is characterized by loose, foul-smelling stools and abdominal discomfort described as cramping or bloating (Table 1). Fatigue is very common, but fever is unusual and when present, is mild and occurs only within the first few days. Malabsorption and weight loss are often present. The majority of cases resolve within several weeks, but occasionally the symptoms will last for months in the absence of treatment. Relapse is relatively uncommon after effective treatment.

Table 1

Symptoms of Giardiasis*

Symptom                                                                                                                                              Average (%)
Diarrhea 95
Abdominal cramps 70
Weakness or malaise 70
Nausea 60
Weight loss 50
Anorexia  (decreased appetite) 50
Abdominal  distention (bloating/distension) 50
Flatulence 50
Vomiting 30
Fever 20

From Hunter 2012; Giardiasis by R.  Adam.

* The table includes the approximate frequency of the signs and symptoms reported in six studies of symptomatic giardiasis, but it is important to note that there is substantial variability of symptoms among studies.

Diagnosis

The gold standard of diagnosis has been the microscopic evaluation of three separate fecal samples, including concentrated specimens for cysts or, less commonly, trophozoites. The identification of trophozoites is nearly always associated with symptomatic infection, but cysts may be found in asymptomatic persons. Because of the challenges in obtaining three fecal specimens and the interobserver variability in skill at identifying Giardia cysts, antigen detection tests have come into widespread use. The enzyme immunoassays are more commonly used and have high degrees of sensitivity and specificity.

A direct fluorescent assay is slightly more sensitive than the enzyme immunoassays and can also detect Cryptosporidium species, but it requires the availability of fluorescent microscopy. PCR tests have also been described, but are not widely available. Some patients have negative workups of stool samples, but Giardia trophozoites can be detected in duodenal contents with the string test. The patient swallows a capsule on a string, which is left in situ for four hours to overnight. The string is then removed and examined microscopically for trophozoites. Alternatively, endoscopy with sampling of duodenal contents and duodenal biopsy can be used. Endoscopy has the added advantage of being able to detect other possible diagnoses, such as celiac disease or tropical sprue.

Differential Diagnosis

The diagnosis of giardiasis should be suspected in patients presenting with prolonged (> 5–7 days) diarrhea without blood in the stools and no fever. In patients presenting relatively early in the course of illness, the major considerations in the differential diagnosis are other infectious etiologies of diarrhea, particularly Campylobacter jejuni, Salmonella, Cryptosporidium, and Cyclospora cayetanensis. Thus, patients presenting with compatible symptoms should have stool samples submitted for culture and for microscopic examination for ova and parasites (O and P). Watery diarrhea is uncommon, and bloody stools are not seen with giardiasis; thus, these findings should prompt the search for other etiologies.

For patients presenting with more prolonged symptoms, a number of noninfectious illnesses should be added to the differential diagnosis. Irritable bowel syndrome and lactose intolerance are among the more common etiologies and should be considered in patients presenting with diarrhea but no weight loss. Gluten enteropathy, tropical sprue, and, rarely, Whipple’s disease are among the noninfectious etiologies of diarrhea accompanied by weight loss.

Treatment

Patients with symptomatic giardiasis should be treated. The criteria for treatment of patients with asymptomatic giardiasis are not well defined, but in general, patients in regions with low prevalence or linked with outbreaks should be treated. On the other hand, in settings where the prevalence is high and recurrence rates are high, there is probably no value to treating asymptomatic infection.

The most commonly used agents for treatment of giardiasis are the nitroimidazoles. Metronidazole (Flagyl)1 and tinidazole (Tindamax) are available in the United States, and others, including secnidazole (Secnil)2 and ornidazole (Tiberal),2 are available in other countries (Table 2). These agents are completely absorbed from the gastrointestinal tract and are inactivated primarily by hepatic metabolism. Metronidazole has been available in the United States for decades and has generally been considered the drug of choice for treatment of giardiasis in most situations. More recently, tinidazole has become available and is the only agent available in the United States with a high degree of efficacy when given as a single dose.

Metronidazole is mutagenic in bacterial assays and showed some carcinogenic activity in an animal model. However, carcinogenicity in humans has not been documented. Serious adverse reactions to the nitroimidazoles are rare, but nausea and a metallic taste are common and may decrease the compliance of patients with metronidazole. The problem with noncompliance can be addressed by the use of tinidazole or the other agents that can be given as a single dose.

Table 2

Treatment of Giardiasis

*  The adult dose is the maximum pediatric dose.

†  Not approved by the FDA specifically for  giardiasis.

‡  Not available commercially in the United States, but available at a compounding   pharmacy.

Albendazole (Albenza)1 is a tubulin inhibitor that was introduced as a broad-spectrum antihelminthic, but it also has good activity against Giardia trophozoites. It is generally well tolerated and in areas with endemic helminth infections has the added advantage of antihelminthic activity.

The first trimester of pregnancy poses a special problem because none of the agents have been adequately studied or approved for use during this time. Paromomycin1 is a nonabsorbed aminoglycoside and is expected to be safe during pregnancy. Therefore, it is usually the preferred choice in that setting; however, it is somewhat less effective than other agents. Specialty consultation should be considered for treatment of patients in their first trimester. Metronidazole is used extensively during the second and third trimesters for other indications; thus, it can be considered the drug of choice for those patients. Albendazole is known to be teratogenic and should be avoided during pregnancy.

Nitazoxanide (Alinia) has been approved in the United States for treatment of giardiasis (and cryptosporidiosis) and is very well tolerated. However, the somewhat lower efficacy compared to nitroimidazoles and albendazole, along with the requirement for twice daily dosing, limits its role.

Quinacrine (Atabrine)2 was one of the first effective treatments for giardiasis, but has fallen into disfavor because of toxicity. Nausea and vomiting are common, and toxic psychosis is occasionally seen.

Treatment failures are not uncommon, but may or may not be due to true drug resistance since in vitro cultures are not routinely performed and in vitro testing is not standardized. When treatment failure occurs, the patient may respond to the same or an alternative drug. Treatment-refractory cases have been treated successfully with a combination of metronidazole1 plus quinacrine2 or albendazole.1 The most common reason for persistence of symptoms after treatment is due to post-giardiasis irritable bowel syndrome, which can occur in up to 25% of patients. Thus, it is important to re-evaluate stool specimens from patients with symptoms that persist after therapy.

Diet

Lactose intolerance is quite common while patients have giardiasis and potentially for months thereafter, so lactose ingestion should be moderated or eliminated as needed.

References

1.     Adam R.D. Biology of Giardia lamblia. Clin Microbiol Rev. 2001;14:447–475.

2.    Adam R.D. Giardiasis. In: Magill A.J., Ryan E.T., Hill D., Solomon T., eds. Hunter’s Tropical Medicine and Emerging Infectious Disease. Philadelphia: Elsevier; 2013:668–672.

3.     Cooper M.A., Sterling C.R., Gilman R.H., et al. Molecular analysis of household transmission of Giardia lamblia in a region of high endemicity in Peru. J Infect Dis. 2010;202:1713– 1721.

4.    Cotton J.A., Beatty J.K., Buret A.G. Host parasite interactions and pathophysiology in Giardia infections. Int J Parasitol. 2011;41:925–933.

5.     Hanevik K., Dizdar V., Langeland N., Hausken T. Development of functional gastrointestinal disorders after Giardia lamblia infection. BMC Gastroenterol. 2009;9:27.

6.      Lengerich E.J., Addiss D.G., Juranek D.D. Severe giardiasis in the United States. Clin Infect Dis. 1994;18:760–763.

7.    Morrison H.G., McArthur A.G., Gillin F.D., et al. Genomic minimalism in the early diverging intestinal parasite Giardia lamblia. Science. 2007;317:1921–1926.

8.    Nash T.E., Ohl C.A., Thomas E., et al. Treatment of patients with refractory giardiasis. Clin Infect Dis. 2001;33:22–28.

9.       Rossignol J.F. Cryptosporidium and Giardia: treatment options and prospects for new drugs. Exp Parasitol. 2010;124:45–53.

10.       Yoder J.S., Gargano J.W., Wallace R.M., Beach M.J.Centers for Disease Control and Prevention. Giardiasis surveillance— United States, 2009–2010. MMWR Surveill Summ. 2012;61:13– 23.

1  Not FDA approved for this  indication.

2  Not available in the United  States.

1  Not FDA approved for this  indication

2  Not available in the United States

1  Not FDA approved for this  indication

2  Not available in the United States

1  Not FDA approved for this  indication

KNOWLEDGE BASE
About Genomic Medicine UK

Genomic Medicine UK is the home of comprehensive genomic testing in London. Our consultant medical doctors work tirelessly to provide the highest standards of medical laboratory testing for personalised medical treatments, genomic risk assessments for common diseases and genomic risk assessment for cancers at an affordable cost for everybody. We use state-of-the-art modern technologies of next-generation sequencing and DNA chip microarray to provide all of our patients and partner doctors with a reliable, evidence-based, thorough and valuable medical service.

X