Infectious Diseases

Giardia (see Chronic Diarrhea)

OVERVIEW: What every clinician needs to know

Parasite name and classification

Giardia lamblia – flagellated intestinal protozoan parasite (also known as Giardia duodenalis or Giardia intestinalis)

What is the best treatment?

  • 5-nitroimidazole compounds (e.g., metronidazole, tinidazole, ornidazole, secnidazole) are the preferred anti-infective agents for the treatment of Giardia. Of these, metronidazole has been in wide use for more than 40 years in clinical practice and is still the most commonly used worldwide.

  • Oral metronidazole is rapidly absorbed and has a half-life in plasma less than 7 hours.

  • Clinical trials of metronidazole have employed a range of different dosing regimens, including twice and thrice daily dosing (usually 250mg/dose) for 5-10 days; short courses of 1-3 days, or daily single dose therapy.

  • In trials looking at patients treated for 5-10 days, cure rates between 60 and 100% have been reported in both adults and children, with a median efficacy of approximately 90%.

  • In the clinical trials looking at shorter courses or daily single dose therapy using metronidazole, there is a reduction in efficacy.

  • Side effects appear to be dose-related and are generally self-limited; they include metallic taste, nausea, headache, vertigo, and leukopenia. Hepatotoxicity is a rare side effect. Patients should be warned to refrain from ingesting alcohol when taking metronidazole.

  • Tinidazole is an alternative to metronidazole. Several studies have evaluated the effectiveness of a single dose of tinidazole, 2g in adults and 50mg/kg in children. The efficacy of single dose tinidazole ranges between 72 and 100%, with a median efficacy of about 89%.

  • A single dose of tinidazole is much better tolerated than a 7-10 day course of metronidazole. Since the efficacy of both regimens are similar, we recommend using tinidazole when available.

  • Current US treatment guidelines recommend as first line treatment either a 5-7 day course of metronidazole or a single dose of tinidazole or a 3-day course of nitazoxanide.

  • There are clinical failures with metronidazole. Additionally, there are reports of decreased in vitro susceptibility to metronidazole.

  • First line agents include:

    • Other 5-nitroimidazoles (e.g., Secnidazole, Ornidazole)

      • Ornidazole is an alternative to metronidazole or tinidazole. Several studies have demonstrated an efficacy of 90-100% after a single dose or 1 or 2g in adult patients.

      • Secnidazole is another alternative. Clinical trials employing a single dose have demonstrated an efficacy between 80 and 98%.

      • Both drugs are tolerated reasonably well, with reported side effects that include nausea, vomiting, and abdominal pain. Three cases of hepatitis with associated cholangitis have been reported with the use of ornidazole, all of which improved after discontinuation of the drug.

      • The availability of these agents is more limited than metronidazole or tinidazole.

    • Benzimidazoles

      • Two members of the benzimidazole class of drugs, albendazole and mebendazole, have been studied both in vitro and in vivo in the treatment of Giardia lamblia.

      • Albendazole and mebendazole have a wide spectrum of effectiveness against helminths and some protozoa. They are minimally absorbed from the intestine and are relatively well tolerated.

      • In vitro testing of these compounds in the 1990s suggested that they have in vitro activity against Giardia equal to or better than nitroimidazoles.

      • Cure rates in children with Giardia of 78-86% are seen with 3-5 day courses of mebendazole.

      • A study in Mexico demonstrated a similar efficacy with mebendazole (80.4%) as compared to nitazoxanide (78%) in the treatment of Giardia in children.

      • A trial comparing a 3-day course of mebendazole to a single dose of secnidazole in children in Cuba demonstrated cure rates of 78.1 and 79.4%, respectively. The difference was not statistically significant, and both treatment regimens were well tolerated.

      • A study of children with Giardia in Cuba demonstrated a 64% efficacy with a 1-day course of mebendazole versus an 82% efficacy with a single dose of tinidazole, suggesting that a single day of mebendazole is inferior to a single dose of tinidazole.

      • Albendazole has also been shown to be an effective alternative treatment for giardiasis, and is generally preferred over mebendazole because of more favorable pharmacokinetics.

      • Although divergent results have been shown in trials using anything from a single dose of albendazole to a 5-day course with cure rates between 35 and 96%, clinical trials using a 5-day course of albendazole have yielded cure rates of 78-90%. One trial demonstrated a similar efficacy with a 5-day course of albendazole (90.4%), as compared to a 7-day course of metronidazole (90.4%), suggesting that albendazole is a viable alternative to metronidazole in the treatment of Giardia in children.

      • A meta-analysis of the effectiveness of albendazole versus metronidazole found that albendazole, when given as a single dose of 400mg/day for 5 days, was equally as effective as metronidazole in the treatment of giardiasis.

      • Given the safety, effectiveness, and low cost of albendazole, as well as its broad spectrum of action against helminthes, this drug can be used as an alternative to metronidazole, especially in areas in which co-infection with Giardia and helminths frequently occur.

      • Side effects with benzimidazoles are uncommon but include nausea, vomiting, diarrhea, and epigastric pain.

      • Benzimidazoles may be particularly useful in areas in which infections with Giardia and soil-transmitted helminths frequently occur.

    • Nitazoxanide

      • Both in vitro and clinical studies have demonstrated the efficacy of nitazoxanide in the treatment of giardiasis. The 2010 “Drugs for Parasitic Infections” Treatment Guidelines, published in the Medical Letter, recommend a 3-day course of Nitazoxanide as one of the first-line treatment alternatives for giardiasis.

      • Nitazoxanide has been shown to be effective in children and adults with Giardia lamblia infection with an efficacy of 70-90%.

      • In one study, a 3-day course of nitazoxanide was shown to be as efficacious as metronidazole with cure rates of 85 and 80%, respectively. Nitazoxanide has also been reported to be effective in the treatment of Giardia in HIV patients with clinical failures with metronidazole and albendazole.

      • In a study of children in Cuba, a single dose of tinidazole was shown to have a significantly higher cure rate than that of a 3-day course of nitazoxanide (90.5% with tinidazole versus 78.4% with nitazoxanide).

      • Nitazoxanide is usually well tolerated with few side effects (reported side effects include abdominal pain, diarrhea, vomiting, and headache).

  • Alternative agents include

    • Quinacrine

      • Quinacrine is a drug shown to be effective against Giardia as early as 1937. Clinical efficacy has been reported as being as high as 90% in some studies that used a 5- to 10-day course.

      • Side effects include headache, nausea, vomiting, and a bitter taste. Other side effects reported are hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD)-deficiency, toxic psychosis, and exacerbation of psoriasis. It is contraindicated during pregnancy because of its possible link with spina bifida and renal agenesis. Its availability and clinical use in giardiasis is now relatively limited.

    • Furazolidone

      • Furazolidone has shown to be effective in vitro and in vivo and has been in use since the 1960s.

      • In clinical studies, furazolidone has been shown to be less effective than metronidazole and quinacrine. When used for 7-10 days, efficacy is up to 85%. Courses of less than 5 days have a substantially diminished efficacy.

      • Common side effects include nausea, vomiting, diarrhea, and hemolysis in patients with G6PD-deficiency.

      • Recommended dosing is 100mg PO qid for 7-10 days (6mg/kg/d for children).

    • Paramomycin

      • Paramomycin is a relatively broad spectrum aminoglycoside with activity against many protozoa, helminthes, and some bacteria.

      • Paramomycin is poorly absorbed, and, for that reason, it achieves high concentrations in the gut.

      • Clinically, the efficacy of paramomycin is regarded to be lower than other antigiardial compounds; cure rates of 55-91% have been reported.

      • The recommended dosing is 25-35mg/kg/d PO in 3 divided doses for 5-10 days.

  • For people who do not tolerate or do not respond to one agent, a different drug should be tried. In recalcitrant infections, combination of two different classes of agents may be successful (e.g., tinidizazole plus albendazole or tinidazole plus paromomycin or quinacrine plus metronidazole or nitazoxanide plus one of these agents). However, there are no robust data on comparative efficacies of the different combination choices, and evidence for their success is at the level of case reports/case series.

What are the clinical manifestations of infection with this organism?

  • Asymptomatic Infection

    • Asymptomatic giardiasis is a well-recognized entity, and studies looking at outbreaks of giardiasis have shown rates of asymptomatic infection as high as 76%. Asymptomatic cyst shedding can last 6 months or more, and asymptomatic cyst passers are potentially a source of infection for their household and also for the community. Treatment of asymptomatic individuals is an issue that remains controversial. In hyper-endemic areas, studies have shown high reinfection rates of up to 35% 3 months after treatment. The American Academy of Pediatrics does not recommend the treatment of asymptomatic children. However, in certain circumstances, particularly if intra-household reinfection is suspected, it may be reasonable to consider.

  • Acute giardiasis

    • Symptoms usually develop after an incubation period of 1-2 weeks and may last 2-4 weeks. Symptoms of acute giardiasis as reported in studies of Giardia outbreaks include:

      • Diarrhea (sudden in onset; initially may be watery; 70-100%)

      • Malaise (70-85%)

      • Nausea (70-75%)

      • Foul-smelling and fatty stools (steatorrhoea; 55-70%)

      • Flatulence (35-75%)

      • Abdominal discomfort, cramps, or pain (30-80%)

      • Weight loss (40-65%)

      • Bloating (40-45%)

      • Vomiting (15-30%)

      • Fever (10-20%)

  • Chronic infection

    • Chronic giardiasis may or may not have been preceded by an acute phase of illness. Although most chronic infections occur in patients with normal immunity, certain patient groups, including those with common variable immunodeficiency (CVID) and Bruton’s X-linked agammaglobulinemia (XLA), are more prone to chronic giardiasis. Surprisingly, symptoms of giardiasis in HIV-infected individuals appear to be similar to, and no more severe than, those of giardiasis in HIV-negative individuals, with asymptomatic infection occurring commonly in the presence of HIV.

    • Symptoms of chronic giardiasis may include:

      • Intermittent or periodic episodes of diarrhea

      • Steatorrhoea

      • Weight loss

      • Malabsorption

      • Malnutrition

      • Failure to thrive

      • Malaise

      • Fatigue

    • Even when the infection is asymptomatic, chronic giardiasis can lead to malabsorption of fats, sugars, carbohydrates, and vitamins, resulting in lactase deficiency and deficiencies of vitamin A, vitamin B12, and folate.

    • Acquired lactose intolerance is common after Giardia infection and occurs in up to 40% of patients; clinically, this manifests with exacerbation of intestinal symptoms following ingestion of dairy products.

    • Infection with Giardia lamblia in early childhood has been shown to be associated with poor cognitive function, failure to thrive, and stunted growth.

  • Physical findings are non-specific but may include:

    • Weight loss

    • Dehydration

    • Malnutrition

    • Stunted growth (children)

    • Failure to thrive (children)

    • Abdominal tenderness

Do other diseases mimic its manifestations?

Other diseases that mimic Giardia include:

  • Cryptosporidiosis (Cryptosporidium parvum infection)

  • Cyclosporiasis (Cyclospora cayetanensis infection)

  • Amoebiasis (Entamoeba histolytica infection)

  • Dientamoeba fragilis infection

  • Irritable bowel syndrome

  • Inflammatory bowel disease

  • Blastocystis hominis (pathogenic role is still somewhat controversial)

  • Coeliac disease

What laboratory studies should you order and what should you expect to find?

Results that confirm the diagnosis

  • Stool samples, tissue samples

  • Identification of cysts or trophozoites of Giardia lamblia by light microscopy on fresh and concentrated stool specimens is the diagnostic gold standard for detecting Giardia infection.

  • However, microscopy is labor intensive, time-consuming, and lacks sensitivity when single stools are examined. When three stool samples are examined using microscopy, sensitivity and specificity are very high (99 and 97%, respectively).

  • Giardia detection can be significantly improved with the use of a “Triple Faeces Test,” which combines multiple sampling (on 3 consecutive days), a fixative, a concentration method, and an easy-to-use permanent stain.

  • Microscopic examination of a small bowel biopsy or duodenal fluid aspirate can identify cysts or trophozoites of Giardia lamblia; however, this requires an invasive test (endoscopy).

  • Other samples, polymerase chain reaction (PCR), etc.

  • Progress has been made in the past 15 years in developing and validating non-morphologically-based diagnostic tests for Giardia antigens and parasite DNA. Commercial kits using enzyme-linked immunosorbent assays (ELISA), immunochromatographic assays, and direct immunofluorescence assays (DFA) are used routinely in many laboratories.

  • DFAs (or direct fluorescent-antibody) use fluorescein-labeled antibodies directed against cell wall antigens of Giardia cysts and allow visualization of intact parasites. These tests are reported to have a sensitivity of 96-100% and specificity of 99.8-100%.

  • ELISAs or enzyme immunoassays (EIA), which detect antigens of Giardia lamblia,have been reported to have a sensitivity of 88-100% and specificity of 97-100.

  • Antigen detection by immunochromatographic assay on stool specimens has a sensitivity that ranges from 58 and 100%, depending on the brand of test strip used and a specificity of 97-100%.

  • PCR-based methods have excellent specificity and sensitivity compared with antigen detection and an increased sensitivity compared with microscopy. However, this is not widely available as a diagnostic tool in clinical practice.

  • Many commercially available assays can detect both Giardia and Cryptosporidium.

  • Immunoassays are often done routinely to detect Giardia, but they should not replace microscopy, as there are many pathogens that can mimic Giardia that require microscopic examination

  • In humans, the clinical effects of Giardia infection range from the asymptomatic carrier state to a severe malabsorption syndrome.

  • Factors possibly contributing to the variation in clinical manifestations include the virulence of the Giardia strain, the number of cysts ingested, the age of the host, and the state of the host immune system at the time of infection.

  • The host-microbial interactions that govern the pathogenesis of Giardia infection are still incompletely understood, and symptoms can be present in the absence of any significant morphologic injury to the intestinal mucosa.

  • Studies using models in vivo and in vitro have demonstrated that Giardia lamblia causes malabsorption of glucose, sodium, and water, as well as reduced disaccharidase activity. Malabsorption and maldigestion are due to diffuse shortening of epithelial microvilli. Other mucosal changes include crypt hyperplasia and increased numbers of intraepithelial lymphocytes.

  • Enterocytic injury has been shown in murine (mouse) models to be mediated by activated host T lymphocytes. Loss of the intestinal brush border surface area, reduced disaccharidase activities, and increased crypt/villus ratios appear to be mediated by CD8+ T cells, whereas CD4+ and CD8+ cells appear to mediate the influx of intraepithelial lymphocytes.

What imaging studies will be helpful in making or excluding the diagnosis of Giardia?

  • Imaging does not assist in the diagnosis of giardiasis; however, it may help rule out other diseases, such as inflammatory bowel disease.

What common complications are associated with this infection,, and are there additional treatments that can help to alleviate these complications?

  • Giardiasis has been implicated in a variety of chronic disorders of the gastrointestinal (GI) tract, including food allergy, irritable bowel syndrome and inflammatory bowel disease. The mechanisms by which Giardia infection may initiate or exacerbate these conditions is not well understood.

  • Case reports of hypersensitivity phenomena, including maculopapular rash, pruritis, urticaria, uveitis, reactive arthritis, and apthous ulceration have been reported; however, these are rare.

  • Chronic giardiasis can lead to malabsorption of fats, sugars, carbohydrates, and vitamins, resulting in lactase deficiency and deficiencies of vitamin A, vitamin B12, and folate. Temporary lactose intolerance is common after Giardia infection.

  • Infection with Giardia lamblia in early childhood has been shown to be associated with poor cognitive function, failure to thrive, and stunted growth.

What is the life cycle of the parasite, and how does the life cycle explain infection in humans?

  • Parasite Life cycle (see Figure 1)

    • Giardia has two morphological forms, cysts and trophozoites, both of which can be found in the faeces of infected patients

    • The cyst is the infectious form and is relatively environmentally resistant – under favorable conditions of temperature and humidity, such as water at 4-10°C, the cysts may remain viable for several months.

    • Infection occurs by the ingestion of cysts in contaminated water, food, or by the faecal-oral route (via hands or fomites).

    • Ingestion of as few as 10 cysts can lead to giardiasis.

    • Following cyst ingestion, excystation, producing two trophozoites from each cyst, occurs in the proximal small bowel as a result of exposure to the acidic gastric pH and the pancreastic enzymes chymotrypsin and trypsin.

    • Trophozoites are pear-shaped, binucleate, multi-flagellated parasite forms that replicate in the crypts of the duodenum and upper jejunum and reproduce asexually by binary fission.

    • An adhesive disk on the ventral surface of the trophozoite facilitates attachment to the mucosal surface of the duodenum and jejunum.

    • When conditions are favorable, trophozoites can localize to other sites, such as the gallbladder, urinary tract, gastric mucosa, colonic and ileal mucosa, and pancreas.

    • Trophozoites that do not adhere to the small bowel transit toward the colon and undergo encystation in the ileum, possibly as a result of exposure to bile salts or from cholesterol starvation. They are eventually passed as cysts in faeces.

    • Cysts are the most common form of Giardia found in non-diarrheal faeces.

    • In the setting of diarrhea, trophozoites can also be found in the stool.

    • Giardia can be transmitted by ingestion of contaminated water or food, via the faecal-oral route (via fomites or person-to-person spread), via animal-to-person spread, or via oral or anal sexual contact.

    • A significant seasonal variation has been shown in a number of surveillance studies in Canada and the United States, with a peak of cases in summer and early autumn.

    • This seasonal variation may be confounded by the fact that this period coincides with increased outdoor activities in these countries, such as swimming in swimming pools, water parks, lakes, and rivers.

    • Environmental conditions that provide predisposition to Giardia include:

      • Contact with recreational fresh water

      • Poor sanitation

      • High intra-/peridomicillary concentration of domestic animals

      • Contact with animals

      • Day-care settings

  • Prevalence of Giardia Infection

    • Giardiasisoccurs worldwide and is especially common in areas in which there are poor sanitary conditions and insufficient water treatment facilities

    • Prevalence of Giardia lamblia in children in developing countries has been reported as 3-38%.

    • In developed countries, Giardia lamblia infects about 2% of adults and 6-8% of children and is responsible for frequent waterborne outbreaks of diarrhea.

    • Groups at higher risk of Giardia infect include infants and young children, especially those in child care settings; international adoptees; travelers to disease-endemic areas; those in close contacts of infected persons; persons who swallow contaminated recreational water; campers; backpackers; hunters; persons who have contact with infected animals; and men who have sex with men (MSM).

    • An Australian study showed that MSM were two to three times as likely to be infected with Giardia as the general population (1.5%), with rates higher in HIV-positive MSM (4.5%) compared to HIV-negative men (3%).

    • A study of Ecuadorian children showed that the most consistent predictor of Giardia risk was a high peri-domicillary concentration of domestic animals; living in such a household increased the Giardia infection risk two- to five-fold.

    • Surveillance data from the United States suggests that the incidence of giardiasis remains relatively stable. Limited surveillance data is available from the developing world.

    • Giardia has been included in the World Health Organization (WHO) Neglected Diseases Initiative since 2004. Part of this initiative has been the introduction of new guidelines for drinking water quality in the hopes of preventing waterborne transmission of this and other diseases.

  • Infection control issues

    • An anti-infective prophylaxis is not recommended.

    • There are no vaccines

    • Giardia cysts are relatively resistant to chlorination and to disinfection by ultraviolet light.

    • Boiling water is very effective for inactivating Giardia cysts.

    • Filtration with a pore size less than or equal to 2µm is very effective.

    • Cysts may survive freezing even after a few days.

    • Frequent hand-washing should be employed in areas with an increased risk of faecal-oral transmission, such as day-care centers.

    • Soiled diapers should be appropriately disposed of.

Figure 1.

Giardia life cycle (from CDC Website)

How does this organism cause disease?

  • Giardia is not invasive

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

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