Mitra Ranjbar M.D. Associate Professor of Medicine Giardiasis Mitra Ranjbar M.D. Associate Professor of Medicine

Giardia lamblia (also known as G. duodenalis or G Giardia lamblia (also known as G. duodenalis or G. intestinalis) is a flagellated protozoan parasite which is one of the two most common gastrointestinal parasites in the world.

G. lamblia causes both epidemic and sporadic disease and is an important etiology of water-borne and food-borne diarrhea, day-care center outbreaks, and diarrhea in international travelers.

There are different strains of G There are different strains of G. lamblia and antigenic variations within single isolates, but the significance of this heterogeneity for pathogenicity and the development of immunity is unclear.

LIFE CYCLE AND PATHOGENESIS G. lamblia exists in two morphological forms: cysts and trophozoites. Cysts are the infectious form of the parasite which can survive for prolonged periods in the environment, if kept moist.

After ingestion, excystation occurs in the upper small bowel to release trophozoites, pear-shaped, binucleate, multi flagellated organisms that measure 9 to 15 µm long, 5 to 15 µm wide, and 2 to 4 µm thick.

Trophozoites are the replicating form of the parasite, dividing by binary fission. Trophozoites possess an adhesive disk on the ventral surface for attachment to the mucosal surface of the duodenum and jejunum.

This form establishes residence in the proximal small bowel but does not invade or cause necrosis of the mucosal epithelium. For the organism to persist in the infectious form, trophozoites must revert to cysts, which occurs in the large intestine.

The pathogenesis of the diarrhea and malabsorption that can occur in giardiasis is incompletely understood since Giardia are not invasive organisms. The major structural and functional abnormalities associated with giardiasis are found in the small intestine.

Human infection may be associated with a spectrum of light microscopic changes that range from no abnormalities, to mild or moderate partial villous atrophy, to subtotal villous atrophy in severe cases. An increase in crypt depth may also be seen.

Even in the absence of changes in villous and crypt architecture, shortening and disruption of microvilli may occur. In addition to these microscopic changes, deficiencies in epithelial brush border enzymes (eg, lactase) can develop. These alterations in epithelial structure and function probably play a role in pathogenesis.

New cysts are passed back into the environment in feces New cysts are passed back into the environment in feces. When patients have diarrhea, trophozoites can also be found in the stool.

EPIDEMIOLOGY G. lamblia is found worldwide. It is especially common in areas where there are poor sanitary conditions and insufficient water treatment facilities.

In symptomatic individuals in the developing world, the prevalence of Giardia has been reported to be as high as 20 to 30 percent . High risk groups include infants, young children, travelers and the immunocompromised.

Intestinal protozoa account for only one to three percent of acute traveler's diarrhea but for up to 30 percent of cases of chronic diarrhea.

Giardiasis is a frequent infectious cause of traveler's diarrhea lasting more than two weeks. Attack rates are particularly high after travel to parts of the former Soviet Union, notably St. Petersburg, which reportedly has had hyperendemic levels of giardiasis over the last few decades.

Giardia infects animals including dogs, cattle, and sheep Giardia infects animals including dogs, cattle, and sheep. The role these animals play in acting as a reservoir for human disease is unclear since molecular typing of various isolates indicates that many animal parasites are not infectious in humans.

Infection derives from fecally excreted cysts, which are immediately infectious when passed, unlike the oocysts of Cyclospora. Ingestion of as few as 10 to 25 cysts can lead to giardiasis. Hypochlorhydria predisposes to infection; thus, previous gastric surgery or reduced gastric acidity are risk factors for the acquisition of giardiasis.

Routes of transmission Three patterns of potential transmission of giardiasis are recognized : Person-to-person Food-borne Waterborne

  Person-to-person transmission — Person-to-person transmission accounts for the heightened prevalence of giardiasis in several settings.

Giardiasis can be endemic in institutions where there is fecal incontinence and poor hygiene and can be an important source of intestinal infections in child care centers

The risk of acquisition and transmission is greatest for young children who are not yet toilet trained; such children can also serve as a source for secondary cases within their families.

Person-to-person transmission is also responsible for the prevalence of giardiasis among male homosexuals. Anal intercourse was associated with an increased risk for the acquisition of Giardia in a study of 100 patients infected with the human immunodeficiency virus (HIV); this practice allows for the direct transfer of infectious cysts.

Food-borne transmission — Cysts are killed by cooking  Food-borne transmission — Cysts are killed by cooking. Thus, food-borne spread occurs uncommonly and only when cysts contaminate food that is uncooked or after it has been cooked.

Waterborne transmission — Water is a major source for the endemic or epidemic spread of giardiasis. Deep well water is usually safe because filtration of water through soil removes Giardia cysts.

In contrast, surface water, including mountain streams and municipal reservoirs, can harbor Giardia cysts, which are hardy in cold water and resistant to routine levels of chlorination.

In addition, water-dwelling mammals, such as beavers, can become infected and may serve as continuing sources of water contamination.

It may be difficult to recognize a water supply as the common source of giardiasis because many who become infected are asymptomatic or have few symptoms.

Waterborne transmission accounts for the acquisition of giardiasis by many international travelers and for the development of infection in those who have been hiking or camping in wilderness areas.

CLINICAL PRESENTATION A curious, and still unexplained, feature of giardiasis is the varying severity of clinical disease that it can cause.

A significant number of people with giardiasis are asymptomatic, even following experimental infections with isolates derived from highly symptomatic patients.

As an example, in one well-studied outbreak of waterborne giardiasis, two-thirds of those infected were asymptomatic. The spectrum of clinical disease includes asymptomatic infection, self-limited acute giardiasis, and chronic infection.

The virulence of the giardial isolate, the parasite load, the host immune response, and perhaps other host determinants probably all contribute the manifestations in an individual patient.

Asymptomatic infection Asymptomatic infection occurs in approximately 60 percent of people exposed to Giardia and is seen in both children and adults. Asymptomatic cyst carriage can last over six months.

Acute giardiasis — Acute giardiasis occurs in less than half of people infected with Giardia. Symptoms include:

Diarrhea that is sudden in onset and may be initially watery — 90 percent Malaise — 85 percent Foul-smelling and fatty stools (steatorrhea) — 70 percent Abdominal cramps and bloating — 70 percent Flatulence — 75 percent Nausea — 70 percent Weight loss — 65 percent Vomiting — 30 percent

Fever occurs in only 10 to 15 percent of patients and may be unrelated to giardiasis. Symptoms usually develop after an incubation period of one to two weeks (range 1 to 45 days).

Distinguishing features of giardiasis are the prolonged duration of symptoms, often at least two to four weeks, and the associated significant weight loss (10 percent of body weight) that occurs in over 50 percent of cases.

Clinical findings that have helped identify cases of giardiasis in epidemiologic studies include a duration of illness lasting seven or more days with at least two of the following six symptoms: diarrhea, flatulence, foul-smelling stools, nausea, abdominal cramps, and excessive fatigue.

Chronic giardiasis Chronic giardiasis may follow the acute phase of illness or may develop without an antecedent acute illness. In one study, 84 percent of experimentally infected people self-cured by a mean of 18.4 days following inoculation, while the remainder became chronically infected.

A chronic syndrome can develop in as many as 30 to 50 percent of symptomatic patients characterized by: Loose stools but usually not diarrhea Steatorrhea Profound weight loss Malabsorption Malaise Fatigue Depression

Malabsorption is well documented and may be responsible for the significant weight loss that can occur in giardiasis (10 to 20 percent of body weight). Even when the infection is asymptomatic, malabsorption of fats, sugars, carbohydrates and vitamins may occur

This can lead to vitamin deficiencies (A, B12), folate deficiency, hypoalbuminemia, and especially secondary lactase deficiency.

Acquired lactose intolerance occurs in up to 20 to 40 percent of cases and can take many weeks to normalize even after clearance of the parasite. Clinically, this can lead to augmentation of intestinal symptoms especially after the ingestion of milk products.

Complications Studies about chronic giardiasis and effects on growth and development in children have yielded conflicting results. One prospective study in 45 Guatemalan children suggested a significant inverse relation between weight gain and increasing duration and severity of giardiasis.

For a small number of patients, especially children, the persistence of infection is associated with the development of moderate to marked malabsorption and weight loss . Chronic giardiasis may resemble other diseases associated with malabsorption , including inflammatory bowel disease.

Occasionally, hypersensitivity phenomena such as rash, urticaria, aphthous ulceration, and reactive arthritis or synovitis are seen in giardiasis, although these manifestations are rare. G. lamblia can also uncommonly spread from the duodenum to the biliary and pancreatic ducts.

Cases of cholecystitis, cholangitis, and granulomatous hepatitis due to this pathogen have been reported. Impaired exocrine pancreatic function with diminished secretion of trypsin and lipase has been noted.

DIAGNOSIS Nonspecific laboratory tests and radiographic imaging are not useful in diagnosing giardial infection. Patients with giardiasis do not have a peripheral leukocytosis or eosinophilia, and white cells are usually absent in stool specimens.

Fecal fat excretion and other laboratory tests of malabsorption may be abnormal. An upper GI series may demonstrate mucosal edema but often shows no significant radiologic changes.

Stool microscopy Most laboratories processing a stool sample for ova and parasite (O&P) examination will divide the sample into portions. One part is examined fresh mixed with saline to look for both trophozoites and cysts

Other portions are placed in polyvinyl alcohol for permanent staining and/or in formalin for concentration which can increase the diagnostic yield.

Substances such as barium, antacids, and mineral oil interfere with fecal microscopic evaluations and should be postponed until stool examinations for O&P are complete.

A loose watery stool is more likely to be positive for trophozoites, while a semiformed or formed stool will probably only contain cysts. Since Giardia is excreted intermittently, it will be detected in 50 to 70 percent of cases with a single specimen and in 90 percent after three specimens.

Immunoassays A number of immunoassays have been developed to try to improve the ease and sensitivity of diagnosis. These assays use antibodies directed against either cyst or trophozoite antigens. The different types of kits available include: Enzyme-linked immunosorbent assays (ELISA) Non-enzymatic immunoassays

The various assays have demonstrated a sensitivity of 90 to 100 percent and a specificity of 95 to 100 percent when compared to stool microscopy.

One study of 325 stool specimens showed that an ELISA against a specific Giardia antigen (antigen 65) was able to detect 30 percent more cases of Giardia than stool O&P.

Other studies that have compared results obtained using fecal specimens for O&P examination, direct immunofluorescent assay, and immunodiagnostic techniques found that immunologic methods are more sensitive and quicker than conventional O&P methods.

Antigen assays have a similar cost to O&P examinations Antigen assays have a similar cost to O&P examinations. While more sensitive than conventional microscopy for the diagnosis of Giardia, antigen testing should not replace the stool O&P for most patients with diarrhea.

The stool O&P examination can also reveal other pathogens and multiple parasites, which is particularly important in returning travelers.

Duodenal aspirates or biopsies Duodenal sampling methods (eg, string test, duodenal aspiration or duodenal biopsy) are more invasive than the above diagnostic techniques.

These tests are generally reserved for confusing cases after noninvasive tests have been performed or for situations where small bowel architecture needs to be examined.

Small bowel biopsies of patients with giardiasis can reveal a range of pathologic findings, but usually no histopathologic abnormalities are identified.

Serology Serologic tests are not of value in the diagnosis of acute giardiasis. IgG and IgM antibodies to the organism can be demonstrated, but these antibodies persist after infection and thus are less helpful for establishing an etiology in the individual symptomatic patient. However, serology is useful in epidemiologic studies.

Culture Giardia lamblia can be cultivated in the laboratory, but this is only used as a research tool.

Polymerase chain reaction Polymerase chain reaction (PCR) diagnostic techniques are currently only experimental. One study using PCR to detect Giardia in stool samples showed that parasite concentrations as low as 10 parasites/100 uL of stool could be detected.

TREATMENT A number of drugs are available for the treatment of giardiasis. But the first question that should be addressed is who requires treatment.

Who should be treated Since many patients are asymptomatic, it is not automatic that all patients diagnosed with Giardia should receive antimicrobial therapy. Any patient with symptoms should be receive specific therapy.

A reason for treating asymptomatic patients, particularly children, is to prevent spread of the infection. Thus, therapy is often given to children in developed countries, especially those attending a day care center.

Children in developing countries are so likely to be reinfected within a short period of time that treatment is not usually practical . All food handlers should be treated since they can transmit infection. There is no need to repeat a stool examination to check for parasite clearance in individuals who symptomatically improve.

Antimicrobials Metronidazole, although not approved for the treatment of giardiasis by the Food and Drug Administration (FDA), is the principal agent used to treat this infection.

Metronidazole (250 mg PO TID for five days) has an efficacy of 80 to 95 percent. Side effects include nausea, headache, and a metallic taste in the mouth; less commonly, dark urine, paresthesias, and dizziness occur.

Metronidazole may have a disulfiram-like effect, and alcohol consumption should be avoided. Isolates of Giardia with decreased susceptibility to metronidazole have been described.

Tinidazole, a congener of metronidazole, is highly effective for the treatment of giardiasis. A single 2 g dose (or 50 mg/kg for children) of tinidazole has an efficacy of over 90 percent with few associated side effects [65,66], and consequently this is a practical alternative.

Quinacrine, the first effective drug for giardiasis, is no longer distributed in the United States (although it is available from specific formulating pharmacies). The recommended dose is 100 mg (2 mg/kg) three times daily for five days.

Newer agents that have been used for therapy include albendazole Newer agents that have been used for therapy include albendazole. Albendazole (400 mg or 22.5 mg/kg PO daily for 5 days) had an efficacy of 97 percent in children in Bangladesh. It was also as effective as metronidazole with fewer side effects in two other pediatric studies of giardiasis.

Furazolidone, a nitrofuran compound, is available as a suspension and is another alternative therapy. It is effective and well-tolerated, although its efficacy is generally reported to be slightly lower than metronidazole (approximately 80 percent). The recommended dose is 100 mg (1.5 mg/kg) four times a day for 7 to 10 days.

Nitazoxanide has been demonstrated to have equal or superior efficacy compared with metronidazole or mebendazole. It is usually administered at a dose of 100 to 500 mg twice daily for three days. A number of studies have shown this agent to be at least as effective as metronidazole in relieving symptoms in individuals with giardiasis, with efficacy ranging from 81 to 85 percent.

Drug choices in pregnancy Treatment of giardiasis in pregnancy can be difficult. Metronidazole is often avoided based upon old reports of teratogenic effects in rats, although human studies have not documented such risks.

If symptoms of giardiasis are minimal, therapy can be withheld until after delivery. If symptoms are bothersome, paromomycin (25 to 35 mg/kg per day PO in three divided doses for seven days) can be used.

Paromomycin, a nonabsorbable aminoglycoside, eliminates cysts in only 60 to 70 percent of patients , but it may provide symptomatic relief.

If giardiasis in pregnancy is associated with dehydration, malabsorption, or severe symptoms, therapy with metronidazole is warranted. Malabsorptive symptoms may persist in any patient receiving antiparasitic therapy since regeneration of functioning intestinal mucosa requires time.

Recurrence of symptoms Recurrent diarrhea following treatment may be due to lactose intolerance rather than to recurrent or relapsed infection, so reevaluation of stool specimens should be undertaken before empiric retreatment is given.

Patients should be counseled to avoid lactose-containing foods for one month after therapy.

If a patient has relapsed after therapy, either a second course of the original agent or a different treatment can be administered. Options for treatment of refractory cases include: Longer repeat courses or higher doses of the original agent. The dose of metronidazole, for example, can be increased to 750 mg PO TID for 10 days.

Combination regimens can be used, such as metronidazole (or tinidazole) plus quinacrine (usual dose metronidazole 250 mg TID plus quinacrine 100 mg for 14 to 21 days ) or albendazole plus metronidazole.

This latter combination has been reported to have 100 percent efficacy in patients who had failed standard metronidazole therapy.

PREVENTION Attention to hygiene is necessary to prevent person-to-person transmission of giardiasis. (See "Travel advice"). Boiling or heating water to at least 70ºC for 10 minutes eliminates Giardia cysts.

For hikers and campers, iodine-based water treatments are more efficacious than chlorine-based treatments, but iodine disinfection must be carried out for at least eight hours.

High quality water filtration units are also available and have proven effective for Giardia cyst removal.

Strict handwashing, care with diaper disposal, and treatment of symptomatic children can prevent the spread of giardiasis in day care centers. The treatment of asymptomatic infected children is more controversial.

Breast milk contains detectable titers of secretory IgA which is protective for nursing infants; this protective mechanism is particularly important in developing countries . No vaccine against this parasite is available.