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[Case Report]

Giardiasis

An Elusive Cause of Gastrointestinal Distress

Howard D. Backer, MD, MPH

THE PHYSICIAN AND SPORTSMEDICINE - VOL 28 - NO. 7 - JULY 2021


In Brief: The common protozoan Giardia lamblia has a fecal-oral mode of transmission, usually from contaminated water or food or person-to-person contact. Infection may be asymptomatic or result in a broad spectrum of symptoms—most commonly, subacute illness that is mistaken for other gastrointestinal problems. Although most infections are self-limited, treatment is indicated due to the long duration and the risk of transmission. Several therapeutic agents are available, but none is 100% effective. Prevention for people involved in outdoor sports or recreation and for international travelers includes treatment of all surface water and rigorous personal hygiene.

Giardia lamblia is a flagellate protozoan that is an important human pathogen. It has a worldwide distribution and is the most common intestinal parasite in the United States, so athletes and travelers may face infection wherever they go. Infection usually produces subacute intestinal symptoms that cause discomfort and fatigue and may prevent maximal performance. The symptoms mimic other common intestinal ailments, so healthcare providers must suspect Giardia infection to make the diagnosis. Anyone who participates in outdoor sports or recreation and may drink surface water should be aware that Giardia is widespread in various water sources, and they should take steps to reduce their risk of infection.

The Life Cycle of Giardia

G lamblia was first observed in 1681 by Leeuwenhoek, but only in the last 40 years has it been recognized as an important human pathogen (1). The classification of Giardia remains controversial, but most experts currently recognize three species (G agilis, G muris, and G duodenalis) based on morphologic criteria. G lamblia (instead of G duodenalis) has persisted in the medical literature to designate the species that infects humans and many other mammals and causes giardiasis.

The Giardia life cycle involves two stages. Active trophozoites (figure 1) are responsible for symptomatic illness. These organisms attach to the mucosa of the duodenum and proximal jejunum, where they multiply rapidly via binary division. Trophozoites are rarely infective because they are not resistant to gastric acid and die rapidly outside the body. Responding to unknown stimuli, possibly bile salts, some trophozoites encyst in the ileum and are eliminated in the stools of infected hosts. Cysts are infectious as passed in the host stool; no period of maturation or intermediate development stage is required. Furthermore, they are very hardy in the external environment. When ingested by a potential host, excystation is stimulated by passage through the stomach, and the motile trophozoite migrates to the small bowel to complete the cycle (2-4).

Epidemiology and Transmission

Giardia is the most common protozoan intestinal parasite isolated worldwide. In the United States, 7.2% of stool specimens examined by state diagnostic laboratories contained G lamblia (estimated prevalence of 2% to 5%) (5); in developing countries, the prevalence is often 20% to 30%. All age-groups are affected.

Transmission occurs by a fecal-oral route. The infective dose of Giardia for humans is low: 10 to 25 cysts caused infection in 8 of 25 subjects; more than 25 cysts caused infection in 100% (6). This allows person-to-person spread, which may be the most common means of transmission for humans. Areas and populations with poor hygiene and close physical contact have higher rates of giardiasis. Epidemics as well as carrier rates of 30% to 60% have been reported among children in day care centers and in Native American reservations. Venereal transmission occurs among homosexuals through direct fecal-oral contamination. Water is a major vehicle of infection in community outbreaks (7).

Giardia causes only a small percentage of travelers' diarrhea (8), but the organism may be the predominant travelers' infection in certain areas. For example, in St Petersburg, Russia, contaminated tap water caused many cases, and recently in Greece a large outbreak occurred in a tourist hotel (9). Because of the relatively long incubation period and persistent symptoms, Giardia is a common cause of persistent diarrhea in travelers who have returned from any developing region (10).

Waterborne Transmission

Although contaminated food can transmit Giardia (11,12), most outbreaks are waterborne. In the United States from 1964 to 120214, epidemiologists traced 90 outbreaks (24,000 cases) of giardiasis to water. Most of these occurred in small drinking water systems that used untreated or inadequately treated surface water (13,14). For the past 30 years, Giardia has been the most commonly identified cause of waterborne disease outbreaks in the United States (15). Recently, its position as the leading waterborne protozoan has been challenged by Cryptosporidium (13,16).

Endemic areas. Every region of the United States has experienced waterborne outbreaks, but giardiasis must be considered endemic in the western mountain regions (Rocky Mountains, Cascades, and Sierra Nevadas) that have reported most of the outbreaks. Cysts are found as often in pristine water and protected sources as in unprotected waters (17-20). Distinct seasonal variation is seen, with most cases from recreational areas occurring during the summer.

Two factors account for the organism's prevalence in relatively pristine mountain water. One is the durability of cysts in the environment; cysts retain viability in cold water for as long as 2 to 3 months (21). The other is a zoonosis: Giardia isolates from humans and animals are indistinguishable, and cross-species infectivity experiments have produced infection. However, the extent of cross-species infection is not clear (22,23). Many of the species apparently capable of passing Giardia cysts to humans are common domestic and wildland animals, including dogs, cattle and other ungulates such as deer, and beavers.

Recreational infections. Anyone may become infected with Giardia, but people whose activities bring them in contact with contaminated recreational water or surface water used for drinking have a higher risk of infection. This may include participants in outdoor activities such as hiking, running, rock climbing, cross-country skiing, mountain biking, swimming, water skiing, and whitewater boating. These activities are no longer purely recreational; competition ultra-endurance events through remote mountain terrain are also becoming commonplace. The small infective dose of Giardia also allows infection from contact with recreational water via inadvertent drinking, as was demonstrated by an outbreak among lap swimmers in a fecally contaminated pool (24).

Pathophysiology of Infection

The pathophysiologic mechanisms of diarrhea and malabsorption in giardiasis are poorly understood (4). Reversible malabsorption of fats, vitamins B and A, folate, and disaccharides has been demonstrated in some, but not all, patients with diarrhea. Several explanations for malabsorption have been proposed: physical blockade by large numbers of trophozoites blanketing the intestinal mucosa, deconjugation of bile acids, bacterial or fungal overgrowth in the small intestine, increased turnover of cells on the mucosa of the villi, and epithelial damage. Altered gut motility and hypersecretion of fluids, perhaps via increased adenylate cyclase activity, may also play a pathophysiologic role. Histologic changes of villous atrophy and inflammatory infiltrates with epithelial cell destruction have been observed. In some studies, these changes have correlated with the degree of malabsorption, and, after treatment, normal absorption returned. However, in human patients, most small-bowel biopsies reveal minimal or no change, with only occasional mucosal invasion (trophozoites found intracellularly and extracellularly), and no local inflammatory response or enterotoxins. Most likely, more than one mechanism is involved in the pathophysiology of giardiasis (3).

Clinical Effects

Most infections are asymptomatic, and in endemic areas the role of Giardia in diarrhea is obscure (25). The percent of infections that result in symptoms varies from 5% to 70%. Asymptomatic carriers may secrete high numbers of cysts in stools (6). Correlation between inoculum size and infection rates has been noted, but not between inoculum size and numbers of cysts passed or severity of symptoms (26). Infectivity depends on both host and parasite factors (1), and many conditions such as hypochlorhydria, certain immunodeficiencies, blood type A, and malnutrition can predispose patients to symptomatic infection. The incubation period averages from 1 to 2 weeks, with a mean of 9 days (27).

Typical clinical presentations. A spectrum of clinical presentation may occur (28). A few people experience abrupt onset of explosive, watery diarrhea accompanied by abdominal cramps, foul flatus, vomiting, low-grade fever, and malaise. These symptoms commonly last 3 to 4 days before they evolve into the more common subacute syndrome.

In most patients, the onset is more insidious and symptoms are persistent or recurrent. Stools become mushy, greasy, and malodorous. Watery diarrhea may alternate with soft stools and even constipation. Upper gastrointestinal symptoms, typically exacerbated after meals, accompany stool changes but may be present without soft stool. These symptoms include mid- and upper-abdominal cramping, substernal burning, acid indigestion, sulfurous belching, nausea, distention, early satiety, and foul flatus. Constitutional symptoms of anorexia, fatigue, and weight loss are common (29,30).

Unusual presentations include allergic manifestations such as urticaria, erythema multiforme, and bronchospasm. Some Giardia infections lead to chronic illness. Adults (mainly those who are immunocompromised) may have a long-standing malabsorption syndrome and marked weight loss, and children may have a failure-to-thrive syndrome (10).

Immunologic responses. Immunologic responses to Giardia infection appear complex. Acquired resistance has been demonstrated by epidemiologic studies showing lower rates of infection and illness among residents of endemically infected areas compared with visitors and among adults compared with children. However, reinfection certainly occurs. Both cellular and humoral responses to Giardia have been demonstrated.

Patients with hypogammaglobulinemia have a higher incidence of symptomatic giardiasis, implying an important protective function of immune globulins. Host immunologic responses are effective in most infections because spontaneous clinical recovery with or without the disappearance of organisms is common. Average duration of symptoms in all ages ranges from 3 to 10 weeks.

Laboratory Diagnosis

Laboratory confirmation of giardiasis can be difficult. Stool examination remains the primary means of diagnosis but is being replaced by newer immunodiagnostic tests that detect antigens in the feces.

Standard methods. Trophozoites may be found in fresh, watery stools but disintegrate rapidly. Cyst passage is extremely variable and not related to clinical symptoms. In the office, fresh stool can be mixed with an iodine solution (such as Gram's iodine) or methylene blue and examined for cysts on a wet mount slide. Many antibiotics, enemas, laxatives, and barium studies mask or cause disappearance of parasites from the stools, so examinations should be delayed for 5 to 10 days after these interventions. The current recommendation is to examine three samples taken at intervals of 2 days, which should provide a diagnostic sensitivity of 90%. Another noninvasive office test currently used less frequently is duodenal mucus sampling with a string test that has a reported sensitivity of 10% to 80% (31). Duodenal biopsy is rarely necessary for diagnosis but may be the most sensitive test.

New methods. A commercial enzyme-linked immunoassay method for stool has demonstrated the same sensitivity as microscopic examination, but with 100% specificity, making it a convenient screening method. Enzyme-linked immunoassays are much easier and require less experience than microscopy (32). Serologic diagnosis is not currently useful for diagnosis of giardiasis, though it is used for epidemiologic studies. G lamblia can be cultured in vitro, but culture is not practical for clinical diagnosis (28).

Directed Treatment

Symptomatic patients should be treated to relieve their symptoms and to prevent the development of chronic illness. Asymptomatic carriers in nonendemic areas should be treated when identified because they may transmit the infection or develop symptomatic illness. Treatment is not straightforward because some of the medications are not available in the United States and no drug is effective in all cases (33).

Typical drug therapies. Three groups of drugs are currently being used: nitroimidazoles (metronidazole, tinidazole, albendazole, ornidazole, and nimorazole), nitrofuran derivatives (furazolidone), and acridine compounds (mepacrine and quinacrine; table 1) (3,28).


TABLE 1. Drug Therapies for Giardiasis
Drug Dosage Cure Rate Comments

First Choice
Metronidazole Adults: 250 mg tid for 5-7 days

Children: 5 mg/kg tid for 7 to 10 days

85%-95% Therapeutic drug of choice in US, but not approved for this purpose by the FDA
Alternatives
Quinacrine 100 mg tid for 5 days 90%-95% Not commercially available, but some pharmacies can make capsules containing the compound; drug is poorly tolerated by children and has been withdrawn from the market by the manufacturer
Albendazole 400 mg/day in 3 doses for 5-7 days Data limited Available as a suspension
Mebendazole 300-400 mg/day in 3 doses for 5-7 days Data limited Available as chewable tablets
Tinidazole Adults: 1 g/day in 1 dose for 2 days

Children: 50 mg/kg/day in 1 dose for 2 days

85%-90% Not available in US; the drug of choice in many countries
Children
Furazolidone 1.5 mg/kg qid for 7-10 days 80% Suspension for children; albendazole or mebendazole may prove more effective
Pregnant Women
Paromomycin 25-35 mg/kg tid for 5-10 days with meals 50%-70% Nonabsorbable aminoglycoside; may use in latter stages of pregnancy
Persistent Infection Course of treatment with different agent; Repeat course of treatment with the same agent; Use two medications concurrently

tid = three times a day; FDA = US Food and Drug Administration; qid = four times a day


Metronidazole (250 mg three times a day for 5 days for adults) is most commonly used in the United States and achieves cure rates of 85% to 90%. Tinidazole (1,000 mg single dose or 1,000 mg on 2 successive days) has the same success rate with better compliance, but it is not available in the United States, in part because of cost and difficulty in obtaining approval (34). Furazolidone is used most commonly in children because it is available in a liquid suspension and is well tolerated (35). Most experts consider it less effective than metronidazole, with cure rates in patients with giardiasis of only about 80%.

Quinacrine (100 mg three times a day for 5 days), had been considered the drug of first choice in adults because of cure rates around 95%. Although extensive clinical experience and excellent results have been obtained with quinacrine, it is no longer available commercially because of the limited market and fears of possible liability; however, it remains approved by the US Food and Drug Administration. In the United States, some pharmacies can custom fill capsules with the powdered drug (36). Quinacrine causes more frequent side effects than metronidazole, including rare incidences of toxic psychosis, but it is indicated for patients with metronidazole-resistant giardiasis and for patients who should not receive or who cannot tolerate metronidazole.

Therapies for special cases. In persistent cases and severely symptomatic individuals, paromomycin (25 to 30 mg/kg in three divided doses for 5 to 10 days) has been successful. Paromomycin has also been suggested for use in pregnant patients because it is not absorbed (37). The benzimidazole derivatives (mebendazole and albendazole) that are widely used in helminth infections have been investigated recently (38,39). They are well tolerated, and results have been promising but inconsistent (40).

In resistant cases, longer courses of two drugs taken concurrently (metronidazole plus quinacrine) have been suggested. Relapses may occur up to several weeks after treatment, necessitating a second course of the same medication or an alternative drug. Relapses are common in immunocompromised patients. Malabsorption usually resolves with treatment, and persistent diarrhea may result from lactose intolerance or a syndrome resembling celiac disease, rather than from treatment failure. Given the difficulty, time, and expense of confirming the diagnosis in some patients, a therapeutic trial of drugs may be attempted when suspicion is high.

Methods of Water Treatment

Basic preventive measures. Two basic measures are important for prevention. The first is personal hygiene to prevent person-to-person spread from asymptomatic carriers. Careful hand washing before preparing meals and after going to the bathroom or changing children's diapers is basic hygiene, but it is often neglected when people are outdoors where no running water is available. The second measure is to ensure potable water by treating surface water (even in North America) and tap water in many developing countries.

Although Giardia has been considered the most important enteric pathogen in North American surface water, its presence indicates fecal contamination, so enteric bacteria and viruses may also be present. Cryptosporidium oocysts have also been found in most waters in which Giardia is present, albeit in very small numbers in pristine surface waters. Protocols for water treatment are not straightforward because microorganisms vary in their susceptibility to various purification techniques. However, Giardia cysts are susceptible to all major field methods of water treatment.

Boiling. The cysts are highly susceptible to heat and can be inactivated when heated to 150°F (45°C) for 5 minutes; inactivation occurs sooner at higher temperatures (41). All enteric pathogens, including Cryptosporidium oocysts, are susceptible to heat, and any water brought to a full boil will be safe to drink (42).

Filtration. Filtration is also effective for Giardia cysts because the cysts are relatively large (5 by 10 microns). Most commercially available microfilters have a pore size of less than 1 micron, so they can remove bacteria as well as Giardia and Cryptosporidium. However, viruses are small enough to pass through most commercially available filters.

Chemical methods. Halogens, including chlorine and iodine, are widely available in several different forms and will kill Giardia when used in sufficient concentrations with adequate contact time (tables 2 and 3) (43,44). Since bacteria and viruses are more susceptible to chemical disinfectants, inactivation of Giardia cysts will guarantee destruction of these other microorganisms (45). One should be aware that the contact time required may be more than 1 hour in very cold water (46,47). Unfortunately, Cryptosporidium oocysts are highly resistant to halogens and are not killed at the concentrations used to kill Giardia cysts. Because most wilderness surface water has a low level of contamination, any of the previous techniques should provide an adequate margin of safety. For more highly contaminated water or cloudy water, additional care is needed, and the reader should consult a more complete discussion (48).


TABLE 2. Halogen-Mediated Water Disinfection for Elimination of Giardia in 1 L of Water
Requirement for
Iodination Methods 4 ppm 8 ppm

Iodine tablets (tetraglycine hydroperiodide) 1/2 tablet 1 tablet
2% iodine solution (tincture) 0.2 mL (5 drops) 0.4 mL (10 drops)
Saturated solution of iodine crystals in water 13 mL (0.5 oz) 26 mL (1 oz)

Requirement for
Chlorination Methods 5 ppm 10 ppm

Household bleach (5% sodium hypochlorite) 0.1 mL (2 drops) 0.2 mL (4 drops)
Commercially available purification tablets:
AquaClear (sodium dichlorotisocyanurate) 1 tablet
Chlorine plus flocculating agents 1 tablet (= 8 ppm)

ppm = parts per million (equivalent to mg/L)



TABLE 3. Recommended Halogen-Mediated Treatment Time to Kill 99.9% of Giardia Cysts
Contact Time (min) at Various Water Temperatures
Halogen Concentration 5°C (41°F) 15°C (59°F) 30°C (86°F)

2 ppm 240 180 60
4 ppm 180 60 45
8 ppm 60 30 15

Contact times have been extended from the usual recommendations to account for recent data that show that prolonged time is needed in very cold water to kill Giardia cysts.


Giardia Awareness

Athletes who travel internationally and anyone who may ingest surface water during wilderness recreation is at increased risk of giardiasis. Clinicians should be aware that Giardia is the most common intestinal parasite in the United States, and that subacute symptoms often suggest other intestinal ailments, resulting in expensive evaluations that miss the diagnosis. Several options are available for diagnosis and treatment. Prevention should include basic hygiene and treatment of water in the field.

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Dr Backer is a staff physician in the emergency department at the Kaiser-Permanente Medical Center in Hayward, California. Address correspondence to Howard D. Backer, MD, MPH, 109 Bonita Ave, Piedmont, CA 94611; e-mail to [email protected].


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