Giardia Lamblia

Trichomonas Vaginalis

Other Trichomonads

Trichomonas tenax in the mouth and T hominis in the intestine are considered harmless commensals.

Cryptosporidium

Clinical Manifestations

Giardia infection may be asymptomatic or it may cause disease ranging from a self-limiting diarrhea to a severe chronic syndrome. The length of the incubation period, usually 1 to 3 weeks, depends at least partly on the number of cysts ingested.

Most Giardia infections are asymptomatic. For this reason, and because these organisms are so widespread, it was earlier believed that Giardia was a nonpathogenic commensal. Enough evidence has accumulated, however, to show that G lamblia can cause disease. For example, in some cases of diarrheal disease, Giardia is the only known pathogen present, and treatment with any of a number of antiprotozoal agents promptly results in the disappearance of both disease and organisms. Reinfection is accompanied by return of symptoms. Normal human hosts with giardiasis may have any or all of the following signs and symptoms: diarrhea or loose, foul-smelling stools, steatorrhea (fatty diarrhea), malaise, abdominal cramps, excessive flatulence, fatigue and weight loss.

Some patients with giardiasis develop a severe disease that is not self-limited. Signs and symptoms may include interference with the absorption of fat and fat-soluble vitamins, retarded growth, weight loss, or a celiac-disease-like syndrome. Although most cases are seen in hosts with some concurrent condition, such as an immune deficiency, protein-calorie malnutrition, or bacterial overgrowth of the small intestine, some cases of severe giardiasis occur in apparently normal hosts. Different strains of G lamblia possibly vary in virulence.

Structure

The Giardia life cycle involves two stages: the trophozoite and the cyst. The G lamblia trophozoite is easily recognized under a microscope: it is about 12 to 15 μm long, shaped like a pear cut in half lengthwise, and has two nuclei that resemble eyes, structures called median bodies that resemble a mouth, and four pairs of flagella that look like hair; these combine to give the stained trophozoite the eerie appearance of a face (Fig. 80-1). The flagella help these organisms to migrate to a given area of the small intestine, where they attach by means of an adhesive disk to epithelial cells and thus maintain their position despite peristalsis. The Giardia cyst - the form usually seen in the feces - is ovoid, 6 to 12 μm long, and can often be seen to contain two to four nuclei at one end and prominent diagonal fibrils (Fig. 80-1).

Figure 80-1

Protozoa found in human stool specimens. (From Brooke, MM, Melvin, DM: Morphology of Diagnostic Stages of Intestinal Parasites of Man. Public Health Service Publication No. 1966, 1969.)

Multiplication and Life Cycle

The trophozoite, or actively metabolizing, motile form, lives in the upper two-thirds of the small intestine (duodenum and jejunum) and multiplies by binary fission. Trophozoites that are swept into the fecal stream lose their motility, round up, and are excreted as dormant, resistant cysts (Fig. 80-2).

Figure 80-2

Giardia life cycle in humans. A similar life cycle occurs in other mammals, with probable transmission to humans.

Excreted trophozoites disintegrate. The cyst, although not as resistant as many bacterial endospores, is sufficiently hardy to survive host-to-host transfer. For example, some Giardia cysts excyst successfully after more than 2 months storage in water at refrigerator temperatures.

Giardia infection is acquired by ingesting cysts. The exposure of cysts to host stomach acidity and body temperature triggers excystation, which is completed in the small intestine with the emergence of trophozoites that promptly attach to host intestinal epithelium.

Pathogenesis

The mechanisms that cause the signs and symptoms of giardiasis are not known. Ordinarily, the trophozoites remain in the intestinal lumen. It seems unlikely that their mere presence, even in enormous numbers, is sufficient to interfere mechanically with digestion. Rather, the symptoms probably result from inflammation of the mucosal cells of the small intestine, which Giardia is known sometimes to cause. Inflammation results in an increased turnover rate of intestinal mucosal epithelium. The immature replacement cells have less functional surface area and less digestive and absorptive ability. Additional mechanisms of pathogenesis may well exist.

Host Defenses

The fact that many Giardia infections in humans and experimental animals resolve spontaneously implies that an effective host immune response develops. There is evidence that both humoral and cellular immune mechanisms are involved. Hosts with gamma globulin deficiencies are prone to severe disease, suggesting that humoral immunity plays a role. Although the fact that milk from immune mothers can prevent infection in suckling mice seems to indicate a role for IgA, the nature of this protection is not clear. Furthermore, experiments with nude (congenitally athymic) mice suggest that the thymus-dependent (T-cell mediated) immune system also plays a role. In these mice, wasting and premature death may result from Giardia infection, whereas nude mice “reconstituted” with thymus transplants are able to reduce the numbers of infecting Giardia.

In vitro studies have found that normal human milk (but not cow's milk or goat's milk) kills trophozoites of both G lamblia and Entamoeba histolytica, and that this killing does not depend on secreted IgA. This finding raises the possibility that even mother's milk that does not have antiprotozoal antibody may protect infants exposed to these parasites.

Epidemiology

Giardia infection occurs worldwide, with an incidence usually ranging from 1.5 to 20 percent. Higher incidences are likely where sanitary standards are low. Although people of all ages may harbor these organisms, infants and children are more often infected than are adults. Carriers are probably more important in the spread of these organisms than symptomatic patients because cysts are less likely to be present in diarrheic stool. Like other diseases spread by the fecal-oral route, giardiasis can be a problem in institutions, nurseries, and day-care centers.

Recent outbreaks, some of epidemic proportions, have occurred, particularly in North America and the Soviet Union. These outbreaks have been caused by drinking contaminated water from community water supplies or directly from rivers and streams.

Many animals harbor Giardia organisms that are indistinguishable from G lamblia. In the past, these isolates were assumed to be host-specific. Recent evidence suggests this is not always the case; at least some of the Giardia strains that parasitize animals may also infect humans and vice versa. This possibility complicates the problem of defining species in this genus. It also raises the question of the existence of animal reservoirs of Giardia from which humans may be infected. The finding of Giardia-infected animals in watersheds from which humans acquired giardiasis, and the successful interspecies transfer of these organisms, strengthens the possibility that giardiasis is a zoonotic infection. Infected beavers are believed to be one source of water-borne giardiasis. Beaver Giardia isolates were found capable of infecting dogs and humans. Canines thus may be another source of human giardiasis.

It has been recognized only recently that Giardia infection may be transmitted by sexual activity, particularly among homosexual men, but also heterosexually. Physicians should attempt to determine if giardiasis is being acquired in this way so that they can distinguish from failure of drug treatment and prompt reinfection. Perhaps more important, a Giardia infection that may have been acquired in this way should alert the physician to the possible presence of more serious fecal-oral infections such as amebiasis, syphilis, gonorrhea, or hepatitis.

Diagnosis

The symptoms of giardiasis are not pathognomonic. The patient's history may indicate recent exposure to Giardia, but the infection is diagnosed, as in most parasitic infections, by identifying the organism. In the case of giardiasis, cysts are found in formed stool. Diarrheal specimens may also contain trophozoites. If still motile, the trophozoites exhibit a typical “falling leaf” movement.

Because cysts are often shed intermittently, three stool specimens should be obtained at approximately 48-hour intervals. Examination of these specimens permits detection of the organism in most cases. The chance of finding cysts in a light infection increases if the stool specimen is subjected to a concentration method, such as the zinc sulfate centrifugal flotation technique. When stools are negative, giardiasis can be diagnosed by obtaining trophozoites directly from the small intestine by duodenal intubation, by capsule (the Enterotest capsule), or by the use of a long nylon thread. One end of the thread is swallowed. The trophozoites attach to it, and it is then retrieved and examined microscopically.

Identification of Giardia in a specimen does not necessarily mean that this organism is responsible for the patient's symptoms. Giardia should be treated and eliminated when found, but other pathogens should be sought as well.

Control

Attention to personal hygiene is the key to preventing the spread of giardiasis. Controlling the spread of Giardia in drinking water should be possible where community water treatment methods (e.g., disinfection and filtration) are available. For example, iodine and chlorine kill Giardia cysts under appropriate conditions. Destruction of Giardia cysts is more difficult if the water is near freezing or contains considerable organic matter, because under such conditions so much iodine or chlorine must be added that the water is not palatable. Boiling promptly inactivates Giardia cysts and is the best solution.

The drug of choice for treating Giardia infections is quinacrine hydrochloride. This drug frequently causes dizziness, headache, and vomiting. Metronidazole and furazolidone also may be used. Although metronidazole is highly effective, its use in treating Giardia infections has not been officially approved in the United States. One draw back is that it frequently causes headache and nausea; another is that it is believed to be carcinogenic in rodents and mutagenic in bacteria. Its use in pregnant women is generally contraindicated, particularly in the first trimester. Furazolidone is less effective against Giardia than the other two drugs, but its availability in liquid form makes it useful for treating young children. None of these drugs can cure all Giardia infections, and none is particularly well tolerated. An anti-Giardia agent without these drawbacks would be welcome.

Clinical Manifestations

Although the incidence of T vaginalis infections varies widely, trichomoniasis is one of the commonest, if not the most common, of the sexually transmitted diseases. In some areas of the United States, the incidence among women is as high as 50 percent. More women than men are infected with T vaginalis. In both sexes, most infections are asymptomatic or mild. Symptomatic infection is common in women, rare in men.

Trichomoniasis in women is frequently chronic and is characterized by vaginitis, a vaginal discharge, and dysuria. The inflammation of the vagina is usually diffuse and is characterized by hyperemia of the vaginal wall (with or without small hemorrhagic lesions) and migration of polymorphonuclear leukocytes into the vaginal lumen.

Structure

All the trichomonads are morphologically similar, having a pear-shaped body 7 to 23 μm long, a single anterior nucleus, three to five forward-directed flagella, and a single posteriorly directed flagellum that forms the outer border of an undulating membrane. A hyaline rod-like structure, the axostyle, runs through the length of the body and exits at the posterior end (Fig. 80-1).

Of the three trichomonads that commonly colonize humans, only one, T vaginalis, causes disease. T vaginalis inhabits the vagina in women, the prostate and seminal vesicles in men, and the urethra in both sexes.

Multiplication and Life Cycle

Trichomonads have the simplest kind of protozoan life cycle, in which the organism occurs only as a trophozoite. Division is by binary fission. Because there is no resistant cyst, transmission from host to host must be relatively direct.

Pathogenesis

Although the cause of the inflammatory response in trichomoniasis is not known, it may be the mechanical irritation resulting from contact between the parasite and vaginal epithelium. However, inflammation can occur in areas where parasites are not found, suggesting that the full explanation may be more complicated.

Host Defenses

Relatively little is known about the human immune response to T vaginalis infection. Studies employing experimental animals suggest that antibody may play a protective role.

Whatever protective antibodies are elicited are short-lived, however, and disappear completely in 6 to 16 months.

Epidemiology

Trichomoniasis is a common, worldwide infection. Although sexual intercourse is believed to be the usual means of transfer, some infections probably are acquired through fomites such as towels, toilet seats, and sauna benches; the organisms may spread through mud and water baths as well. Survival studies of T vaginalis in vaginal discharges have shown that these trophozoites can be cultured from toilet seats for 30 minutes or more.

It has been suggested that this organism is frequently transmitted from a woman, serving as a reservoir of infection, to a man, the carrier, and subsequently to another woman. Although non-venereal spread of T vaginalis is a subject of conjecture, little evidence exists on the importance of this means of transmission.

Diagnosis

A wet mount preparation of discharge from the patient should be examined microscopically as a first step in diagnosing T vaginalis infection. The presence of typical pear-shaped trophozoites, usually 7 to 23 μm in length, with “bobbling” motility and, on careful examination, the wavelike movement of the undulating membrane, are usually sufficient to identify T vaginalis. Material that is negative by wet mount examination should be cultured because culturing is a considerably more sensitive, although time-consuming, method of diagnosis.

Control

Because of the frequent role of asymptomatic men in spreading trichomoniasis, control of this infection necessitates examination and, if necessary, treatment of male sex partners. Avoidance of sexual intercourse and the use of condoms are effective ways to prevent transmission.

A number of 5-nitroimidazole compounds are effective antitrichomonal agents. The chemical in this group that is approved for treating trichomoniasis in the United States is metronidazole. (The potential drawbacks of this drug are discussed in the section on control of Giardia.) Treatment of both sexual partners at the same time is recommended to prevent “ping pong” reinfection.

Dientamoeba Fragilis

As its name suggests, this organism was early considered to be an amoeba. More recent studies indicate that it is a flagellate lacking flagella. D fragilis does not form a cyst stage; its trophozoites (most of which have 2 nuclei) usually average 9 to 12 μm (Fig. 80-1). Because these protozoa lack cysts, the question arises as to how the trophozoites, during the process of infection, escape destruction by gastric acidity. The observation that Dientamoeba and Enterobius infections frequently occur in the same individual has produced speculation that D fragilis may transit the stomach inside the pinworm eggs. Clinical infections with Dientamoeba are recorded infrequently, but more in children than in adults. Symptoms may include diarrhea, abdominal distention, nausea, vomiting and weight loss. It is not known whether the relatively infrequent reporting of this parasite is because the disease is self-limiting or because of difficulty in identifying the protozoan stool samples. Therapy includes broad spectrum antibiotics, tetracycline, or paromomycin.

Chilomastic mesnil

Chilomastix mesnili is a nonpathogenic intestinal commensal of humans. The trophozoite is pear-shaped, usually 10 to 15 μm long, with a large anterior cytostome, three forward-directed flagella, and a sharply pointed posterior end. The organism also occurs as a lemon-shaped, uninucleate cyst 7 to 9 μm long (Fig. 80-1).

Balantidium coli

Balantidium coli, the only ciliate and by far the largest organism in this group, is a pathogen. The trophozoites, which are ovoid, 40 to 70 μm or longer, and covered with cilia (Fig. 80-1) live in the large intestine of humans, swine, and perhaps other animals. The trophozoites divide by transverse binary fission. They have a large, kidney-shaped macronucleus and a smaller ovoid micronucleus; conjugation has been described. The cyst form is usually 50 to 55 μm in diameter. Although the usual diet of B coli is believed to be host intestinal contents (hence some infections are asymptomatic), at times these organisms attack the host large intestine (aided apparently by a boring action and the enzyme hyaluronidase) and cause ulcers. In contrast to E histolytica, B coli does not invade extraintestinal tissues. Balantidiasis often is accompanied by diarrhea or dysentery, abdominal pain, nausea, and vomiting. Diagnosis is made by demonstrating cysts or trophozoites in stools or host tissue.

Balantidium infection is acquired by ingesting cysts in fecal material from another parasitized host; water-borne epidemics have been reported. The precise relationship between human and pig Balantidium strains is not clear. The organism is relatively rare in humans and common in pigs. Tetracyclines are the most effective drugs for treating Balantidium infections, but their use for this purpose has investigational status in the United States.

Isospora

Organisms in the genus Isospora are uncommon intestinal parasites of humans. Like Cryptosporidium and Toxoplasma, Isospora is a coccidian parasite, and hence has a complex life cycle including both sexual and asexual stages occurring within the cells of the host's intestinal mucosa. The Isospora life cycle in the human host has been described from intestinal biopsy material from chronically infected patients.

The diagnostic forms of human isosporids are oocysts, inside of which are sporocysts (Fig. 80-1); however, oocysts are transparent and are easily overlooked in stool specimens. The immature oocyst has a single nucleus. Division within the oocyst yields two sporocysts, each with a cyst wall containing four elongate sporozoites. The mature oocyst, usually 28 to 30 μm in length, thus contains two sporocysts, each with four sporozoites.

Most Isospora infections are believed to be asymptomatic. Experimental infections are usually mild and self-limited, consisting of diarrhea and abdominal pain. However, this organism causes severe chronic diarrhea in patients with acquired immune deficiency syndrome (AIDS). It has also been reported to be a cause of chronic travelers' diarrhea in the normal host, where it can mimic giardiasis or cryptosporidiosis. Diagnosis is made by demonstrating oocysts in the feces. Although no animal reservoir has been identified, the rarity (but wide distribution) of human infection raises the possibility that humans are incidental hosts. The treatment of choice is furazolidone; alternatively, trimethoprim-sulfamethoxazole is recommended.

Clinical Manifestations

It is now clear that Cryptosporidium species may be pathogenic for humans. Evidence from clinical studies indicates that these organisms can produce illness in some cases. Cryptosporidium oocysts—the form excreted in feces and used for diagnosis—were found in some of a series of patients with gastroenteritis, but not in patients without intestinal symptoms. The infection occurs most often in children and is characterized by an incubation period averaging 4 to 12 days and a moderate-to-profuse diarrhea lasting 4 to 30 (average 10) days. Although the disease is self-limiting in normal persons, the diarrhea can be chronic and fatal in immunocompromised individuals.

Structure

Members of this genus are intracellular parasites, occurring in large numbers in small intestinal mucosal epithelial cells (Fig. 80-3). The oval oocyst (the form passed in the feces) is 4 to 5 μm long and may be seen to contain four sporozoites.

Figure 80-3

The life cycle of Cryptosporidium. (1-4) Asexual cycle of the endogenous stage: (1) sporozoite or merozoite invading a microvillus of a small intestinal epithelial cell; (2) a fully grown trophozoite; (3) a developing schizont with eight nuclei; (4) a (more...)

Multiplication and Life Cycle

The usual habitat of Cryptosporidium is the vertebrate host intestine, in which the protozoa grow attached to the epithelial cell membrane in the brush border. Both sexual and asexual forms are found in this area (Fig. 80-3). Whether this organism should be regarded as an intracellular or an extracellular parasite is not resolved.

Cryptosporidia have been found in a variety of mammals, birds, and reptiles since their discovery in 1907, but they were not reported to be associated with human disease until 1976. Until recently, they received little attention because few diagnosticians were aware of their existence, because they were considered not pathogenic, and because they are not likely to be encountered in routine stool examinations.

Pathogenesis

Little is known about the mechanism by which these organisms cause disease. They are believed to be noninvasive. Examination of biopsy material from symptomatic patients has revealed a variety of changes in intestinal mucosa, including partial villous atrophy, crypt lengthening, low cuboidal surface epithelium, cellular infiltration of the jejunal and ileal lamina propria, and inflammation. The cause of one fatal case was probably malabsorption resulting from the intestinal damage caused by prolonged protozoal infection.

Although host cells are damaged in cryptosporidiosis, the means by which the organism causes damage is not known. Mechanical destruction and the effects of toxins, enzymes, or immune-mediated mechanisms, working alone or together may be instrumental.

Host Defenses

The fact that cryptosporidiosis is self-limiting in normal persons but usually severe and long-lasting in lower animals and immunocompromised humans indicates that host immune mechanisms are probably involved in eliminating the parasite. Cell-mediated immunity appears to be the primary defense mechanism. Neonatal infections of calves and lambs can produce a severe or fatal diarrhea. Serum antibodies to Cryptosporidium have been shown to develop during recovery from infection.

The importance of cryptosporidiosis in immunocompromised patients generally, and in AIDS patients in particular, should not be underestimated. In this group, cryptosporidiosis can cause diarrhea that is severe, prolonged, and life-threatening. In cryptosporidiosis patients who are immunosuppressed because of drug treatment, the disease can be reversed by withdrawing the drug. Unfortunately, this cure cannot be resorted to with AIDS patients.

Epidemiology

Many questions remain about the epidemiology of cryptosporidiosis. These organisms are not highly host specific, and human infections may be acquired from other humans or from animals. Infection probably is by ingestion of oocysts, although the identification of this infection in the upper respiratory tract of at least three animal species, including humans, raises the possibility that the respiratory route also may be involved. At least one massive outbreak of this infection via drinking water has also been reported.

Diagnosis

Traditionally, cryptosporidiosis is diagnosed by microscopic observation of developmental stages of the organism in an intestinal biopsy specimen. Because Cryptosporidium oocysts have been found to be shed in feces during infection, many researchers have experimented with techniques for recovering these forms in stool specimens. Several studies have found that formalin concentration techniques and a modified Ziehl-Neelsen acid-fast stain are effective (Fig. 80-4). Routine procedures for diagnosing ova and parasites in stools do not generally detect this organism. The physician who suspects Cryptosporidium should so indicate to the laboratory when the specimen is submitted, to ensure appropriate staining. The development of serologic tests employing antibody against these organisms would be a valuable contribution.

Figure 80-4

Cryptosporidium oocysts recovered from stool material and stained by the modified acid-fast techniques (X2,700). (From Garcia LS, Bruckner DA, Brewer TC, Shimizu RY: Cryptosporidium oocysts from stool specimens. J Clin Microbiol 18:185, 1983, with permission.) (more...)

Control

Because so much remains to be learned about the epidemiology of cryptosporidiosis, the only recommendations for prevention of this infection are those usually made for avoiding any pathogen transmitted by the fecal-oral route. Most persons with normal immunity recover spontaneously from cryptosporidiosis and thus do not require therapy directed at the parasite, although they may require supportive treatment. Because this infection may be life-threatening in immunocompromised individuals, however, many antimicrobial agents have been tested for anticryptospiridial effects; no safe, effective therapeutic agent has been discovered.