Chapter 55: Tissue Nematodes

Four of them—Toxocara canis, Baylisascaris procyonis, Trichinella spiralis, and Ancylostoma braziliense—are zoonotic, meaning natural parasites of domestic and wild animals. Although they are capable of infecting humans, they cannot complete their life cycle in the human host. Humans therefore serve only as “accidental hosts,” injured bystanders rather than major participants in the life cycle of these parasites.

The remaining four major tissue nematodes—Wuchereria bancrofti, Brugia malayi, Onchocerca volvulus, and Loa loa—are members of a single superfamily (Filarioidea). All are anthroponotic, meaning they use humans as their definitive host. The thin, thread-like adults live for years in the subcutaneous tissues and lymphatic vessels, where they discharge their live-born offspring called “microfilariae.” These progeny circulate in the blood or migrate in the subcutaneous tissues until they are ingested by a specific bloodsucking insect. Within this insect, they transform into filariform larvae capable of infecting another human when the vector again takes a blood meal.

Table 55–1 summarizes these nematodes, diseases they cause, their definitive host, and usual routes of human infection.

TOXOCARA CANIS: PARASITOLOGY AND LIFE CYCLE

Toxocara canis is a large, intestinal ascarid of canines, including dogs, foxes, and wolves (Figure 55–1). Occasionally, a related organism found in cats (T cati) can behave in a similar fashion. Each female worm discharges approximately 200 000 thick-shelled eggs daily into the fecal stream. After reaching the soil, these eggs embryonate for a minimum of 2 to 3 weeks. Thereafter, the eggs are infectious to canines, humans, and other mammals. The eggs may remain infectious in the soil for months to years. When ingested by a puppy, the larvae exit from the eggshell, penetrate the intestinal mucosa, and migrate through the liver and the right side of the heart to the lung. Here, like the offspring of Ascaris lumbricoides, they burst into the alveolar airspaces and are coughed up and swallowed; thereafter, they mature in the small bowel. However, in fully grown dogs, the life cycle is different: Most of the migrating larvae pass through the pulmonary capillaries and reach the systemic circulation. These larvae eventually are filtered out and encyst in the dog’s tissues, where they lie dormant for months or longer. Hormonal changes and/or diminished immunity in the pregnant bitch stimulate the larvae to resume development, migrate across the placenta, and infect the unborn pups. Larvae may also pass to the newborn puppies in their mother’s milk. Approximately 4 weeks after birth, both the puppies and the lactating mother begin to pass large numbers of eggs in their stools, shed by the adult worms that inhabit their intestinal tract. These eggs embryonate in the soil for 2 to 3 weeks before becoming infectious. The mother may then be superinfected by ingesting the eggs from the soil or eating visceral cysts in an intermediate host such as a rodent.

When humans ingest infectious eggs, the liberated larvae are small enough to pass through the pulmonary capillaries and reach the systemic circulation. Only rarely do larvae break into the alveoli, get coughed up and swallowed to reach the intestine to mature into adults. Instead, larvae in the systemic circulation continue to grow there. When their size exceeds the diameter of the vessel through which they are passing, they penetrate its wall and enter the tissue. The larvae induce a T_H2-type CD4+ response characterized by eosinophilia and IgE production.

TOXOCARIASIS

EPIDEMIOLOGY

Toxocara canis is a cosmopolitan parasite. The infection rate in the 50 million dogs inhabiting the United States is very high; over 80% of puppies and 20% of older animals are parasitized. “Man’s best friend” deposits more than 3500 tons of feces daily in the streets, yards, and parks of America, and there is a real health risk. In some areas, between 10% and 30% of soil samples taken from public parks have contained viable Toxocara eggs. Moreover, serologic surveys of humans indicate that 4% to 20% of the population has ingested these eggs at some time. The incidence of infection appears to be higher in the Southeastern United States; presumably the warm, humid climate prolongs survival of the eggs, thereby increasing exposure. Indeed, seroprevalence rates of more than 50% have been noted in some developing nations. Puppies in the home increase the risk of infection. Clinical manifestations occur predominantly among children 1 to 6 years of age; many have a history of geophagia, suggesting that disease transmission results from direct ingestion of eggs in the soil. Most infections are subclinical, but the incidence of overt disease is likely underreported.

TOXOCARIASIS: CLINICAL ASPECTS

MANIFESTATIONS

The larvae of Toxocara that reach the systemic circulation may invade any tissue of the human body, where they can induce necrosis, bleeding, eosinophilic granulomas, and subsequent fibrosis. The liver, lungs, heart, skeletal muscle, brain, and eye are involved most frequently. The severity of clinical manifestations is related to the number and location of these lesions and the degree to which the host has become sensitized to larval antigens. Children with more intense infection may have fever and an enlarged, tender liver. Those who are seriously ill may develop a skin rash, an enlarged spleen, asthma, recurrent pulmonary infiltrates, abdominal pain, sleep and behavioral changes, focal neurologic defects, and seizures. This illness, called “visceral larva migrans,” often persists for weeks to months. Death may result from respiratory failure, cardiac arrhythmia, or brain damage. In older children and adults, these systemic manifestations are uncommon, although eye invasion by larvae (“ocular larva migrans”) is more common. Typically, unilateral strabismus, loss of red reflex (leukocoria), or decreased visual acuity causes the patient to consult an ophthalmologist. Examination reveals granulomatous endophthalmitis, a reaction to larvae that are often already dead; it is sometimes mistaken for malignant retinoblastoma, and unnecessary enucleations have been performed.

DIAGNOSIS

Stool examination for eggs is not helpful because the parasite seldom reaches adulthood in humans. Definitive diagnosis requires demonstration of the larva in a liver biopsy specimen or at autopsy. A presumptive diagnosis may be made based on the clinical picture: Eosinophilic leukocytosis, elevated serum levels of IgE, and elevated antibody titers to blood group antigens, particularly the group A antigen. An enzyme immunoassay (EIA) using larval antigens has been developed, providing clinicians with a reasonably sensitive (75%) and specific (90%) serologic test. A western blot procedure is somewhat more sensitive but is not widely available. Unfortunately, many patients with related ocular infections remain seronegative; some demonstrate elevated antibody titers within the ocular fluids.

TREATMENT AND PREVENTION

Reduction of the exuberant host immune response is the main goal of treatment. Corticosteroid treatment may be lifesaving if the patient has serious pulmonary, myocardial, or central nervous system (CNS) involvement. Anthelmintic therapy using albendazole is often administered after steroids are started, although the efficacy of this drug remains uncertain. Prevention requires control of indiscriminate defecation by dogs and repeated deworming of household pets. Deworming must begin when the animal is 3 weeks of age and should be repeated every 3 months during the first year of life and twice a year thereafter.

Another nematode that shares clinical and epidemiologic similarities with Toxocara has been increasingly recognized. Baylisascaris procyonis (raccoon roundworm) has predominantly affected children playing in wooded areas that are frequented by raccoons. Raccoon “latrines” may teem with infective eggs, which, when accidentally ingested, may cause a disease that mimics toxocariasis. Unfortunately, this organism has a predilection for neural and eye tissue, and can lead to devastating eosinophilic meningoencephalitis and retinitis. The diagnostic and therapeutic approaches are like those for Toxocara, but the clinical outcome may be fatal, especially when therapy is delayed.

TRICHINELLA SPIRALIS: PARASITOLOGY AND LIFE CYCLE

Adult Trichinella live in the duodenal and jejunal mucosa of carnivores throughout the world, particularly swine, rodents, bears, canines, felines, and marine mammals. Originally thought to be members of a single species, it is now clear that arctic, temperate, and tropical strains of Trichinella demonstrate significant epidemiologic and biologic differences, and they have been reclassified into eight distinct species. Only two species, T spiralis and the arctic species T nativa, display a high level of pathogenicity for humans. This discussion focuses on the former, while highlighting the unique epidemiologic and clinical characteristics of the latter.

Within the host intestinal tissue, the tiny (1.5 mm) male copulates with his larger (3.5 mm) mate and, apparently spent by the effort, dies. Within 1 week, the inseminated female begins to discharge offspring. Unlike those of most nematodes, these progeny undergo intrauterine embryonation and are released as second-stage larvae. The birthing continues for the next 4 to 16 weeks, resulting in the generation of some 1500 larvae, each measuring 6 by 100 μm.

From their submucosal position, the larvae find their way into the vascular system and pass from the right side of the heart through the pulmonary capillary bed to the systemic circulation, where they are distributed throughout the body. Larvae penetrating tissue other than skeletal muscle disintegrate and die. Those finding their way to striated muscle continue to grow, molt, and gradually encapsulate over a period of several weeks. Calcification of the cyst wall begins 6 to 18 months later, but the contained larvae may remain viable for 5 to 10 years (Figure 55–2). The muscles invaded most frequently are the extraocular muscles of the eye, the tongue, the deltoid, pectoral, and intercostal muscles, the diaphragm, and the gastrocnemius. If a second animal feeds on the infected flesh of the original host, the encysted larvae are freed by gastric digestion, penetrate the columnar epithelium of the intestine, and mature just above the lamina propria. This cycle is summarized in Figure 55–3.

TRICHINOSIS

EPIDEMIOLOGY

Trichinosis, also called trichinellosis, is widespread in carnivores worldwide. Among domestic animals, swine are most frequently involved. They acquire the infection by eating dead rats or garbage containing cyst-laden scraps of uncooked meat. Human infection, in turn, results largely from the consumption of improperly prepared pork products. In the United States, agricultural regulations have greatly reduced the incidence of trichinosis, and most pig-associated outbreaks have been traced to pork sausage prepared in the home or in small, unlicensed butcheries. Clusters have also followed feasts on wild pig in California and Hawaii. At present, however, the majority of human cases in the United States, particularly those in Alaska and other western states, have been attributed to consumption of wild animal meat, especially bear meat. Outbreaks among Alaskan and Canadian Inuit populations have followed the ingestion of raw T nativa-infected walrus meat. Outbreaks in Europe have involved horse meat or wild boar flesh. In other areas of the world, infection is commonly acquired from wild animals (“sylvatic sources”), including wild boar, bush pigs, and warthogs.

Human infections occur worldwide. In the United States, the prevalence of cysts found in the diaphragms of patients at autopsy has declined substantially. This decline has been attributed to decreased consumption of pork and pork products; federal guidelines for the commercial preparation of such foodstuffs; the widespread practice of freezing pork, which kills all but arctic strains of T nativa; and legislation requiring the thorough cooking of any meat scraps to be used as hog feed. Nevertheless, it is estimated that many Americans carry live Trichinella in their musculature and that more acquire it annually. Fortunately, the overwhelming majority has a small number of larvae and are asymptomatic. Only 5 to 15 clinically recognized cases are reported annually to federal officials.

PATHOGENESIS AND IMMUNITY

The pathologic lesions of trichinosis are related almost exclusively to the presence of larvae in striated muscle, heart, and CNS. Invaded muscle cells enlarge, lose their cross-striations, and undergo basophilic degeneration. Intense inflammation surrounds the involved area, consisting of neutrophils, lymphocytes, and eosinophils. With the development of specific IgG and IgM antibodies, eosinophil-mediated destruction of circulating larvae begins, production of new larvae is slowed, and the expulsion of adult worms is hastened. A vasculitis demonstrated in some patients has been attributed to deposition of circulating immune complexes in the walls of the vessels.

TRICHINOSIS: CLINICAL ASPECTS

MANIFESTATIONS

One or two days after the host ingests tainted meat, the newly matured adults penetrate the intestinal mucosa, producing nausea, abdominal pain, and diarrhea. In mild infections, these symptoms may be overlooked, except in a careful retrospective analysis; in more serious infections, they may persist for several days and render the patient prostrate. Diarrhea persisting for a period of weeks has been characteristic of T nativa outbreaks after ingestion of walrus meat by the Inuit population of northern Canada. Larval invasion of striated muscle begins approximately 1 week later and initiates the more characteristic phase of the disease, which may last for about 6 weeks. Patients in whom 10 or fewer larvae are deposited per gram of tissue are usually asymptomatic; those with 100 or more generally develop significant disease; and those with 1000 to 5000 have a very stormy course that occasionally ends in death. Fever, muscle pain, muscle tenderness, and weakness are the most prominent manifestations of trichinosis. Patients may also display eyelid swelling, a maculopapular skin rash, and small hemorrhages beneath the conjunctiva of the eye and the nails of the digits. Hemoptysis and pulmonary consolidation are common in severe infections. If there is myocardial involvement, electrocardiographic abnormalities, tachycardia, or congestive heart failure may be seen. Central nervous system invasion is marked by encephalitis, meningitis, and polyneuritis. Delirium, psychosis, paresis, and coma can follow.

DIAGNOSIS

Trichinosis presents in a protean fashion, which can delay diagnosis and impact clinical outcomes. The most consistent laboratory abnormality is an eosinophilic leukocytosis during the second week of illness, which persists for the remainder of the clinical course. Eosinophils typically range from 15% to 50% of the white cell count, and in some patients, this may induce extensive damage to the cardiac endothelium. In severe or terminal cases, the eosinophilia may disappear altogether. Serum levels of IgE and muscle enzymes are elevated in most clinically ill patients.

There are a number of valuable serologic tests, including indirect fluorescent antibody and enzyme-linked immunosorbent assay. Significant antibody titers are generally absent before the third week of illness, but may then persist indefinitely.

Biopsy of the deltoid or gastrocnemius muscles during the third week of illness often reveals encysted larvae (Figure 55–2B).

TREATMENT

Patients with severe edema, pulmonary manifestations, myocardial involvement, or CNS disease are treated with corticosteroids. The value of specific anthelmintic therapy remains controversial. The mortality rate of symptomatic patients is 1%, rising to 10% if the CNS is involved. Mebendazole and albendazole halt the production of new larvae, but in severe infection, the destruction of tissue larvae may provoke a hazardous hypersensitivity response in the host. This may be moderated by initiating corticosteroids before treating with antihelminthics.

PREVENTION

Control of trichinosis requires adherence to feeding regulations for pigs, and limiting contact between domestic pigs and wild animals, particularly rodents, who might be carrying Trichinella larvae in their tissues. Domestically, care should be taken to cook pork to an internal temperature of at least 76.6°C, or freeze it at −15°C for 3 weeks before cooking. Trichinella nativa in the flesh of arctic animals may survive freezing for a year or more. All strains may survive apparently adequate cooking in microwave ovens due to the variability in the internal temperatures achieved.

Cutaneous larva migrans, or “creeping eruption,” is an infection of the skin caused by the larvae of a number of animal and human parasites, most commonly the dog and cat hookworm A braziliense. Adult worms live and copulate in the intestines of infected animals. Eggs discharged in animal feces onto warm, moist, sandy soil then develop into filariform larvae capable of penetrating mammalian skin on contact, just as with human hookworm infection. These parasites are common in tropical areas worldwide; in the United States, parasite transmission is particularly common in the beach areas of the southern Atlantic and Gulf states.

However, these species are not well adapted to human hosts, and larvae rarely make it across the lung to reach the human intestines or develop further within them. Rather, they may migrate within the skin for a period of weeks to months. Clinically, the patient notes a pruritic, raised, red, irregularly linear lesion 10 to 20 cm long. Skin excoriation from scratching enhances the likelihood of secondary bacterial infection. Some patients develop transient, migratory pulmonary infiltrations associated with peripheral eosinophilia, probably reflecting pulmonary migration of larvae. Larvae are rarely found in either sputum or skin biopsies, and the diagnosis must be established on clinical grounds (Figure 55–4).

Cutaneous larva migrans responds well to albendazole or ivermectin. Antihistamines and antibiotics may be helpful in controlling pruritus and secondary bacterial infection, respectively.

Lymphatic filariasis encompasses a group of diseases produced by certain members of the superfamily Filarioidea (“thread-like”) that inhabit the human lymphatic system. Their presence induces an acute inflammatory reaction, chronic lymphatic blockade, and, in some cases, grotesque lymphedematous swelling of the extremities and genitalia. When the skin becomes rough and thickened over time, this is called elephantiasis.

WUCHERERIA AND BRUGIA: PARASITOLOGY AND LIFE CYCLE

The two agents most commonly responsible for lymphatic filariasis are W bancrofti and B malayi. Both are thread-like worms that lie coiled in the lymphatic vessels, male and female together, for the duration of their decade-long lifespan. The female W bancrofti measures 100 mm in length, and the male 40 mm. Brugia malayi adults are approximately half these sizes. The gravid females produce large numbers of embryonated eggs. At oviposition, the embryos uncoil to their full length (200-300 μm) to become microfilariae (“small threads”). The shell of the egg elongates to accommodate the embryo and is retained as a thin, flexible sheath. Although the offspring of the two species resemble each other, they may be differentiated on the basis of length, staining characteristics, and internal structure (Table 55–2). The microfilariae eventually reach the blood (Figure 55–5). In most W bancrofti and B malayi infections, they accumulate in the pulmonary vessels during the day. At night, possibly in response to changes in oxygen tension, they spill out into the peripheral circulation, where they are found in greatest numbers between 9 pm and 2 am. A Polynesian strain of W bancrofti displays a different periodicity, with the peak concentration of organisms occurring in the early evening. Periodicity has an important epidemiologic consequence, because it happens in response to the species of mosquito that serves as vector and intermediate host: To improve their chances of being taken up during the blood meal of a mosquito, the different filarial species enter the bloodstream during the nighttime when that mosquito is most likely to bite. Presumably, they do not spend all their time in the peripheral blood because doing so would increase their odds of being cleared via the spleen and liver.

Once ingested by a mosquito during the blood meal, the microfilariae enter its thoracic muscles and transform first into rhabditiform and then into filariform larvae. The latter actively penetrate the human skin at the feeding site when the mosquito takes its next meal. Within the new host, the parasite migrates to the lymphatic vessels, undergoes a series of molts, and reaches adulthood in 6 to 12 months (Figure 55–6). Bancroftian filariasis is exclusive to humans, whereas certain strains of brugian filariasis can also infect domestic and wild animals. The life cycle is illustrated in Figure 55–7.

Adult filarial worms have a fascinating feature: They carry endosymbiotic bacteria of the genus Wolbachia in their gut. These bacteria are beneficial to the worm in ways that are not yet fully understood. However, adult worms seem much healthier when their Wolbachia are healthy, and when Wolbachia are not present they are less able to reproduce. This observation has implications for disease treatment and control, as described below.

LYMPHATIC FILARIASIS

EPIDEMIOLOGY

Lymphatic filariasis currently infects about 120 million people in Africa, Latin America, the Pacific Islands, and Asia; most of these cases are concentrated in Asia. Wuchereria bancrofti, transmitted primarily by mosquitoes of the genera Anopheles or Culex, is the more cosmopolitan of the two species; it is found in patchy distribution throughout the poorly sanitized, densely crowded urban areas of all three continents.

Brugia malayi, transmitted by mosquitoes of the genus Mansonia, is confined to the rural coastal areas of Asia and the South Pacific. Strains with an unusual periodicity have been found in animals. In the eastern Indonesian archipelago, a closely related species, B timori, is transmitted by night-feeding anopheline mosquitoes.

PATHOLOGY AND PATHOGENESIS

Pathologic changes, which are confined primarily to the lymphatic system, can be divided into acute and chronic lesions. In acute disease, the presence of molting adolescent worms and dead or dying adults stimulates dilatation of the lymphatics, hyperplastic changes in the vessel endothelium, lymphatic infiltration by lymphocytes, plasma cells, and eosinophils, and thrombus formation (ie, acute lymphangitis). These developments are followed by granuloma formation, fibrosis, and permanent lymphatic obstruction. Repeated infections eventually result in massive lymphatic blockade. The skin and subcutaneous tissues become edematous, thickened, and fibrotic. Dilated lymphatics may rupture, spilling lymph into the tissues or body cavities, including the ureters. Bacterial and fungal superinfections of the skin often supervene and contribute to tissue damage.

LYMPHATIC FILARIASIS: CLINICAL ASPECTS

MANIFESTATIONS

Individuals who enter endemic areas as adults and reside therein for months to years often present with acute lymphadenitis, urticaria, eosinophilia, and elevated serum IgE levels; they seldom go on to develop lymphatic obstruction. A significant proportion of indigenous populations present with asymptomatic microfilaremia. Some of these spontaneously clear their infection, whereas others go on to experience “filarial fevers” and lymphadenitis 8 to 12 months after exposure. The fever is typically low grade; in more serious cases, however, temperatures as high as 40°C, chills, muscle pains, and other systemic manifestations may be seen. Classically, lymphadenitis is first noted in the femoral area as an enlarged, red, tender lump. The inflammation spreads centrifugally down the lymphatic channels of the leg. The lymphatic vessels become enlarged and tender, the overlying skin warm, red, and edematous. In Bancroftian filariasis, the lymphatic vessels of the testicle, epididymis, and spermatic cord are frequently involved, producing a painful orchitis, epididymitis, and funiculitis; inflamed retroperitoneal vessels may simulate an acute abdomen. Epitrochlear, axillary, and other lymphatic vessels are involved less frequently. These acute manifestations last a few days and resolve spontaneously, only to recur periodically over a period of weeks to months.

With repeated infection, permanent lymphatic obstruction develops in the involved areas. Edema, ascites, pleural effusion, hydrocele, and joint effusion may result. The lymphadenopathy persists and the palpably swollen lymphatic channels may rupture, producing an abscess or draining sinus. Rupture of intraabdominal vessels may give rise to chylous ascites or urine. In patients heavily and repeatedly infected over a period of decades, elephantiasis may develop. Such patients may continue to experience acute inflammatory episodes. Recurrent streptococcal and staphylococcal skin infections are common sequels to this condition, which in turn lead to more lymphatic damage, perpetuating a cycle of pain and suffering.

In southern India, Pakistan, Sri Lanka, Indonesia, Southeast Asia, and East Africa, an aberrant form of filariasis is seen. This form, termed tropical eosinophilia syndrome or tropical pulmonary eosinophilia, is characterized by an intense eosinophilia, elevated levels of IgE, high titers of filarial antibodies, the absence of microfilariae from the circulating blood, and a chronic clinical course marked by massive enlargement of the lymph nodes and spleen in children or chronic cough, nocturnal bronchospasm, and pulmonary infiltrates in adults. Untreated, it may progress to interstitial pulmonary fibrosis. Microfilariae have been found in the tissues of such patients, and the clinical manifestations may be terminated with antifilarial treatment. It is believed that this syndrome is precipitated by the removal of circulating microfilariae by an IgG-dependent, cell-mediated immune reaction. Microfilariae are trapped in various tissue sites, where they incite an eosinophilic inflammatory response, granuloma formation, and fibrosis.

DIAGNOSIS

Eosinophilia is usually present during the acute inflammatory episodes, but definitive diagnosis requires the presence of microfilariae in the blood or lymphatic, ascitic, or pleural fluid. They are sought in Giemsa- or Wright-stained thick and thin smears. The major distinguishing features of these and other microfilariae are listed in Table 55–2. Because the appearance of the microfilariae is usually periodic, specimen collection must be properly timed. If the parasitemia is below the threshold of detection, the specimen may be concentrated before it is examined. If this procedure proves fruitless, the patient may be retested after being challenged with the antifilarial agent diethylcarbamazine (DEC). This drug stimulates the migration of the microfilariae from the pulmonary to the systemic circulation and enhances the possibility of their recovery. Once found, the microfilariae can be differentiated from those produced by other species of filariae. A number of serologic tests have been used for the diagnosis of microfilaremic disease, but until recently they have lacked adequate sensitivity and specificity; IgG4 testing is the most specific for filarial infection, although cross-reactivity to other tissue parasites is well described, and these tests are of little diagnostic significance in individuals indigenous to the endemic area, because many people have experienced a prior filarial infection. Circulating filarial antigens can be found in most microfilaremic patients and also in some seropositive nonmicrofilaremic individuals. Antigen detection may thus prove to be a specific indicator of active disease, although the test is not widely available. Tropical eosinophilia is diagnosed as described previously.

TREATMENT AND PREVENTION

Diethylcarbamazine eliminates the microfilariae from the blood and may injure or even kill some of the adult worms, resulting in long-term suppression of the infection or parasitologic cure in some cases. Frequently, the dying microfilariae stimulate an allergic reaction in the host. This response is occasionally severe, requiring antihistamines and corticosteroids. This phenomenon is even more common among patients coinfected with onchocerciasis (see later), and thus coinfection with that condition should be ruled out before DEC is dosed in endemic areas. However, DEC use in lymphatic filariasis is generally safe, so much so that it is sometimes added to cooking salt in highly endemic areas or dosed intermittently on a mass scale; the idea is to suppress microfilaremia, which benefits the individual patient and the entire community by reducing transmission pressure. Ivermectin has a similar effect on microfilariae, and it can temporarily clear microfilaremia after the administration of a single dose. Albendazole seems to have beneficial effects on both microfilariae and adult worms. The antibiotic doxycycline has been demonstrated to kill endosymbiotic Wolbachia bacteria, and with prolonged administration, alone or in combination with other agents such as albendazole, may ultimately help to kill the adult worms. The tissue changes of elephantiasis are often irreversible, but the enlargement of the extremities may be ameliorated with pressure bandages or plastic surgery. Treatment and prevention of bacterial superinfection is essential, and can be augmented by access to proper shoe gear plus soap and water. Control programs combine mosquito control with mass treatment of the entire population.

Onchocerciasis, or “river blindness,” is produced by the skin filaria O volvulus. The disease is characterized by subcutaneous nodules, thickened pruritic skin, and—in some cases—blindness.

ONCHOCERCA VOLVULUS: PARASITOLOGY AND LIFE CYCLE

The 40 to 60 cm long, thread-like female adults lie with their diminutive male partners in coiled masses within fibrous subcutaneous and deep tissue nodules. The female gives birth to more than 2000 microfilariae each day of her 15-year lifespan. These progeny lose their sheaths soon after leaving the uterus, exit from the fibrous capsule, and migrate for up to 2 years in the subcutaneous tissues, skin (Figure 55–8), and eye. In contrast to the microfilariae of lymphatic filariasis that travel in the bloodstream, the microfilariae of onchocerciasis migrate through the subcutaneous tissues, where ultimately they die or are ingested by black flies of the genus Simulium. After transformation into filariform larvae, they are transmitted to another human host. There they molt repeatedly over 6 to 12 months before reaching adulthood and becoming encapsulated. Like the worms of lymphatic filariais, adult O volvulus parasites appear to harbor endosymbiotic Wolbachia bacteria. The name “river blindness” derives from the association of the infection with exposure to turbulent, fast-moving streams, where the vector Simulium fly breeds. The Onchocerca life cycle is illustrated in Figure 55–9.

ONCHOCERCIASIS

EPIDEMIOLOGY

Onchocerciasis infects approximately 37 million persons, rendering approximately 500 000 of them blind. Most of the afflicted live in sub-Saharan Africa, over half of these in Nigeria and the Congo. Foci of infection are also found in Yemen, Saudi Arabia, and Latin America from southern Mexico through the northern half of South America. It has been suggested that the disease was introduced into South America by West Africans enslaved and transported to the New World for the purpose of mining gold in the mountain streams of Venezuela and Colombia. The Central American foci probably date from Napoleon III’s use of Sudanese troops to support his invasion of Mexico in 1862. Onchocerciasis persists on the high slopes of the Sierra, where coffee plantations lie along the rapidly flowing streams that serve as breeding places for Simulium species.

ONCHOCERCIASIS: CLINICAL ASPECTS

MANIFESTATIONS

The subcutaneous nodules that harbor the adult worms can be located anywhere on the body, generally over bony prominences. In Mexico and Guatemala, where flies typically bite the upper part of the body, they are concentrated on the head; in South America and Africa, they are found primarily on the trunk and legs. Although nodules may number in the hundreds, most infected persons have fewer than 10. The nodules are firm, movable, and measure 1 to 3 cm in diameter. Unless the nodule is located over a joint, pain and tenderness are unusual.

Of greater consequence to the patient are the effects of the presence of microfilariae in the tissues. An immediate hypersensitivity reaction to antigens released by dead or dying parasites results in acute and chronic inflammatory reactions. In the skin, this manifests as a papular or erysipelas-like rash with severe itching. In time, due to the trauma of repeated scratching, the skin thickens and lichenifies. As subepidermal elastic tissue is lost, wrinkles and large skin folds or “hanging groins” may form. In parts of Africa, fibrosing, obstructive lymphadenitis may result in elephantiasis. The most devastating lesions, however, are caused by invasion of the eye. Iritis and chorioretinitis can lead to decreased visual acuity and, in time, total blindness. Even if the anterior eye alone is infected, scarring and opacification of the cornea may cause irreversible blindness when the optic disk atrophies due to lack of light perception. In Central America, eye lesions may be seen in up to 30% of infected patients. In certain communities in West Africa, 85% of the population has ocular lesions, and 50% of the adult male population is blind. Onchocerca volvulus microfilariae may be responsible for an unusual form of epilepsy called “nodding syndrome,” although this is not proven.

DIAGNOSIS

Patients from endemic areas who present with subcutaneous nodules, unexplained pruritus, or ocular changes should be ruled out for onchocerciasis. The diagnosis is confirmed by demonstrating the microfilariae in thin skin snips taken from an involved area (Figure 55–10). When the eye is involved, the organism may sometimes be seen in the anterior chamber with the help of a slit lamp. Topical DEC can be applied safely to a patch of skin, which will yield a local wheal and flare when microfilariae die and release antigens. Previously, a technique called the “Mazzotti test” was performed, in which DEC was administered in a low dose to patients, who were then observed for a flare of their pruritus due to rapid microfilariae death and resultant inflammatory reactions. However, this practice is generally discouraged for safety concerns, especially when skin snips can be obtained.

TREATMENT AND PREVENTION

Traditionally, DEC has been used to kill the microfilariae. Treatment was begun with very small doses to prevent rapid parasite destruction and the attendant allergic consequences. This consideration was particularly important when the eye was involved, because a treatment-induced inflammatory reaction can damage the eye further. This hypersensitivity reaction, sometimes called a “Mazzotti reaction,” can have grave consequences for the patient.

Ivermectin is a safer and more effective microfilaricide than DEC and does not appear to induce the severe allergic manifestations seen with the latter agent. However, because it does not kill the adult worm, periodic re-treatment is necessary. Mass treatment or chemoprophylaxis with ivermectin has been a major achievement. The manufacturer of this drug has pledged a virtually unlimited, cost-free supply of ivermectin to governments that administer it on a mass scale to endemic populations. This improves symptoms, and may reduce parasitism in biting Simulium flies, helping to interrupt the transmission cycle. Mass ivermectin administration has allowed communities to reclaim large areas of arable land in Africa previously abandoned because of disease burden. However, because ivermectin does not fully cure the individual patient, retreatment is required. Furthermore, ivermectin carries a risk of perversely facilitating the entry of Loa loa worms (see later) into the CNS of patients coinfected with that parasite, thus posing challenges for mass drug administration in areas endemic for both infections.

The finding that doxycycline is toxic to endosymbiotic Wolbachia has led to interest in an approach similar to that being adopted in lymphatic filariasis, in which doxycycline is combined with ivermectin or albendazole. The goal is to simultaneously kill microfilariae with the antihelminthic while gradually killing—or at least rendering sterile—the adult worms with the antibiotic. Unfortunately, prolonged courses of doxycycline are not practical to administer on a mass scale, and thus this approach is generally reserved for individual patients.

Progress has been substantial, although no fully satisfactory methods of control have yet been developed. There is no effective vaccine. Application of insecticides to the vector’s breeding waters must be sustained for decades to disrupt transmission permanently, because the parasite is so long-lived within humans. A World Health Organization-funded Simulium larva control program using aerial insecticides has succeeded in interrupting transmission of onchocerciasis in parts of the savanna regions of West Africa.

Loiasis is a filarial disease of West Africa produced by the eye worm, L loa. Biting deer flies of the genus Chrysops serve as vectors. The female produces sheathed microfilariae, which are found in the bloodstream during daytime hours—because that is the time when the flies bite their victims (Figure 55–11). Unlike onchocerciasis, and more similar to lymphatic filariasis, it is the adult worm rather than the microfilariae that cause clinical illness. The long-lived adults migrate continuously through the subcutaneous tissues of humans at a maximum rate of about 1 cm/hour. During migration, they may produce localized areas of allergic inflammation termed “Calabar swellings.” These may appear as egg-sized lesions or swollen extremities which persist for 2 to 3 days and may be accompanied by fever, itching, urticaria, and pain, before they resolve fully and spontaneously. Occasionally, the adult worms may cross under the conjunctiva of the eye, producing tearing, pain, and alarm (Figure 55–12). However, in contrast to onchocerciasis, this phenomenon is harmless and does not threaten the patient’s sight.

The diagnosis is made by recovering the adult worm from the eye or by isolating the characteristic microfilariae from the blood or Calabar swellings. Eosinophilia is common. Diethylcarbamazine destroys microfilariae, but is less effective in killing the adults, and must be administered cautiously to avoid marked allergic reactions. Albendazole slowly decreases microfilarial levels without producing allergic reactions, possibly by preferential action on the adult worms. In some cases, symptoms persist for years, in spite of treatment, until the adults are removed while they cross the eye, or until they die of old age. As described above, ivermectin is contraindicated in patients with loiasis: for unknown reasons, ivermectin may ironically make things worse by facilitating adult L loa entry into the CNS, thus causing dangerous meningoencephalopathy. Unfortunately, L loa adults do not harbor endosymbiotic Wolbachia bacteria, making doxycycline ineffective.

Other microfilarial parasites have been detected in humans, including species of Mansonella. These are transmitted to people during the bite of the Culicoides midge. For generations, these worms were felt to be harmless to patients, and their importance in parasitology was limited to distinguishing them from “pathogenic” microfilariae found in the blood. However, this opinion may be changing. It is now believed that M perstans may cause a wide variety of problems, including fever, fatigue, headache, arthralgias, CNS disturbances, and occasionally migration across the eye, as seen in loiasis. Like most other microfilarial infections, their adults contain endosymbiotic Wolbachia, and treatment with doxycycline may accelerate clearance of the adult parasites; whether this will lead to widespread clinical benefit is unclear.

The guinea worm, Dracunculus mediensis, deserves inclusion here as an example of successful control of a parasitic infection. Guinea worms are transmitted when humans drink water contaminated with infected, tiny copepods of the Cyclops family. Larval Dracunculus worms exit Cyclops in the human gut, then migrate to the loose connective tissues and mate. The female may grow to more than 60 cm in length. Eventually she migrates to the skin, where her uterus protrudes into the environment, releasing young into the water when the patient bathes. These exit sites are exquisitely painful, often become secondarily infected, and may cause orthopedic injury if an ankle or knee joint is involved. Pulling on the uterus too quickly leads to worm injury and death, making the situation worse; only painstaking, gradual removal over time may succeed. Prevention of this painful and disfiguring condition has been achieved to a tremendous degree by simply filtering the water before it is consumed, as well as by applying larvicides to the water supply. Currently, only Sudan is still believed to have ongoing transmission. The recent discovery that dogs are also parasitized poses a barrier to full global eradication of this parasite.