Lymphatic Filariae

Onchocerca Volvulus

Minor Filariae

Several other minor filarial nematodes parasitize humans; the pathology depends on the tissues preferred by the worms. In addition, humans occasionally are infected with dog heartworm larvae, which are unable to mature in human tissues but can cause lesions.

Clinical Manifestations

In lymphatic filariasis, disease is caused by the presence of worms in the regional lymphatic vessels and, particularly, by the host response to the worms and worm products. The microfilariae are released into the blood. Infections involving small numbers of worms are often asymptomatic. Early symptoms of lymphatic filariasis consist of intermittent fever and enlarged, tender lymph nodes. The inguinal lymph nodes are very often involved. The lymphatic vessels that drain into the lymph nodes and that harbor the developing and adult worms also become inflamed and painful. In more chronic infections, there may be pain also in the epididymis and testes. Swollen lymphatics may burst and drain into the genitourinary system; the resulting chyluria is sometimes the symptom that brings the patient to a doctor.

In a small number of chronic cases, permanent lymphatic dysfunction caused by repeated exposure to infection over a number of years results in the massive lymphedema and accumulation of excess tissue known as elephantiasis.

Structure and Classification

Adult Wuchereria and Brugia are elongated and slender (30 to 100 mm by 100 to 300 μm); males are about half the size of females. Microfilariae are the diameter of a red blood cell and 250 to 300 μm long. They are enclosed in a characteristic sheath. In addition to B malay i, some other, related Brugia species can infect humans or animals; they resemble B malayi in structure and life cycle, and are not discussed here. B timori, found only in Indonesia, is similar to B malayi, but is larger.

Multiplication and Life Cycle

The filariae require an intermediate arthropod host to complete their life cycle (Fig. 92-1). However, no multiplication takes place in the intermediate host. Adult male and female worms live in regional lymphatic vessels, where the female produces a large number of microfilariae, which circulate in the blood and may be ingested by a feeding vector mosquito. The female worms show a circadian periodicity in microfilaria production. The time of peak production varies among the species and geographic strains of worms and usually corresponds to the peak feeding period of the vector mosquitoes. Microfilariae ingested by a vector mosquito migrate out of the midgut to the thoracic muscles, where they develop, molt several times, and finally migrate to the mouthparts of the mosquito as infective larvae. As the infective mosquito feeds on another host, the larvae leave the proboscis and enter the puncture wound made by the mosquito. Larvae quickly migrate to the lymphatics, where they mature, mate, and produce microfilariae in the new host. The time from infection until microfilariae can be detected in the blood varies from 3 to many months. There is no reliable information on the average life span of adult worms; however, humans who leave endemic areas have been observed to have circulating microfilariae for several years.

Figure 92-1

Life cycle of Wuchereria and Brugia.

Pathogenesis

Infective larvae from a feeding vector mosquito migrate to the regional lymphatic vessels and by inducing a host inflammatory reaction cause the eventual blockage and edema characteristic of W bancrofti and B malayi infections (Fig. 92-1). The pathology varies greatly from one individual to another, and the exact mechanisms are not completely understood. The host reaction to the parasite is considerable and worsens when the worms molt, when the females first begin to produce microfilariae, and when the worms die and degenerate. Lymphatic vessels are often partially or completely blocked by lymph thrombi, by masses of dead worms, or by endothelial proliferation, fibrin deposition, and granulomatous reactions. Lymph stasis favors secondary bacterial and mycotic infection. The initial inflammation of regional lymph nodes and major lymphatic vessels may be followed by a prolonged asymptomatic period and then by recurring attacks of lymphangitis and “filarial fever” over a period of years. Figure 92-2 shows an example of elephantiasis, a grotesque enlargement of the infected area that develops when recurring attacks of lymphangitis result in permanent lymphatic blockage and lymphedema. The exact cause of elephantiasis is not understood; however, repeated exposure appears to lead to production of abnormally large amounts of collagenous material and to fibrosis of the tissue around the affected lymphatics.

Figure 92-2

Elephantiasis of leg caused by chronic infection with the filarial nematode Wuchereria bancrofti. (Courtesy of Shoyei Yamauchi, Honolulu, HI.)

Host Defenses

The reaction to developing and adult worms results in endothelial cell proliferation and thrombus formation within the lymphatic vessels. Some aspects of the wide disease spectrum seen in lymphatic filariasis can be correlated with host immune responses. Individuals living in endemic areas and frequently bitten by infective mosquito vectors vary in clinical manifestations. Patients with characteristic symptoms such as recurring fever and regional lymphangitis may or may not have microfilariae in peripheral blood. Although antibodies to microfilariae and adult worms may be present, they do not seem to prevent reinfection or disease, since in endemic areas the proportion of exposed individuals who have microfilariae or clinical symptoms may increase until middle age. As a general rule, adults not previously infected with lymphatic filariae will show symptoms, but not circulating microfilariae, following infection with large numbers of infective larvae. Patients with elephantiasis also usually do not have circulating microfilariae. They do, however, have high levels of antibody to microfilariae and increased lymphocyte proliferative responses to adult worm antigens.

Epidemiology

Wuchereria bancrofti is prevalent in many parts of the tropics and subtropics. Species from three major genera of mosquitoes that serve as vectors are the common house mosquito Culex pipiens quinquefasciatus (C fatigans) in many urban centers, Aedes species in the South Pacific islands, and Anopheles species in more isolated rural areas. The relation between the degree and frequency of infection and the development of the disease is still not fully understood; severe disease such as elephantiasis develops gradually as a result of repeated exposure. Circulating microfilariae may persist for many years in the absence of specific symptoms.

Humans previously were assumed to be the only hosts for W bancrofti; however, studies have shown that several species of monkeys can be infected experimentally with infective stage W bancrofti larvae recovered from mosquitoes allowed to feed on infected human volunteers. No naturally infected reservoirs other than humans have been identified.

Brugia malayi differs somewhat from W bancrofti in epidemiology. Whereas W bancrofti is prevalent in tropical areas all over the world, B malayi is found mainly in Southeast Asia. In contrast to W bancrofti, which is transmitted by mosquitoes of the three major genera, the principal mosquito vectors of B malayi belong to the genus Mansonia. B malayi is less host-specific than W bancrofti; it has been recovered from naturally infected monkeys, cats, and dogs, and has been maintained in several laboratory animals.

Diagnosis

Enlarged and tender lymph nodes, especially in the inguinal region, or inflammation of lymphatic vessels in the extremities should alert physicians in an endemic area to filariasis. Definitive diagnosis may be accomplished by identifying microfilariae in thick blood smears (Fig. 92-1). Species identification is based on the presence of a sheath and the position of terminal nuclei and the size of the cephalic space. Because of the nocturnal periodicity of microfilariae, blood smears are better made at night when microfilarial levels are usually higher. Light infections may be detected by using one of several concentration methods.

Unfortunately, microfilariae may not be present in the blood during the early and late stages of the disease. When microfilariae are not detectable, a history of recurrent episodes of lymphangitis and lymphadenitis may form the basis for a presumptive diagnosis. Skin tests have been largely unsatisfactory, and commercial antigen is not widely available. Serologic tests are useful in epidemiologic studies, but to date have had limited value in the management of individual cases. Molecular cloning of antigens and antigen capture techniques are showing promise. New developments in ultrasonography and lymphoangioscintigraphy may also contribute to diagnosis.

Control

Attempts to reduce the prevalence of lymphatic filariae include vector control and mass treatment campaigns using diethylcarbamazine citrate. Some mass treatment programs have used table salt medicated with diethylcarbamazine. This drug significantly reduces the level of microfilariae in the blood. However, it must be given over a prolonged period, and frequent side effects, such as fever, vertigo, headaches, nausea, and lymphatic inflammation, discourage patient cooperation. Ivermectin, a drug that has recently been shown to be effective in the treatment of onchocerciasis, is being evaluated for use in lymphatic filariasis. Neither drug is very effective at killing adult worms. Combinations of diethylcarbamazine and ivermectin are being tested. In some areas single doses of these drugs in combination or singly are also being evaluated. Fewer side effects are experienced with the shorter treatments.

Clinical Manifestations

Changes in skin pigmentation are often the first obvious signs of Onchocerca infection. Later stages of dermatitis present as atrophy and loss of skin elasticity. Although lymph nodes may become involved in onchocerciasis, involvement is not as prominent as with the lymphatic filariae. The subcutaneous nodules that harbor adult Onchocerca are usually firm and non-tender. They vary in size and location but usually are easily recognized when they occur in geographic areas where the disease is endemic. However, in some geographic regions, nodules may be in deeper tissue, and thus not easily palpable.

The most serious clinical manifestation of onchocerciasis is blindness, caused by microfilariae that wander into the eye. In endemic areas, corneal opacities resulting from the reaction to dying microfilariae often suggest onchocercal infection. Alternatively, active living microfilariae may be seen when the eye is examined with a slit lamp.

Structure

Adult Onchocerca may be up to 60 cm long, but are usually coiled in subcutaneous nodules. The microfilariae are slightly smaller than those of W bancrofti and B malayi and differ from them in lacking a sheath, having a different nuclear arrangement, and not usually being found in the blood.

Multiplication and Life Cycle

Figure 92-3 shows the life cycle of Onchocerca. The microfilariae produced by adult female worms in subcutaneous nodules migrate into the skin and connective tissue; they do not generally enter the circulatory system. Microfilariae are ingested by vector blackflies, develop to the infective stage in the muscles of the flies, and then migrate to the mouth parts. When the infected flies feed on a new host, the larvae leave the mouth parts and enter the wound produced by the biting fly. Developing male and female worms congregate in subcutaneous tissue where they usually induce formation of a nodule.

Figure 92-3

Life cycle of Onchocerca.

Pathogenesis

Adult worms in the subcutaneous tissues cause varying degrees of inflammation and may induce subcutaneous nodules. Nodules appear 3 to 4 months after infection, but microfilariae are not generally detectable until I year after infection. Adult worms may be surrounded by an inflammatory response that progresses to granuloma formation and fibrosis or calcification, depending on the condition of the worm and age of the nodule (Fig. 92-3).

Microfilariae appear to move upward, and in chronic heavy infections may be seen in the eye. Ocular damage is thought to be due both to the trauma caused by living microfilariae and to a hypersensitivity reaction to dead ones. A major problem in the management of onchocerciasis patients is the acute inflammatory response to dying microfilariae in the eye during treatment. Antigen-antibody complexes probably play a role in the development of eye lesions resulting from microfilariae.

Host Defenses

Nodules containing adult worms are surrounded by inflammatory cells that are replaced by collagen and fibrotic tissue, thereby localizing the worms. A study of nodules has shown that they are areas of high cellular activity. Some microfilariae appear to be killed before they ever leave the nodules where they are produced by the female worm. Obviously many others escape the chronic inflammatory responses and the granulomas commonly seen surrounding nematodes in tissue. The exact composition of the nodules varies, depending on the distance from the adult worms and the age of the nodule. In general, neutrophils are followed by eosinophils and macrophages. The involvement of eosinophils in killing microfilariae in untreated patients suggests specific immune reactions similar to those reported in other helminth infections. The fibrous outer layer of the nodule contains blood vessels, which may be surrounded in older nodules by cellular infiltrates that include plasma cells and eosinophils.

Epidemiology

Transmission occurs through bites of vector blackflies in the family Simuliidae. Although a few vector species breed in slow-moving streams, most require fast-flowing, highly oxygenated streams or rivers. For this reason, ocular onchocerciasis is often called “river blindness.”

Onchocerciasis is prevalent in many parts of tropical Africa and has been reported in a few places in the Middle East. In the Western hemisphere, it is an important and widespread infection in Guatemala and the southern states of Mexico. It also appears in other areas of Central America, and a few foci have been found in Venezuela, Colombia, Surinam, Brazil, and Ecuador.

Diagnosis

Onchocerciasis is suggested by subcutaneous nodules or by the characteristic scaly dermatitis in individuals living in endemic areas. Positive diagnosis is usually made by identifying microfilariae in a superficial skin biopsy made with a scalpel or an appropriate punch. The skin samples, which are usually taken from the shoulder, are placed in a drop of saline or distilled water on a microscope slide, incubated for 30 minutes, and examined (Fig. 92-3). The diagnosis may also be made by finding adult worms in nodules or by observing microfilariae in the eye. Serologic tests are being developed to aid in diagnosis when microfilariae cannot be detected but onchocerciasis is suspected.

Control

Three main measures - vector control, nodule removal, and drug treatment - provide limited control of onchocerciasis. Control of blackfly vectors is difficult because most species breed in fast-flowing streams to which insecticides cannot easily be applied. Nodules harboring adult worms are usually removed, which presumably reduces the rate at which microfilariae are produced and thus the risk to the eyes (as well as the number of microfilariae available to vectors). Mass treatment poses difficulties, because suramin, the drug of choice for killing adult worms, must be given intravenously and is toxic. Diethylcarbamazine kills microfilariae but has limited efficacy against adult worms and has the disadvantage that some patients experience a severe reaction, which may exacerbate eye damage, to dying microfilariae. Ivermectin, a semisynthetic macrolide antibiotic, has recently been shown to be more effective and to produce fewer side effects than diethylcarbamazine.