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Filarial Infections
Filarial worms are nematodes or roundworms that dwell in the subcutaneous tissues and the lymphatics. Although eight filarial species commonly infect humans, four are responsible for most of the pathology associated with these infections. These are (1) Brugia malayi , (2) Wuchereria bancrofti , (3) Onchocerca volvulus , and (4) Loa loa. The distribution and vectors of all the filarial parasites of humans are given in Table 47.1 .
TABLE 47.1
Filarial Parasites of Humans
| Species | Distribution | Vector | Primary Pathology |
|---|---|---|---|
| Brugia malayi | Southeast Asia | Mosquito | Lymphatic, pulmonary |
| Brugia timori | Indonesia | Mosquito | Lymphatic |
| Wuchereria bancrofti | Tropics | Mosquito | Lymphatic, pulmonary |
| Onchocerca volvulus | Africa and Central and South America | Blackfly | Dermal, ocular, lymphatic |
| Mansonella streptocerca | Africa | Midge | Dermal |
| Loa loa | Africa | Deerfly | Allergic |
| Mansonella perstans | Africa and South America | Midge | Probably allergic |
| Mansonella ozzardi | Central and South America | Midge | ? |
In general, each of the parasites is transmitted by biting arthropods. Each goes through a complex life cycle that includes an infective larval stage carried by the insects and an adult worm stage that resides in humans, either in the lymph nodes or adjacent lymphatics or in the subcutaneous tissue. The offspring of the adults, the microfilariae (200-250 µm long and 5-7 µm wide), either circulate in the blood or migrate through the skin. The microfilariae then can be ingested by the appropriate biting arthropod and develop over 1-2 weeks into infective larvae, which are capable of initiating the life cycle over again. A generalized schematic is shown in Figure 47.1 .
General life cycle of the filarial parasites in humans. Microfilariae ( L1 ) are produced by the adult worms. L2 and L3 are larval development stages in the arthropod vector. L3 larval forms are infective for humans. L4 develop from the newly arrived infective larval forms.
Adult worms are long lived, whereas the lifespans of microfilariae range from 3 months to 3 years depending on the filarial species. Infection is generally not established unless exposure to infective larvae is intense and prolonged. Furthermore, clinical manifestations of these diseases develop rather slowly.
There are significant differences in the clinical manifestations of filariasis, or at least in the time course over which these infections are acquired, in patients native to the endemic areas and those who are travelers or recent arrivals in these same areas. Characteristically, the disease in previously unexposed individuals is more acute and intense than that found in natives of the endemic region; also, early removal of newly infected individuals tends to speed the end of clinical symptomatology or at least halt the progression of the disease.
Lymphatic Filariasis
There are three lymphatic-dwelling filarial parasites of humans: B. malayi , Brugia timori , and W. bancrofti . Adult worms usually reside in either the afferent lymphatic channels or the lymph nodes. These adult parasites may remain viable in the human host for decades.
Epidemiology
B. malayi and B. timori
The distribution of brugian filariasis is limited primarily to China, India, Indonesia, Korea, Japan, Malaysia, and the Philippines. In both brugian species, two forms of the parasite can be distinguished by the periodicity of their microfilariae. Nocturnally periodic forms have microfilariae present in the peripheral blood primarily at night, whereas the sub-periodic forms have microfilariae present in the blood at all times, but with maximal levels in the afternoon.
The nocturnal form of brugian filariasis is more common and is transmitted in areas of coastal rice fields (by Mansonia and Anopheles mosquitoes), whereas the subperiodic form is found in the swamp forests ( Mansonia vector). Although humans are the common host, B. malayi can be a natural infection of cats. B. timori has been described only on two islands of the Indonesian archipelago (including East Timor).
W. bancrofti
Bancroftian filariasis is found throughout the tropics and subtropics, including Asia and the Pacific islands, Africa, areas of South America, and the Caribbean basin. Humans are the only definitive host for this parasite and are therefore the natural reservoir for infection. Like brugian filariasis, there is both a periodic and a sub-periodic form of the parasite. Generally, the sub-periodic form is found only in the Pacific Islands (including Cook and Ellis Islands, Fiji, New Caledonia, the Marquesas, Samoa, and the Society Islands); elsewhere, W. bancrofti is nocturnally periodic. The natural vectors are Culex fatigans mosquitoes in urban settings and usually Anopheles or Aedes mosquitoes in rural areas.
Pathology
Most of the pathology associated with bancroftian and brugian filariasis is localized to the lymphatics. Damaged lymphatics first lead to reversible lymphedema and then to chronic obstructive changes (in the limbs, breasts, or genitalia or to chyluria). The location of the lymphatic damage determines the type and site of the pathology.
Although the underlying mechanisms of pathology in this form of the disease are not yet known with certainty, it is thought that adult worms residing in the lymph nodes or neighboring lymphatics induce local inflammatory reactions and/or changes in lymphatic function. These reactions result in dilation of the lymphatics and hypertrophy of the vessel walls, although as long as the adult worm remains viable, the vessel is said to remain patent. Death of the worm, however, leads to local necrosis and a granulomatous reaction around the parasite. Fibrosis occurs and lymphatic obstruction develops. Although some recanalization and collateralization of the lymphatics takes place, lymphatic function remains compromised.
Clinical Manifestations in Those Native to the Endemic Region
The three most common presentations of the lymphatic filariases are asymptomatic (or sub-clinical) microfilaremia, adenolymphangitis (ADL), and lymphatic obstruction.
- 1.
Patients with asymptomatic microfilaremia rarely come to the attention of medical personnel except through the incidental finding of microfilariae in the peripheral blood during surveys in endemic regions or when blood eosinophilia leads to a diagnostic evaluation for lymphatic filariasis. Such asymptomatic persons are clinically unaffected by the parasites, although lymphoscintigraphic evaluation of these individuals suggests that lymphatic dysfunction (and tortuosity) is common, as is scrotal lymphangiectasia (detectable by ultrasound) in men with W. bancrofti infection.
- 2.
Acute filarial ADL is characterized by high fever (and shaking chills), lymphatic inflammation (lymphangitis and lymphadenitis), and transient local edema. The lymphangitis is retrograde, extending peripherally from the lymph node draining the area where the adult parasites reside. Regional lymph nodes are often enlarged, and the entire lymphatic channel can become indurated and inflamed. Concomitant local thrombophlebitis can occur as well. In brugian filariasis, a single local abscess may form along the involved lymphatic tract and subsequently rupture to the surface. The lymphadenitis and lymphangitis occur in both the upper and the lower extremities in both bancroftian and brugian filariasis, but involvement of the genital lymphatics occurs almost exclusively with W. bancrofti infection. Genital involvement can be manifested by funiculitis, epididymitis, scrotal pain, and tenderness.
- 3.
Chronic manifestations of lymphatic filariasis develop in only a small proportion of the filarial-infected population. If lymphatic damage progresses, transient lymphedema can develop into lymphatic obstruction and the permanent changes associated with elephantiasis. Brawny edema follows the early pitting edema, and thickening of the subcutaneous tissues and hyperkeratosis occur. Fissuring of the skin develops, as do hyperplastic changes. Superinfection of these poorly vascularized tissues becomes a problem. In bancroftian filariasis, when genital involvement is evident, scrotal lymphedema or hydrocele formation occurs. Furthermore, if there is obstruction of the retroperitoneal lymphatics, renal lymphatic pressure can increase to the point at which they rupture into the renal pelvis or tubules so that chyluria is seen. The chyluria is characteristically intermittent and is often prominent in the morning just after the patient arises.
Clinical Manifestations in New Arrivals to Endemic Areas
As mentioned previously, there are significant differences in the clinical manifestations of filarial infection, or at least in the time course over which they appear, between individuals who have recently entered the endemic areas (travelers or “transmigrants”) and those who are native to these areas.
Given sufficient exposure to the vector (generally 3-6 months), patients often present with the signs and symptoms of acute lymphatic or scrotal inflammation. Urticaria and localized angioedema are common. Lymphadenitis of the epitrochlear, axillary, femoral, or inguinal nodes is often followed by lymphangitis, which is retrograde.
Acute attacks are short lived and, in contradistinction to filarial ADL, patients, are generally not accompanied by fever. If allowed to continue (by chronic exposure to infected mosquitoes), these attacks become increasingly severe and quickly (compared with the indigenous population) lead to permanent lymphatic inflammation and obstruction. Important to note, however, is that early removal of the patients from continued reexposure seems to hasten the end of the clinical syndrome.
Diagnosis
Diagnosis of filarial diseases can be problematic, because these infections most often require parasitologic techniques to demonstrate the offending organisms. In addition, satisfactory methods for the definitive diagnosis in amicrofilaremic states can be extremely difficult. The diagnostic procedures, however, should take advantage of the periodicity of each organism as well as its characteristic morphologic appearance. Table 47.2 and Figure 47.2 address these issues specifically. The following techniques may be used for examining blood or other fluids, such as chyle, urine, and hydrocele fluid.
TABLE 47.2
Characteristics of Microfilariae in Humans
| Species | Location | Periodicity | Presence of Sheath |
|---|---|---|---|
| Brugia malayi | Blood | Nocturnal, subperiodic | + |
| Brugia timori | Blood | Nocturnal | + |
| Wuchereria bancrofti | Blood, hydrocele fluid | Nocturnal, subperiodic | + |
| Onchocerca volvulus | Skin | None | − |
| Mansonella streptocerca | Skin | None | − |
| Loa loa | Blood | Diurnal | + |
| Mansonella perstans | Blood | None | − |
| Mansonella ozzardi | Blood | None | − |
Direct Examination
A small volume of fluid is spread on a clean slide. The slide is then air dried, stained with Giemsa stain, and examined microscopically.
Nuclepore™ filtration
A known volume of anticoagulated blood is passed through a polycarbonate (Nuclepore) filter with a 3-µm pore. A large volume (50 mL) of distilled (or filtered) water is passed through (the water will lyse or break open the red cells, leaving the microfilariae intact and more easily visible). The filter is then air dried, stained with Wright's or Giemsa stain, and examined by microscopy. For studies in the field, 1 mL of anticoagulated blood can be added to 9 mL of a solution of 2% formalin/10% Teepol and stored for up to 9 months before performing filtration.
Knott's concentration technique
In this technique, 1 mL of anticoagulated blood is placed in 9 mL of 2% formalin. The tube is centrifuged at 1500 rpm for 1 min. The sediment is spread on a slide and dried thoroughly. The slide is then stained with Wright's or Giemsa stain and examined microscopically.
Indirect Measures
Detection of circulating parasite antigen
Assays for circulating antigens of W. bancrofti permit the diagnosis of microfilaremic and cryptic (amicrofilaremic) infection. There are currently two commercially available tests, one in an enzyme-linked immunosorbent assay format (Trop-Ag W. bancrofti , manufactured by JCU Tropical Biotechnology, Townsville, Queensland, Australia), and the other a rapid-format card test (marketed by Allere, Scarborough, ME). Both assays have reported sensitivities that range from 96 to 100% and specificities that approach 100%. There are currently no tests for circulating antigens in brugian filariasis.
Serodiagnosis using parasite extract
Development of serodiagnostic assays of sufficient sensitivity and specificity for routine use has proven difficult, primarily because of their poor specificity. As is the case for serodiagnosis of most infectious diseases, it is difficult to differentiate previous infection or exposure to the parasite (aborted infection) from current active infection. Indeed, most residents of filariasis-endemic regions are antibody positive. Nevertheless, such serologic assays have a definite place in diagnosis, as a negative assay result effectively excludes past or present infection.
Molecular diagnostics
Polymerase chain reaction (PCR)-based assays for DNA of W. bancrofti and B. malayi in blood have also been developed. In a number of studies evaluating PCR-based diagnosis, the method is of equivalent or greater sensitivity compared with parasitologic methods, detecting patent infection in almost all infected subjects.
Imaging studies
In cases of suspected lymphatic filariasis, examination of the scrotum or female breast using high-frequency ultrasound in conjunction with Doppler techniques may result in the identification of motile adult worms within dilated lymphatics. Worms may be visualized in the lymphatics of the spermatic cord in up to 80% of infected men with W. bancrofti . Live adult worms have a distinctive pattern of movement within the lymphatic vessels (termed the “filaria dance sign”). This technique may be useful to monitor the success of antifilarial chemotherapy, by observing for the disappearance of the dance sign.
Radionuclide lymphoscintigraphic imaging of the limbs reliably demonstrates widespread lymphatic abnormalities both in asymptomatic microfilaremic persons and in those with clinical manifestations of lymphatic pathology. While of potential utility in the delineation of anatomic changes associated with infection, lymphoscintigraphy is unlikely to assume primacy in the diagnostic evaluation of individuals with suspected infection.
Differential Diagnosis
The diagnosis of filariasis often must be made clinically, because many patients with lymphatic filariasis are not microfilaremic. In acute episodes, the differential diagnosis includes thrombophlebitis, infection, and trauma. Edema and changes associated with chronic filariasis must be distinguished from the similar changes that are seen to occur with malignancy, post-surgical scarring, trauma, and congestive heart failure, along with the less common congenital or idiopathic lymphatic system abnormalities. The many disorders associated with eosinophil and serum immunoglobulin E elevations must be considered as well.
Treatment
With newer definitions of clinical syndromes in lymphatic filariasis and new tools to assess clinical status (e.g., ultrasound, lymphoscintigraphy, circulating filarial antigen assays), approaches to treatment based on infection status and pathogenesis have been proposed.
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