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.
✺ Adult worms live in lymphatic vessels for a decade
Microfilariae develop from ova
✺ Microfilariae circulate in peripheral blood each night
TABLE 55–2Differentiation of Microfilariae ||Download (.pdf) TABLE 55–2 Differentiation of Microfilariae
|PARASITE ||LOCATION ||SHEATH ||SIZE (MM) ||NUCLEI OF TAIL ||PERIODICITY |
|Wuchereria bancrofti ||Blood ||Yes ||360 ||None ||Usually nocturnal |
|Brugia malayi ||Blood ||Yes ||220 ||Two ||Nocturnal |
|Loa loa ||Blood ||Yes ||275 ||Continuous ||Diurnal |
|Onchocerca volvulus ||Skin ||No ||300 ||None ||None |
Microfilaria of Wuchereria bancrofti in blood film. (Reproduced with permission from Connor DH, Chandler FW, Schwartz DQ, et al: Pathology of Infectious Diseases. Stamford, CT: Appleton & Lange, 1997.)
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.
✺ Mosquito is essential vector and intermediate host
Humans are the only vertebrate hosts for W bancrofti
Lymphatic filariasis. These dilated lymphatics are filled with a gravid adult W bancrofti female. Eggs and developing microfilaria are within the paired uterine tubes. Note the surrounding thickened fibrous tissue. (Reproduced with permission from Connor DH, Chandler FW, Schwartz DQ, et al: Pathology of Infectious Diseases. Stamford, CT: Appleton & Lange, 1997.)
Life cycle of Wuchereria bancrofti and Brugia malayi. (Reproduced with permission from Roberts RL, Janovy J, Nadler S: Foundations of Parasitology, 9th edition. McGraw-Hill, 2013.)
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.
Think ➱ Apply 55-1. The larvae of these animal parasites cause symptoms in humans, when they migrate through our tissues.
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.
Primarily in Asia and other tropical areas
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 blockade with repeated infections
LYMPHATIC FILARIASIS: CLINICAL ASPECTS
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.
Lymphadenitis, urticaria, and eosinophilia are early findings
Acute manifestations can recur
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.
✺ Chronic lymphedema with recurrent inflammation triggered by adult worms in lymphatics
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.
✺ Tropical pulmonary eosinophilia caused by microfilariae in tissues (not found in blood)
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.
Eosinophilia during acute episodes
✺ Search for microfilariae in the blood requires careful timing
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.
✺ Killing microfilariae with DEC may stimulate allergic response
✺ Killing adult worms’ endosymbiotic Wolbachia may achieve full cure
✺ Treatment of complications improves quality of life