Etiology and PathogenesisTop
1. Etiologic agent: Nematodes that typically inhabit subcutaneous tissues, the lymphatic system, or body cavities.
In tropical and subtropical regions, filariases are most commonly caused by:
1) Lymphatic filariases: Wuchereria bancrofti (>90% of all cases of lymphatic filariasis), Brugia malayi, B timorii.
2) Cutaneous filariases: Loa, Onchocerca volvulus, Mansonella streptocerca.
3) Serous cavity filariasis: M perstans, M ozzardi.
2. Reservoir and transmission: The majority of filaria species are transmitted by mosquitoes of the genera Anopheles, Mansonia, Culex, Aedes, and Ochlerotatus. The vectors for O volvulus are Simulium spp blackflies, which breed near fast-flowing rivers and streams (onchocerciasis is otherwise called river blindness), and for L loa, Chrysops deerflies. Infections with Mansonella spp occur through the bites of biting midges of the genus Culicoides.
3. Pathogenesis: The larvae injected during the bite of an insect vector migrate through deep tissues for ~10 days. Following transformation into subsequent larval stages and adult forms, after several months (6-12), they get into the lymphatic system (typically to inguinal and axillary lymph nodes), subcutaneous tissues, or body cavities, and release microfilariae into the bloodstream. The microfilariae survive up to a year. Dead microfilariae may stimulate granuloma formation in the skin and in subcutaneous, lymphatic, and other tissues. Filarial nematode species can host Wolbachia bacterial endosymbionts (discovery of the phenomenon laid the grounds for doxycycline treatment in infections caused by some filaria species), which appears to play a role in the pathogenesis of filarial diseases.
4. Risk factors for infection: Staying in regions endemic for filarial diseases, performing activities that favor exposure to vector bites. In nonendemic countries infections are mainly imported by long-term travelers (after months- or years-long travels) and migrants.
5. Incubation and contagious period: The incubation period in lymphatic filariases is from several weeks to 8 to 16 months. Microfilariae are typically detectable in blood ~12 months following invasion (ie, bite of an infected insect). Adult worms can survive in the human body for 5 years (sometimes up to 15), and during this period the patient may be the source of infection for vectors.
Signs and symptoms of onchocerciasis develop 3 months to 3 years following infection (1.5 year on average).
According to the World Health Organization (WHO) estimates, in 2018 there were ~51 million individuals with lymphatic filariasis worldwide, with the majority of cases being found in Asia. The number of onchocerciasis cases in 2017 approximated 20 million. Over 99% of O volvulus infections are diagnosed in sub-Saharan Africa. An estimated 3 to 13 million of people in Africa are infected with L loa. Infections caused by Mansonella spp are typically asymptomatic, and the number of cases remains unknown.
The Global Programme to Eliminate Lymphatic Filariasis (GPELF) launched by the WHO in the twenty-first century has significantly influenced the epidemiology of filarial infections. Through mass drug administration to whole populations, irrespective of the presence of confirmed infection, the number of patients has been reduced by >70% since 2000, and in some countries transmission has been eliminated. However, lymphatic filariases remain a major concern in endemic regions, as they lead to disabilities and have adverse economic and psychosocial consequences. Onchocerciasis is the second most frequent infectious cause of blindness globally (in ~500,000 people).
Geographic distribution of filaria species:
1) W bancrofti: Sub-Saharan Africa, South and Southeast Asia, some Pacific islands, some regions of South and Middle America and the Caribbean.
2) B malayi: Asia, particularly China and India, Malaysia, the Philippines, Indonesia, some Pacific islands.
3) B timori: Indonesia, India.
4) O volvulus: Africa, Yemen, South and Middle America.
5) L loa: West and Central Africa.
6) M streptocerca: West and Central Africa.
7) M perstans: Sub-Saharan Africa, South and Middle America.
8) M ozzardi: South and Middle America, the Caribbean.
Clinical Features and Natural HistoryTop
1. Lymphatic filariasis: The infection may be asymptomatic. Symptomatic disease has an acute and chronic stage. Acute disease most commonly manifests with adenolymphangitis (ADL) and epididymo-orchitis with fever, sometimes with lower limb edema (or edema in the external genital area), as well as with dermatitis and pruritus. Acute signs and symptoms persist for ~1 week and may recur. In some patients recurrent fever may be the only symptom of the acute phase. The nocturnal activity of the parasite and hypersensitivity reactions to microfilariae may cause cough attacks at night, with bronchial narrowing and fever episodes (tropical pulmonary eosinophilia).
A typical late symptom of the disease is lymphedema related to chronic inflammation of the lymphatic vessels in the legs and arms, and also in the scrotum and spermatic cord area in men and in the nipple area in women. A common presentation in men is hydrocele testis with pronounced scrotal swelling. Elephantiasis of the lower extremities, which develops as a sequela, is very rarely seen in individuals with imported disease but is frequent in massive infections in endemic areas. Some patients have chyluria.
2. Cutaneous and subcutaneous filariasis: Typical manifestations of onchocerciasis include ocular symptoms (the microfilariae penetrate into the cornea, conjunctiva, and anterior eye chamber), pruritus, subcutaneous nodules, and skin lesions: thickened, peeling skin and lichenification. Uveitis and iritis in O volvulus infection may lead to blindness. Patients may have fever, headache, edema, and joint reactions. Chronic skin lesions and eye pathologies frequently seen in inhabitants of endemic areas are usually not observed in travelers with imported O volvulus infection.
L loa infection usually manifests with localized periodic edema, mostly of the face and upper extremities (Calabar swelling), caused by hypersensitivity to the migrating worm and release of microfilariae, as well as with ocular signs and symptoms associated with subconjunctival migration of adult filariae (lacrimation, photophobia, foreign body sensation).
The most typical symptom of M streptocerca infection is pruritus. Skin hardening (without subcutaneous nodules), macular lesions, and axillary and inguinal lymphadenopathy have also been reported.
3. Serous cavity filariasis: Only a small proportion of individuals with Mansonella spp infection reports symptomatic disease. If present, signs and symptoms are related to migration of adult worms and include transient edema resembling Calabar swelling, pericarditis, pleuritis, and ocular involvement. Systemic manifestations (pruritus, weakness), urticaria, arthralgia, and abdominal pain may be present.
Recent stay in endemic regions and exposure to vector bites combined with typical manifestations or eosinophilia not explained by another diagnosis indicate suspected filarial disease.
1. Identification of the etiologic agent:
1) Microscopic examination: Giemsa-stained thick blood smears; blood collection should be done at the time of the parasite’s activity: W bancrofti and B malayi are active at night (10 pm to 2 am); and L loa, during the day. In patients with suspected O volvulus or M streptocerca infection, skin snips are collected for microscopic examination.
2) Antigen tests: Enzyme-linked immunosorbent assay (ELISA) and immunochromatographic tests detect antigens released by adult W bancrofti; in W bancrofti infections antigen tests are more sensitive than microscopic examination.
3) Histologic examination identifies adult O volvulus worms in specimens collected from subcutaneous nodules.
4) Direct identification of adult L loa worms under the conjunctiva on physical examination or following removal from skin.
5) Serologic tests: Tests that detect IgG antibodies are available; however, as they do not differentiate between past and active infections, they are mostly used in travelers with signs or symptoms of disease after return from tropical regions. Serologic tests are usually not useful in the diagnostic workup of filarial infections in inhabitants of endemic areas.
6) Molecular tests (polymerase chain reaction [PCR]) are not widely available.
2. Other tests:
1) Laboratory tests may reveal significant eosinophilia, elevated blood IgE titers, proteinuria and hematuria (in lymphatic filariases), hypergammaglobulinemia (in O volvulus infections).
2) Imaging: In individuals with lymphatic filariasis adult worms may be visualized on ultrasonography of lymphatic vessels (the typical continuous movement of the parasites is referred to as “filarial dance”).
Filarial infections are diagnosed based on microscopic identification of microfilariae (blood smear or skin snips), adult worms in lymphatic vessels, parasitic DNA or antigens (only for W bancrofti), or direct identification of the worm under the conjunctiva (L loa) on physical examination.
Bacterial lymphangitis, lymphadenopathy of other etiology (neoplasms, tuberculosis), scabies, cutaneous larva migrans, strongyloidiasis, leprosy, other causes of eosinophilia.
According to recommendations of the Centers for Disease Control and Prevention (CDC), the drug of choice in lymphatic filariasis is diethylcarbamazine (DEC), which kills the circulating microfilariae and is effective against adult worms. A single dose of oral DEC of 6 mg/kg is equally effective as a regimen of several days, except in patients with tropical lung eosinophilia; in this group a 14- to 21-day regimen should be followed.
Ivermectin is effective against W bancrofti microfilariae but not against adult worms. As a result the effect of treatment is not lasting.
Some studies showed that treatment with oral doxycycline 200 mg once daily for 4 to 6 weeks is effective against adult worms. As part of GPELF the WHO recommends DEC (in onchocerciasis-free regions), albendazole, or ivermectin with albendazole.
The drug of choice in patients with onchocerciasis is oral ivermectin 150 microg/kg every 6 months. The CDC also allows the use of oral doxycycline 200 mg once daily for 6 weeks (the effectiveness of antibiotic therapy is likely due to the drug’s activity against Wolbachia bacteria). This management reduces the number of adult O volvulus females by 60% but is ineffective against microfilariae, which is why doxycycline should be used in combination with ivermectin.
DEC is contraindicated in individuals with concomitant O volvulus infection or massive L loa invasion due to the risk of severe adverse effects (including shock or fatal encephalopathy). If the microfilaria count is >2500/mL in microscopic blood smear examination, parasitemia should be reduced with apheresis or albendazole before DEC administration. Surgical removal of adult L loa effectively relieves local signs and symptoms, but pharmacologic treatment is needed to eliminate infection.
Antiparasitic agents should be used under strict medical surveillance in patients with loiasis, due to the risk of transient exacerbation (edema, pruritus). Some experts recommend concomitant use of antihistamine drugs or glucocorticoids.
In M streptocerca infections the recommended regimen involves oral DEC 6 mg/kg once daily for 12 days.
M perstans is poorly susceptible to standard antiparasitic agents used in filarial infections. Some experts indicate that the best effects are observed in combination treatment with DEC and mebendazole administered for 21 days. The drug of choice in M ozzardi infections is oral ivermectin 200 mg/kg once daily.
1. Physiotherapy in chronic lymphedema.
2. Surgical treatment of hydrocele testis.
Secondary bacterial infections in patients with lymphedema (elephantiasis) associated with lymphatic filariasis; nutrient deficiencies due to chyluria; blindness in patients with onchocerciasis.
Prognosis is good in early diagnosed and properly treated disease. According to the WHO a single dose of a 3-drug regimen of DEC plus ivermectin plus albendazole eliminates microfilariae in 96% of the infected individuals for up to 3 years. However, antiparasitic treatment does not significantly improve the quality of life or performance status in patients with chronic disease.
1. Immunoprophylaxis: None available.
2. Chemoprophylaxis: In long-term travelers to regions endemic for L loa, chemoprophylaxis with DEC (300 mg once weekly) may be considered.
Nonspecific insect bite precautions (see Infection Prevention: Nonspecific Insect and Tick Bite Precautions).