Introduction
Pathogenic filarial parasites affect the lives of millions of people, especially those living in tropical countries and often cause significant dermatologic manifestations. The filarial parasites that pose the most serious public health threats are Wuchereria bancrofti, Brugia malayi, Brugia timori, Onchocerca volvulus, and Loa loa. All of these cause cutaneous manifestations. One filarial nematode, Mansonella streptocerca, is not a significant public health threat. Filarial worms of the genus Dirofilaria and zoonotic Onchocerca species, normally parasitic in animals, occasionally enter a human host and undergo partial or aberrant development. These may cause cutaneous or subcutaneous manifestations (see Table below)
Filarial nematodes enter the human body at their third larval stage by escaping from the mouthparts of their vector arthropod as they bend during biting and enter through the bite wound in the skin. Wolbachia spp, a type of Rickettsia, are symbiotic with filarial nematodes. These bacteria are largely responsible for the pathogenesis of filarial disease in that they are the principal initiators of innate inflammation and their release correlates with a severe adverse inflammatory reaction. In lymphatic filariasis, the bacteria are present in hydrocele fluid and in W bancrofti samples. In onchocerciasis, Wolbachia spp recruit neutrophils to Onchocerca nodules and causes neutrophil-mediated keratitis in a mouse model, and the antibody responses to Wolbachia surface protein is associated with the manifestation of chronic pathology. Recognition of the role of Wolbachia has revolutionized the treatment of filariasis.
Human Filarial Parasites and Their VectorsOpen table in new window
Table
| Disease | Parasite | Vector |
| Onchocerciasis | O volvulus | Blackflies: Simulium species |
| Bancroftian filariasis | W bancrofti | Mosquitos: Anopheles, Aedes, Culex, and Mansonia species |
| Malayan filariasis | B malayi and B timori | Mosquitos: Anopheles, Aedes, Culex, and Mansonia species |
| Loiasis | L loa | Red flies: Chrysops species |
| Mansonelliasis | M streptocerca | Midges: Culicoides species |
| Dirofilariasis | Dirofilaria species | Mosquitos: Culex species |
| Disease | Parasite | Vector |
| Onchocerciasis | O volvulus | Blackflies: Simulium species |
| Bancroftian filariasis | W bancrofti | Mosquitos: Anopheles, Aedes, Culex, and Mansonia species |
| Malayan filariasis | B malayi and B timori | Mosquitos: Anopheles, Aedes, Culex, and Mansonia species |
| Loiasis | L loa | Red flies: Chrysops species |
| Mansonelliasis | M streptocerca | Midges: Culicoides species |
| Dirofilariasis | Dirofilaria species | Mosquitos: Culex species |
Treatment and prevention of filarial skin lesions
Four key treatment modalities are available, as follows: oral and parenteral antihelminthic chemotherapy, antibiotic use against the symbiotic Wolbachia spp, surgical excision, and needle aspiration/injection of entrapped nematodes in tissues. The specific therapeutic options vary with the specific worms. These options are best divided into treatment for onchocerciasis, treatments for lymphatic filariasis, treatment for mansonellosis, and treatment for dirofilariasis; treatment details are discussed under each of those sections.
Vector control, use of mosquito nets, and improved living conditions are still vital for the control of these infections.1 Molecular engineering technology is being applied toward the production of mosquitoes resistant to filarial infections.2 Recently available, simplified, safe, and cost-effective treatment methods and new control strategies have led the International Task Force for Disease Eradication to deem lymphatic filariasis as 1 of 6 eradicable or potentially eradicable infectious diseases.
Related eMedicine pediatrics articles include Bancroftian Filariasis, Filariasis, and Dirofilariasis.
Patient education
For excellent patient education resources, visit eMedicine's Public Health Center. In addition, see eMedicine's patient education article Foreign Travel.
Onchocerciasis
Third-stage larvae (L3) enter human skin from a fly's proboscis (see Media File 1). The L3 molt to fourth-stage larvae (L4) in approximately 4-6 weeks. Then, after a variable period of some months, they molt again to the juvenile adult stage (L5). They then mature and mate after approximately a year and start to produce microfilariae. Adult worms live and mate encysted in fibrous nodules in the dermis and deep fascial planes (see Media File 2).
Third stage larvae of Onchocerca in proboscis of Simulium.
Subcutaneous nodule on hip caused by encysted Onchocerca volvulus.
Each fertile female can produce millions of microfilariae during her lifetime, and the worms can live for 10-15 years. Stretched microfilariae exit through the vulva into the tissues and begin their migration to the skin. They also may enter the eye and cause blindness (see Media File 3). Most microfilariae live in the subepidermal layer of the skin, where they can be taken up by the feeding blackfly.
Man blinded by microfilariae of Onchocerca volvulus.
Microfilariae cause the most serious clinical disease in the skin associated with O volvulus. They are most abundant in the skin but also invade the eyes, lymph nodes, and other deep organs, where they may produce severe and progressive inflammatory lesions. However, adult worms in their nodules and even the vector itself can cause problems. The blackfly bite may leave a bleeding point on the skin, often with surrounding erythema and severe itching. Multiple bites in a nonimmune person produce pruritus, pain, and urticaria.
Specific clinical dermatologic manifestations
Onchocercomas are subcutaneous nodules containing adult worms. Nodules are firm, often flattened or bean-shaped, usually movable, and nontender (see Media File 4); they can be up to several centimeters in diameter. They are most common over bony prominences (ie, skull, scapulae, ribs, elbows, trochanters, iliac crests, sacrum, knees) and in deeper sites near joints and bones or between muscles.
Movable, nontender subcutaneous nodule of Onchocerca volvulus.
The distribution of nodules on the body is different in the various endemic areas. In Africa, nodules occur mainly around the pelvis (see Media File 2); however, in heavy infections, they develop over many other bony prominences and in deeper sites. In Mexico and Guatemala, most nodules arise in the upper part of the body, especially the head.
Subcutaneous nodule on hip caused by encysted Onchocerca volvulus.
Usually, nodules are close to each other and form large masses with small satellite nodules. This gives a lobulated feel to the tumor. Removal may reveal more nodules than those initially palpated.
With experience, O volvulus nodules can be distinguished from lipomata, sebaceous cysts, ganglia, lymph nodes, juxta-articular nodes in late yaws, and cysts around foreign bodies, with approximately 95% certainty.
Onchocercal dermatitis is a major socioeconomic burden in terms of disability-adjusted life-years, and it is the most common clinical manifestation. Microfilariae are the main cause. Microfilariae may be at all levels in the dermis but tend to be most numerous at the dermoepidermal junction; many are predominantly in lymphatic channels of the dermis. Immunological damage is also a factor. Immune complexes from patients with onchocerciasis contain a parasite antigen that is homologous to and immunologically cross-reactive with intermediate filament proteins of human keratin.
Patients with different onchocercal skin pathology have different O volvulus –specific antibody isotypic responses. Recent evidence indicates that differences seen in the severe and mild strains of O volvulus relate to the amount of Wolbachia symbiote found in the different strains.3 HIV infection appears to increase the severity of onchocercal dermatitis.4
Onchodermatitis usually manifests as itching; it is most severe over the lower trunk, pelvis, buttocks, and thighs. Typically, it is confined to one anatomic quarter of the body. Itching, and the consequent lesions caused by scratching, may be the only manifestation of mild infections. The scratching may produce ulcers, bleeding, and secondary infections (see Media File 5). Often, a papular rash, usually involving the buttocks and legs, is present.
Bleeding on skin from scratching itchy skin of onchodermatitis.
Alterations in skin pigmentation (poorly defined areas of hyperpigmentation and hypopigmentation or distinct macules) can occur early in infection. The clinical differential of the itchy rash typical of early stages includes scabies, contact dermatitis, insect bites, food allergies, and prickly heat.
In Africa, chronic skin changes are common. Initially, chronic lesions manifest as scaling, edema, depigmentation, and papule formation (see Media File 6). The edema can produce a peau d'orange effect with pitting around hair follicles and sebaceous glands. Later, either of the following occurs: (1) loss of elasticity, atrophy of the epidermis, and scarring of the dermis manifested as presbyderma (ie, skin with an aged appearance; see Media File 7), with wrinkled skin typically being extremely thin with little subcutaneous tissue, or (2) persistence of epidermal tissue with hypertrophy and lichenification, resulting first in elephantoid (see Media File 8) and later in lizard skin.
One anatomic quarter of body (leg) markedly affected by edema and papule formation of onchodermatitis.
Skin with an aged appearance in a patient with chronic onchodermatitis. Note the subcutaneous nodule.
Chronic onchodermatitis skin demonstrates a loss of elasticity.
In the rain forests of West Africa, a characteristic leopard spot depigmentation over the shins is one of the most striking and common manifestations of long-standing onchocerciasis (see Media File 9). This can be mistaken for leprosy, but unlike lepromatous lesions, no sensory changes are present. The differential diagnosis for the chronic skin lesions of the African variants includes tertiary yaws, eczema, malnutrition, and old age. The leopard skin mimics other forms of vitiligo, leprosy, and streptocerciasis, any of which can exist concomitantly. Finding nodules can aid in these distinctions.
Skin of a West African person with leopard spot depigmentation.
In Latin America, a variety of more acute skin lesions occurs, while chronic skin lesions are less common. Acute lesions, with rare occurrence in Africa, include the (1) erisípela de la costa, a macular rash with edema of the face (see Media File 10), and (2) mal morado, a red-brown discoloration seen mainly on the trunk and upper limbs.
Skin of a Latin American child with erisípela de la costa.
In Arabia, and less commonly in Sudan, West Africa, Guatemala, and Ecuador, some patients develop a black skin change termed sowda. Sowda, a form of hyperreactive onchocerciasis, usually is limited to one limb, but it can affect more than one limb or even the trunk. The involved skin is itchy, swollen, darkened, and covered with scaling papules, and regional lymphadenopathy is present (see Media File 11).
Patient from Cameroon with sowdalike lesions.
Skin pathology
Early changes are minimal. Skin can have edema; a few proliferating fibroblasts; and a few lymphocytes, macrophages, plasma cells, and eosinophils around vessels and appendages. The number of mast cells may be increased, but neutrophils are absent. Microfilariae migrate through the dermal collagen and are most numerous in the upper dermis (see Media File 12). Microfilariae can be rare or plentiful; rarely, they are found within dermal lymphatics.
Microfilariae, most numerous in upper dermis.
More advanced changes include hyperkeratosis, acanthosis, focal parakeratosis, melanophores in the upper dermis, dilated lymphatics, and tortuous dermal vessels, with mucin (acid monosaccharide) between dermal collagen fibers. Destruction of elastic tissue is present.
Continuing fibrosis leads to scarring of papillae and, finally, to replacement of dermal collagen by a hyalinized scar, which tends to have a concentric arrangement around dermal vessels. Of all these changes, fibrosis is the most serious. Fibrosis begins early, persists, and increases so that it ultimately replaces specialized structures of the skin.
Special skin changes
Papules of gale filarienne are intraepidermal abscesses that contain microfilariae (see Media File 13). Degenerating microfilariae provoke a granulomatous reaction or an infiltrate of eosinophils. Leopard skin characteristically shows loss of melanin pigment in the basal layer and a slightly edematous dermis (see Media File 14). Elephantoid skin has a thin epidermis with few, small rete ridges and an edematous dermis with numerous macrophages and a few lymphocytes and plasma cells (see Media File 15). Lizard skin has an even thinner, undulating epidermis that lacks rete ridges and has an edematous dermis affiliated with increased numbers of elastic fibers (see Media File 16).
Intraepidermal abscess containing microfilariae of Onchocerca volvulus.
Loss of melanin pigment in basal layer of leopard skin.
Thin epidermis with a few small rete ridges in elephantoid onchodermatitis.
Very thin undulating epidermis lacking rete ridges in a patient with lizard skin onchodermatitis.
The epidermis in sowda demonstrates hyperkeratosis, parakeratosis, acanthosis, and follicular plugging (see Media File 17). The dermis manifests edema, melanophages in the upper dermis, fibrosis, perivascular and periappendageal chronic inflammation with eosinophils and mast cells, dilated lymphatic channels, and tortuous congested capillaries. Very few neutrophils are present. Microfilariae are rare to absent. Investigators believe that sowda is caused by a hyperreactive immunologic response.
Hyperkeratosis, focal parakeratosis, and follicular plugging in hyperreactive skin of a patient with sowda onchodermatitis.
Immunology
The immune response to O volvulus varies notably from patient to patient, leading to a spectrum of clinical disease. The cell-mediated immune (CMI) response is variable.
Patients with a strong CMI response to O volvulus antigen develop active skin disease; this is probably a reflection of active killing of most of the resident microfilariae. Finding viable microfilariae in such lesions microscopically is difficult. An overzealous immune response can lead to intensified disease, such as in patients with sowda whose severe dermatitis is a direct result of an excessive immunologic response to the microfilariae. Some evidence suggests that patients with very active CMI responses experience more severe corneal complications. Patients with a poor CMI response to O volvulus antigen develop quiescent skin disease, often with high numbers of microfilariae.
Studies in West Africa indicate that infection with O volvulus can cause patients to have a decreased CMI response, leading to problems with vaccination against other infectious agents. Studies suggest that maternal exposure to O volvulus may cause prenatal acquisition of tolerance to O volvulus antigens or that the worm itself may suppress T helper 1 response in some patients.
Eosinophils may play a central role in killing microfilariae and in destroying infective larvae deposited by Simulium species. Interleukin 5 (ie, eosinophil-active cytokine) activates, enhances adhesion, increases tissue sequestration, and prolongs the survival of eosinophils. Eosinophils release major basic protein, eosinophil cationic protein, and eosinophil-derived neurotoxin, which are toxic for helminth larvae.
Eosinophils require antigen-specific antibodies to stick to the microfilariae; complement factors greatly enhance this adhesion. The most effective serum for destroying microfilariae in vitro is that taken from patients who are actively killing microfilariae (eg, those with punctate keratitis), reflecting the importance of antigen-specific antibodies.
Specific antibodies to O volvulus are present on the epicuticle of viable adult worms within nodules and within degenerating worms. Eosinophils and macrophages commonly canopy the surface of adult worms. However, the immune response to adult worms is not yet understood.
The sera of patients contain specific immune complexes and circulating antigens of O volvulus, and those with chorioretinal disease have antiretinal antibodies in their sera. The levels of immune complex in patients with onchocerciasis vary greatly. However, to date, no clear correlation exists between these findings and clinical features.
Heavily infected patients cleared of O volvulus by chemotherapy do not appear to develop protection against reinfection.
Putatively immune (PI) individuals are those who, in spite of exposure to O volvulus, do not develop disease. These individuals preferentially react to a 90-kd antigen of O volvulus that corresponds to a gene sequence E1. E1 produces small amino acid residues resembling human brain ankyrin. This suggests that neuronal proteins may be important targets for immunity against O volvulus in vivo. PI individuals seem to have a better T helper 1 response than those who are not PI.
Zoonotic onchocerciasis
Other species of Onchocerca can produce human disease. Zoonotic onchocerciasis in humans is a rarely diagnosed infection. Thirteen cases are known; 10 full reports exist in the literature,5 2 additional cases were presented in an abstract, and 1 more case appeared in a poster in December 1997. Two separate groups reported the first 2 recognized instances of zoonotic onchocerciasis in 1965. First, Siegenthaler and Gubler reported a nodule on the knee of a 25-year-old Swiss woman; the nodule contained an Onchocerca species other than O volvulus, most likely Onchocerca gutturosa. Azarova and colleagues removed another zoonotic Onchocerca species from the cornea of a 15-year-old Crimean (Russian) girl.
In 1973, Ali-Khan and Meerovitch identified another zoonotic infection in a wrist nodule of a Canadian woman. In 1974, Beaver and colleagues6 identified a fourth instance in a woman from Illinois with no travel history outside of the United States. Recent cases include that of a woman from Colorado who presented with iritis of the right eye caused by a zoonotic Onchocerca entwined in her cornea and that of a 65-year-old man with progressive peripheral visual-field loss.
These zoonotic Onchocerca species are distinguished from O volvulus by counting the number of striae between annular thickenings in the inner layer of the cuticle of the female worm. In nearly all reported infections, the morphological features of the zoonotic worm have resembled those of O gutturosa and, to a lesser extent, Onchocerca cervicalis. One rare case of infection with Onchocerca dewittei japonica, a common parasite of wild boar, has been reported in a 69-year-old woman from Japan.7 Both O gutturosa and O cervicalis have a widespread distribution in cervical ligaments of cattle and horses.
The various species of Onchocerca are distinguished primarily by the structure of the cuticle of the female worm and the anatomy of the microfilariae. Unfortunately, in human tissues, no microfilariae are visible; thus, the cuticle is the sole criterion available to help determine the specific onchocercal species (see Media File 18).
North American patient with subcutaneous abscess containing zoonotic Onchocerca. Note the very pronounced transverse ridges.
Clinical presentation of zoonotic onchocerciasis
Patients have a tender, erythematous, subcutaneous nodule. Surgical excision and microscopic examination reveals an acute inflammatory reaction around the worm that may include many eosinophils encapsulated by host tissues. No further treatment is needed.
A major clinical diagnostic method for determining the prevalence of infection in endemic areas is nodule palpation. This method is useful and recommended for use in highly endemic areas for identifying communities at risk and selecting them for mass drug administration. Nodule palpation is only reliable in highly endemic areas since the false-positive rate increases as the endemicity decreases.8
Treatment of onchocerciasis
The oldest known treatment for onchocerciasis was that performed by Bedouin for the swollen lymph nodes of sowda. The Bedouin bit through the skin to break the nodes into small masses. This treatment was sometimes fatal; deaths were caused by hemorrhage or infection.9
Chemotherapy
- Ivermectin
- Ivermectin (dihydroavermectin B1) is the drug of choice for the treatment of onchocerciasis. In 1996, ivermectin (Stromectol) was registered for human use in the United States; it was registered in France as Mectizan. (For animals in the United States, it was registered previously by Merck Sharpe & Dohme as Heartgard, a widely used veterinary gastrointestinal anthelmintic and ectoparasiticide.)
- Ivermectin is a macrocyclic lactone derived from the actinomycete Streptomyces avermitilis found in a soil sample from a Japanese golf course and is produced by fermentation.10,11 It has structural similarities to the macrolide antibiotics but lacks antibacterial activity. Ivermectin enters the worm by the transcuticular route.
- It functions as a single dose and is a rapidly effective microfilaricide for O volvulus; however, attempts to give a single dose of ivermectin (150 mcg/kg) on the preadult stages of O volvulus did not have any prophylactic effect.12
- Unlike diethylcarbamazine (DEC), ivermectin does not produce a significant Mazzotti reaction in onchocerciasis,13 most likely because it acts by paralyzing the microfilariae in the skin tissue spaces and lymphatics. They are then swept away into the local lymph nodes, which may swell up and only cause some local limb edema. On the other hand, DEC "unmasks" the microfilariae in the tissue spaces and the exposed Wohlbachia organisms within them. Ivermectin elicits a dose-dependent eosinophil sequestration, activation, and degranulation, but the duration apparently is very limited and resolution is quick.14
- Ivermectin kills microfilariae within female worms, as well as those in human tissues. Dead microfilariae within the uteri of the female worm degenerate and prevent further microfilarial production for 6-12 months. Ivermectin not only kills microfilariae, it is also a microfilarial suppressant. Two to 3 months after ivermectin therapy, microfilariae usually disappear from the eyes, halting the advancement of ocular lesions. Patients with visual-field defects, anterior segment disease, and optic nerve damage benefit. Advanced disease of the posterior segment (eg, chorioretinitis) does not improve but stabilizes with treatment.15
- Although up to 30% of patients experience adverse reactions on the first dose, ivermectin seems safe for large-scale use and is proving to be an effective method for reducing the human microfilarial reservoir sufficiently to control transmission by Simulium.16,17,18
- The optimal dose is 150 mcg/kg (usually 6-mg tab bid for adults) of ivermectin given once orally.19 The dosage can be repeated every 6-12 months (6-mo regimen has a higher antiparasite effect and causes fewer adverse reactions after the second and third treatments). Mid-upper arm circumference can be used to adjust the dosage for community-based ivermectin distribution.20 Patients should take each tablet with water.
- Use of ivermectin in children younger than 5 years, in pregnant or breastfeeding women (after a 1-wk limit), and in patients with epilepsy is now permitted. However, the drug is prescribed for patients with other severe illnesses and should not be given during outbreaks of meningitis.21
- The use of ivermectin preceding treatment with suramin may prove an effective way to promote a radical cure of O volvulus infection.
- Multiple dosing at intervals of 3 months may have a slow but steady attrition effect on the adult worms.22
- Data suggest that ivermectin may reduce the development of infective larvae to young adults.23
- Caution is needed in areas endemic for both loiasis and onchocerciasis because ivermectin can initiate serious adverse effects in patients with high L loa microfilarial loads.24,25
- The addition of oral doxycycline (100 mg/d) given for 6 weeks from the start of ivermectin to kill off Wolbachia organisms helps to prevent treatment reactions.26
- Studies have demonstrated that after many rounds of ivermectin treatment, some patients continue to have surprisingly high microfilarial counts. This suboptimal response to ivermectin treatment may indicate a developing drug resistance.27
- Diethylcarbamazine
- DEC is a microfilaricide with no effect on the adult worm.
- It produces Mazzotti reactions that become severe in heavily infected persons. Eosinophilic degranulation is correlated strongly with the Mazzotti reaction.28 A low dose of dexamethasone (3 mg/d), begun after onset of the Mazzotti reaction, modifies the progression of the Mazzotti reaction without interfering with the macrofilaricidal efficacy of DEC.29 This suggests that the Mazzotti reaction is not directly caused by death of microfilariae, but rather is a direct effect of DEC on the immune system.
- Tapering the dose is advisable, beginning with one 50-mg tablet on the first day and followed by two 50-mg tablets on the next 7-10 days.
- Oral and perhaps systemic steroids are advisable to reduce the Mazzotti reaction. Ivermectin has many advantages over DEC, and DEC should not be used if ivermectin is available.
- Suramin
- Suramin is both a macrofilaricide and a microfilaricide. It is given intravenously, starting with a test dose of 100 mg of fresh 10% solution over 2 minutes. If no hypersensitivity develops, weekly dosages of 0.2 g, 0.4 g, 0.6 g, 0.8 g, and 1 g are given to adult patients.
- Rarely, patients experience worsening of eye lesions, exfoliative dermatitis, kidney damage, a Mazzottilike reaction, and/or death. Thus, the use of suramin requires great caution and currently is not recommended.
- Amocarzine
- Amocarzine (CGP 6140) is a new oral macrofilaricidal compound. Amocarzine had promising effects on onchocerciasis in Latin America,30 but more recent studies have been disappointing.
- In the Latin American studies, most adult worms are dead or moribund within 4 months posttherapy. The effect of skin microfilariae lasts approximately 1 year, as reflected by markedly reduced microfilaremia.31
- Doramectin
- Doramectin (Dectomax, Pfizer) is a new avermectin related to ivermectin.
- Its efficacy and safety in onchocerciasis are untested.
Nodulectomy
A useful adjunct to chemotherapy is removal of the palpable nodules. This is popular in Guatemala, Ecuador, and Mexico. In Guatemala and Ecuador, nodulectomy campaigns may have reduced the incidence of ocular onchocerciasis.32 In Africa, nodulectomy has never been practiced widely because the nodules tend to be deeper and located near delicate joint spaces. Alternatively, chloroquine can be injected into young nodules; doing so kills the worms.
Wolbachia organisms appear to play a critical role in the biology and metabolism of filarial worms. The use of tetracycline to kill the Wolbachia organisms appears to be lethal to adult O ochengi, and recent evidence suggests it also is effective for O volvulus and perhaps other filarial worms.33
Prevention of onchocerciasis
The Edna McConnell Clark Foundation Tropical Medicine Program on Onchocerciasis is attempting to produce a vaccine; however, no vaccine is currently available. Control of onchocerciasis has been based on larvicides against the vector. This method was applied effectively in the eradication of Simulium neavei and, thus, of onchocerciasis from Kenya.
Control of transmission by larvicide treatment is now in use against Simulium damnosum by the World Health Organization Onchocerciasis Control Program in West Africa. Population coverage with ivermectin may achieve some control of transmission. Using biological agents to eliminate the vector may be possible.34 The major breakthrough needed for eradication is the development of an inexpensive, nontoxic macrofilaricide deployable on a large scale.35
Bancroftian and Malayan Filariasis
Lymphatic filariasis is endemic in about 80 countries, and an estimated 1 billion people worldwide are at risk of infection. More than 120 million people are already infected, and more than 40 million are incapacitated or disfigured by the disease.36 Three species of filarial parasites commonly inhabit the lymphatic system of humans, W bancrofti, B malayi, and B timori. All 3 of these can produce significant direct dermal injury. Very rarely, other Brugia parasites of animals (eg, Brugia pahangi) cause aberrant infections in humans.
The major symptoms of bancroftian and Malayan filariasis relate to damaged lymphatics. Severe structural and functional abnormalities of lymphatic channels develop even in entirely asymptomatic individuals with microfilaremia. Adult worms induce local reactions by undefined mechanisms that cause dilatation and tortuosity of lymphatic vessels, hypertrophy of vessel walls, loss of valvular function, and backflow of lymph. In 1912, Wise and Minett in British Guiana (Guyana) provided the earliest evidence of the role of bacteria in aggravating and promoting the clinical manifestations of filarial infections. In 1932, O'Connor37 presented evidence suggesting that living worms produced no serious pathology but that dead and dying worms can initiate an immunologic response that leads to clinical elephantiasis independent of any secondary bacterial infection.
Compromised function leads to lymphoedema that is initially reversible. Continued assault on this compromised lymphatic system by persistent parasites, and especially by complicating localized bacterial and fungal superinfection of skin, causes the lymphoedema to become irreversible and leads to chronic elephantiasis of limbs, breasts, and genitalia; hydrocele; and/or chyluria. Additionally, patients may manifest abscesses, ulcers, breast masses, pleural effusions, constrictive pericarditis, and fibrosing mediastinitis. The location of lymphatic damage determines the site and type of clinical manifestations. Dead worms also can cause inflammatory obstruction to lymphatic channels. Collateral lymphatic channels form and some obstructed vessels recanalize, but lymphatic function remains compromised.
As lymphatic damage progresses, the initially transient edema and anatomic distortion transform into the permanent changes of elephantiasis (see Media File 19).
Bancroftian filariasis, causing edema (left) and elephantiasis (right).
Pitting edema becomes a brawny edema with both hyperkeratosis and thickening of subcutaneous tissue. Fissuring of the skin follows, along with nodular and papillomatous hyperplastic changes (see Media File 20).
Nodular and hyperplastic changes cause massive distortion to leg of an Indian man with bancroftian filariasis.
Superinfection (with bacteria and/or dermatophytes) becomes an increasing problem. Patients with bancroftian filariasis also may develop scrotal lymphedema, hydrocele, and chyluria (see Media Files 21-22).
Hydrocele in patient with bancroftian filariasis.
Urine from patient with bancroftian filariasis demonstrating chyluria.
Some patients with elephantiasis develop a crusty, verrucous skin change that resembles mossy foot (lymphostatic verrucosa). See Media File 23.
Foot with verrucous skin change in patient with bancroftian filariasis.
Treatment and prevention of lymphatic filariasis
DEC (6 mg/kg) is the drug registered for use in lymphatic filariasis. Efficacious treatment is the administration of high-dose DEC. Unfortunately, DEC administered in this fashion causes adverse effects, which remained a disincentive to its use in many locales. A low dosage of DEC can be administered to all residents of an endemic area except infants, pregnant women, elderly persons, and persons with debilitating disorders. Sometimes, low-dose DEC is combined with albendazole.38
Ivermectin (400 mcg/kg/d) is an equally potent microfilaricide, and the combination of DEC and ivermectin provides significant synergism.
Tetracycline antibiotics kill Wolbachia endosymbionts and have a macrofilaricidal effect in lymphatic filariasis.39,40,41 Doxycycline at 100 mg/d for 6-8 weeks has demonstrated efficacy against lymphatic filariasis.42
For control, the World Health Organization has long recommended a single, yearly oral dose of ivermectin (400 mcg/kg) with DEC (6 mg/kg), or, under specific conditions, either of these drugs alone or daily use of DEC-fortified salt. DEC is also effective in killing some, but not all, adult worms. Eberhard et al43 report that ivermectin has the same ability as DEC to decrease the level of circulating W bancrofti antigen Og4C3; ivermectin also suppresses microfilaremia for prolonged periods, but it does so without killing the adult worm.44,45
Curiously, a single dose of DEC has essentially the same long-term effectiveness in decreasing microfilaremia and in the apparent killing of adult worms as the 1- to 3-week courses previously recommended. This has enormous implications for control programs, but studies should be performed to decide if the standard 6- to 12-day regimen for most infections and the 34-week regimen for tropical eosinophilic syndrome should be altered for individual patients.
Using DEC alone can cause problems. DEC sometimes can precipitate acute inflammatory reactions, especially in persons with Malayan filariasis, which merely accelerates the natural history of the disease.46 The efficacy of albendazole is now under investigation. SmithKline Beecham is donating albendazole at no cost to organizations and governments wishing to assess the drug's ability to control filariasis.47 Aplysinopsin, an extract from marine sponges that can be produced synthetically, has significant adulticidal activity against filariae. CDRI compound 92/138, a synthetic analogue of aplysinopsin, also destroys developing larval forms (L3 and L4 stages) of filarial nematodes.48
The aggressive treatment of chronic lymphoedema and elephantiasis can lead to a surprising reversal of symptoms. The treatment consists of providing long-term, low-dose DEC (to eradicate persistent or new filarial infections) with diligent attention to the local area of the lymphedematous extremity. The most important local treatments are those measures that prevent superficial bacterial and fungal infection. Additionally, patients should use limb elevation, special massage techniques, and elastic stockings to protect the affected extremity.
Patients with severely damaged extremities may benefit remarkably from surgical decompression of the lymphatic system through endovenous shunt surgery followed by excision of redundant tissue. Surgical correction or repeated drainage is the treatment for hydroceles. Surgical correction sometimes is used to correct chyluria. Interestingly, the diagnostic lymphangiography itself often appears to terminate the leak of chyle into the urine, probably because of its sclerosing effects on the lymphatic vessels that have ruptured into the renal pelvis.
Patients with tropical eosinophilia respond dramatically to DEC. Symptoms of untreated patients may resolve spontaneously, but the eosinophilia usually persists, and these patients frequently have recurrences or relapses. Bronchoalveolar lavage reveals that even patients treated with DEC often have persistent mild chronic alveolitis that can cause a mild, chronic, interstitial lung disease.49 Steroid therapy can be used with anthelminthic therapy to lessen minor allergic reactions. Mebendazole with levamisole is a promising alternative therapy for tropical pulmonary eosinophilia patients who are allergic to DEC.50
Importantly, in places where onchocerciasis and/or loiasis are likely to be co-endemic (eg, sub-Saharan Africa, Latin American countries, Yemen), DEC should not be used for treatment of lymphatic filariasis because of the risk of reactions caused by the presence of one or both of the 2 parasites.
Loiasis
The bite of Chrysops (see Media File 24) causes erythema, swelling, and itching. Entry of the infective larvae (L3) increases the severity of the swelling and itching above that experienced from the bite of an uninfected fly.
Vector for Loa loa, Chrysops, feeding on human skin.
Later, as infective larvae move away under the skin and molt to L4, they often give rise to discrete red urticarial papules in the skin of the affected part. As these L4 larvae mature over the next 3 months or more, the patient may experience vague symptoms, such as pain or temporary swelling of a limb, itching, paresthesia, and, occasionally, hives.
Transient migratory angioedema is a common and classic manifestation of loiasis (see Media File 25). The high incidence of loiasis around the town of Calabar in southeastern Nigeria gave rise to the name Calabar swellings for the angioedema of loiasis.
Angioedema causing swelling of face in woman with Loa loa infection.
Calabar swellings are itchy, red, and nonpitting swollen areas in the skin, 2-10 cm in diameter. They may be painless but are often painful. These "fugitive" swellings may develop in any portion of the skin, but they are most frequent around wrists and ankles and are more common in expatriate Europeans than in Africans. Onset is sudden, but swellings regress gradually over a period of several hours to several days. They usually disappear within 3 days but can recur at irregular intervals and tend to recur at the same sites. Mild local trauma may precipitate their appearance, and swellings recur more often during hot summer months than during colder seasons. Calabar swellings are probably local hypersensitivity reactions to the recent presence of an adult worm.
Expatriate patients may present with only chronic urticaria and Calabar swellings. Sections of skin occasionally reveal microfilariae in dermal vessels and sporadically favor capillaries around sweat glands. A mild chronic focal inflammatory cell infiltrate in the dermis and fibrosis of dermal papillae also are present. Uncommonly, mild dermal eosinophilia is present.
L loa causes a characteristic localized lymphadenitis that generally is found incidentally. Other signs include diffuse edema of the hand or forearm, generalized hives, fever, irritability, confusion, and jacksonian epilepsy. Loiasis also can cause orchitis, scrotitis, and inflammation of the spermatic cord. A dead adult worm in the spermatic cord region may produce a hydrocele. Rarely, patients develop nephropathy, cardiomyopathy, or pulmonary damage, including pulmonary infiltrates and pleural effusion. Acute arthritis with effusion is an uncommon complication, and some evidence suggests that loaiasis can aggravate psoriasis. Eosinophilia is common and may reach 50-80% (10,000/µL); however, no correlation exists between the number of microfilariae in the blood and the eosinophilic response.
Diagnosis
The finding of L loa microfilaria in blood smears, skin snips, or skin biopsy specimens is diagnostic. In a large proportion of infected persons, demonstrating microfilariae in the blood may be impossible. In these patients, an immune response to microfilarial antigens is evidence supporting the clinical impression. Immunologic tests can be general against helminths, nematodes, or filarial nematodes, or it can be specific for L loa. These include antifilarial antibodies, filaria-specific immunoglobulin G type 4, enzyme-linked immunosorbent assay for Schistosoma mansoni, and immunoblot tests. These can reflect a cross-reaction and, thus, yield nonspecific findings.
Travelers returning from endemic areas may have typical Calabar swellings and a high degree of eosinophilia, although peripheral blood examination fails to reveal microfilariae. The most characteristic laboratory findings are elevated white blood cell counts with marked eosinophilia and a rise in immunoglobulin E during the active phase of the disease.
Skin tests and complement fixation tests, using dirofilarial antigens, may be useful in these patients because results are usually positive. However, cross-reaction with other filarial infections, frequently endemic in areas of loiasis, is possible.
Molecular studies are possible because an L loa –specific repetitive DNA sequence is known; however, it is not yet of practical value.
Treatment
Live adult worms can be extracted as they traverse the eye. The use of DEC at 9 mg/kg/d in 3 divided doses for 21 days is recommended.51,52 Although ivermectin decreases microfilaremia, it is contraindicated for loiasis because multiple studies indicate that ivermectin can produce retinal hemorrhages and severe (sometimes fatal) encephalopathy in patients with high blood concentrations of L loa.24,53,54
Mansonelliasis
Infection by filarial worms of the genus Mansonella causes mansonelliasis. Three species routinely infect humans: Mansonella perstans, Mansonella streptocerca, and Mansonella ozzardi. Microfilariae of M perstans and M ozzardi ordinarily dwell in the blood, and those of M streptocerca dwell in tissues, especially dermal collagen.
Mansonella perstans
Infection with M perstans is common in Africa, where it affects, humans, gorillas, and chimpanzees. It is endemic in much of tropical Africa, from Senegal, east to Uganda, and south to Zimbabwe. Biting midges vector this filarial worm. The midge species Culicoides austeni and Culicoides grahamii are the major natural insect vectors. In South America, infections with M perstans develop in persons living along the Atlantic Coast, from Panama and south to Argentina, including Trinidad.
Microfilaremia dramatically increases as the host ages. Adult M perstans are white and threadlike. Female worms are larger (60-80 mm long X 100-150 µm in diameter) than male worms (35-45 mm long X 50-70 µm in diameter). The anterior end is blunt and round, with 2 lateral and 2 submedian papillae. The posterior flexes ventrally to a half coil in the female and a full coil in the male.
Females have 2 terminal papillae at the posterior tip. In cross-section, females have coelomyarial musculature with 8-12 muscle cells per quadrant. The cuticle is 1-2 µm thick, monolayered, very finely striated, and thickened at the lateral chords. Lateral chords contain fine granules of melanin. The anterior region of the male worm contains the intestine and testis, and most of the posterior region contains the intestine and vas deferens. The posterior of male worms also reveals 2 unequal rodlike spicules and 4 preanal and 1 postanal pair of papillae. The cuticle of the male is smooth and thickened at the lateral chords to form internal ridges.
Microfilariae of all species of Mansonella are unsheathed. Microfilariae of M perstans are unsheathed and measure 100-200 µm long by 3.5-4.5 µm wide. The cephalic space is 1-3 µm, with no caudal space. The round terminal nucleus extends to the tip of the tail, and the posterior end is blunt.
Most patients infected with M perstans are asymptomatic. Individuals new to an endemic area tend to experience more symptoms than local inhabitants. Symptoms include subcutaneous swellings of the arms, shoulders, and face; abdominal pain; pruritus; pleuritis; arthralgia; and fatigue. Degenerating worms incite inflammatory exudates composed of eosinophils, neutrophils, plasma cells, and macrophages. These may manifest as focal abscesses that can develop into granulomas and scars (see Media File 26).
Focal abscess in hernia sac caused by degenerating adult Mansonella perstans.
Presumably, breakdown of the worms releases antigenic materials. Some patients may develop periorbital edema and conjunctival irritation, sometimes with granulomatous nodules in the conjunctiva. Acute periorbital inflammation is common in Uganda and is termed bungeye or bulge-eye. Similar periorbital reactions have developed in some patients in Nigeria and Sudan. Dying worms in the conjunctiva provoke necrotizing granulomas with palisading epithelioid cells. The reaction may include degranulating eosinophils.
Microfilariae of M perstans are primarily in peripheral blood (see Media File 27); they are infrequently found in cerebrospinal fluid and urine. Peripheral eosinophilia is common. Microfilariae are more abundant in blood taken at night, but they can be present at any hour of the day (subperiodic).
Microfilariae of Mansonella perstans in peripheral blood smear.
Mansonella streptocerca
M streptocerca produces minor human filarial disease. It causes subcutaneous infection in humans and apes in Africa. M streptocerca occurs in forested areas in Cote d'Ivoire, Ghana, Togo, Benin, Nigeria, Cameroon, Gabon, Central African Republic, Equatorial Guinea, Angola, Democratic Republic of Congo (the former Zaire), and Uganda. The primary vector is C grahamii, a day-biting midge. Its geographic distribution overlaps with that of M perstans, O volvulus, and L loa.
Microfilariae of M streptocerca are 180-240 µm long by 2.5-5 µm wide and are present in the collagen layers of human skin (see Media Files 28-29). The cephalic space is longer (3-5 µm) than it is wide and is followed by a line of 4 staggered but not overlapping elongated nuclei. The nuclei of these microfilariae are smaller than those of O volvulus. The tail curves into the shape of a shepherd's crook and contains rounded-quadrate nuclei in a single column of 9-12 that reach the tip of the tail, leaving only a minute caudal clear space. In life, they make shimmering and stretching movements as opposed to the lashing movements of the thicker microfilariae of O volvulus. The tip of the tail is bifid rather than blunt.
Anterior end of microfilariae of Mansonella streptocerca in collagen layers of skin.
Posterior end of microfilariae of Mansonella streptocerca in collagen layers of skin.
The incubation period of streptocerciasis following infection in humans is unknown but is estimated to be several months. Patients with M streptocerca are usually asymptomatic but can develop pruritus, rash, inguinal adenopathy, and occasional dizziness. The most common presentation is a chronic itching dermatitis often confined to one part of the torso. The constant scratching may thicken the skin. Patients generally present with hypopigmented macules, 1-3 cm in diameter (see Media File 30) that resemble tuberculoid leprosy; however, anesthesia is absent. Skin biopsy results show sclerosis of the papillae; edema; incontinence of melanin; fibrosis; and infiltration with lymphocytes, macrophages, and eosinophils around vessels and appendages.
Hypopigmented macules of streptocerciasis.
Microfilariae are most numerous in the upper dermis (see Media File 31). While alive, adult worms lie in the dermal collagen and provoke no reaction (see Media File 32). Dead or dying worms elicit abscess formation (see Media File 33) and/or granuloma. Inguinal lymph nodes may be enlarged, mobile, and rubbery. In cross-section, they show diffuse fibrosis with thickened septa and capsules, dilated lymphatics, and a proliferation of macrophages in sinuses. Microfilariae of M streptocerca travel through the collagen and sinusoids.
Skin biopsy of Mansonella streptocerca dermatitis.
No reaction to healthy adult female Mansonella streptocerca.
Abscess formation around degenerating adult Mansonella streptocerca following diethylcarbamazine treatment.
The skin reaction, similar to the Mazzotti reaction of onchocerciasis, develops in patients after treatment with DEC (see Media File 34). The skin becomes edematous and intensely itchy, and papules of corresponding size develop around dying microfilariae and adult worms. Following treatment with DEC, new cutaneous papules appear on patients as antigens of the adult worms become evident to the immune system. The inflammatory reaction (composed of eosinophils, neutrophils, and giant cells) attacks these antigens as if they were foreign bodies.
Skin reaction to diethylcarbamazine therapy in a patient with streptocerciasis.
In skin biopsy findings, both O volvulus and M streptocerca travel through collagen fibers and do not tend to enter blood vessels. The features that distinguish these microfilariae of M streptocerca from O volvulus in tissue sections are the smaller size of their nuclei and the appearance of their anterior and posterior ends. Skin snips taken from people living in areas endemic to M streptocerca may contain microfilariae of O volvulus, M perstans, or L loa and (or instead of) M streptocerca. Skin biopsy specimens taken from the shoulder have the highest frequency of finding M streptocerca.55
Mansonella ozzardi
Mansonelliasis by M ozzardi is endemic to the western hemisphere, where it favors remote rural inhabitants, especially the Amerindians. Infection with M ozzardi prevails in the West Indies, Central America, and South America. In South America, endemic countries include northern Argentina, Bolivia, Brazil, Colombia, Ecuador, and Peru. Prevalence is equal in the sexes and increases with age. In the West Indies, Surinam, and Argentina, Culicoides species of biting midges are the vectors of M ozzardi. In Brazil and Colombia, blackflies (Simulium amazonicum and Simulium sanguineum) are the vectors. These vectors take up microfilariae in blood meals, and infective larvae develop in the thoracic muscles. Humans are the only known natural definitive hosts.
The microfilariae are found mainly in the blood but sometimes in skin snips. They are unsheathed and 170-240 µm long by 3-5 µm wide with a 2- to 6-µm cephalic space. The anterior 2 or 3 nuclei either overlap or are side by side. The caudal space is 3-8 µm long, and the terminal nuclei are oval.
Microfilariae of M ozzardi resemble those of M perstans, except that the tail of M ozzardi is pointed, is slightly flexed, and has a longer caudal space (see Media File 35). In the West Indies, no specific manifestations of M ozzardi infection are recognized, but patients in the Amazon region attribute a wide variety of complaints to M ozzardi infection, including lymphadenopathy, varices, pain in the knees and ankles, dermatitis with pruritus, fever, headache, insomnia, and vertigo. Peripheral eosinophilia may be present. No consistent clinical picture has emerged, and these complaints and findings may be incidental.
Microfilariae of Mansonella ozzardi.
In biopsy specimens of the skin and subcutaneous tissue, small numbers of microfilariae are present in blood vessels and sometimes in small perivascular infiltrations of lymphocytes and plasma cells. Diagnosis depends on demonstrating microfilariae of M ozzardi in thick or thin films of peripheral blood, skin snips, biopsy specimens of skin, or by Nuclepore filtration of venous blood. The microfilariae are nonperiodic; thus, specimens may be taken at any time of day.
Prevention and treatment of Mansonella infection
Routine methods to avoid insect bites are preventative. No standard treatment is available for M streptocerca infection. Long-term or pulsed treatment with DEC kills the adult worms and should achieve a radical cure of streptocerciasis. In a study performed in Zaire (now renamed Democratic Republic of Congo), new papules appeared over a 21-day period of therapy, suggesting that early larval forms of M streptocerca are not susceptible to DEC. Care must be taken if administering DEC to patients co-infected with L loa. Recent trials with ivermectin reveal that it has strong microfilaricidal activity against M streptocerca.56 No serious adverse effects are associated, but 45% of patients experienced increased pruritus and acute papular dermatitis after the sixth day of treatment.
For M ozzardi, the prognosis is excellent, even without treatment. Whereas DEC is ineffective, ivermectin has efficacy.57 In a double-blinded, placebo-controlled study of 40 persons with M ozzardi infections in Blanchisseuse, Trinidad, a single dose of ivermectin (6 mg) reduced microfilariae levels after 4 years by 82.2%.58 Albendazole also has been recommended.59
For M perstans, therapy with DEC eliminates the microfilaremia of M perstans infection but only after prolonged therapy (ie, 2 mg/kg of body weight qid for 8 periods of 10 d each, with 3-wk intervals between each period). The slow elimination of microfilariae from the blood stream suggests an effect on adults rather than on the microfilariae. Treatment seems to have a salutary clinical effect. Several degenerating adult M perstans seen in random surgical specimens were from patients who had taken DEC. Mebendazole (100 mg bid for 4-7 wk) appears to be more active than DEC in eliminating M perstans infection. Ivermectin and praziquantel are not effective for M perstans infection; they do not alter the microfilariae concentration. Thiabendazole has small but significant activity against the infection. Combination treatments using DEC and mebendazole appear to be the ideal treatment.60
Because Mansonella perstans is resistant to standard antiparasitic treatment, doxycycline is sometimes used to eradicate Wolbachia, an endosymbiont found in most filarial species. Doxycycline treatment typically results in death or sterility of the filarial nematode. In an open-label, randomized trial, Coulibaly et al recruited patients infected with M perstans from 4 African villages in Mali. Patients were randomly assigned to receive doxycycline at 200 mg/d orally for 6 weeks (n = 106) or no treatment (n = 110). At 6 months, patients co-infected with Wuchereria bancrofti underwent a second randomization to receive a single dose of albendazole (400 mg) plus ivermectin (150 mcg/kg) or no treatment. At 12 months, 97% of patients who received doxycycline had no detectable blood levels of M perstans, compared with 16% in the group that did not receive treatment (P <.001). At 36 months, M perstans remained suppressed in 75% of patients who received doxycycline. This suggests that doxycycline is an effective therapy for M perstans infection.61
Dirofilariasis
Filarial nematodes of the genus Dirofilaria cause dirofilariasis. The number of human dirofilariasis cases reported has increased dramatically in recent years.62 However, humans are poor hosts for all Dirofilaria species such that the worm usually dies before reaching sexual maturity and does not release viable microfilariae. These worms produce an inconspicuous granulomatous reaction in the subcutaneous tissue or a single, small, pulmonary infarct.
Two subgenera, Dirofilaria (Dirofilaria) species and Dirofilaria (Nochtiella) species are recognized. Dirofilaria (Dirofilaria) immitis is the most frequent agent of pulmonary dirofilariasis. Although D (Dirofilaria) immitis primarily causes lung lesions, it has, on rare occasion caused intra-abdominal infection and even subcutaneous nodules.63,64 Dirofilaria Nochtiella species are the most frequent agents of subcutaneous dirofilariasis.
Approximately 20 species of Dirofilaria are in the subgenus Nochtiella; of these, Dirofilaria (Nochtiella) repens, Dirofilaria (Nochtiella) tenuis, and Dirofilaria (Nochtiella) striata have produced human infection, while Dirofilaria (Nochtiella) ursi –like infections that represent either D (Nochtiella) ursi or
Dirofilaria (Nochtiella) subdermata, or both, rarely can cause human infections. Most human infections by members of the subgenus Nochtiella are D (Nochtiella) tenuis in the western hemisphere and D (Nochtiella) repens in the eastern hemisphere.
Members of the D (Nochtiella) subgenera have external longitudinal cuticular ridges. The lateral chords of these worms extend into the body cavity and are divided into sublaterals. Distinguishing the various D (Nochtiella) species is difficult in tissue section, but careful observation of the size, number, and spacing of the external longitudinal cuticular ridges with properly oriented worms can reveal the specific species (see Media File 36). In some transverse sections, especially in degenerated worms, external cuticular ridges are difficult to identify. In addition, the intraspecies variation is marked, and it generally is sufficient for diagnosis of an infection with a worm of a member of the Nochtiella subgenera.
Cuticle of Dirofilaria (Nochtiella) repens demonstrating thick 3-layered cuticle with prominent external longitudinal ridges. Note the acute inflammatory cells responding to the infection.
Adult D (Nochtiella) tenuis females are 8-13 cm long and 260-360 µm in diameter. Adult males are 4-4.8 cm long and 190-260 µm in diameter. The cuticle in both sexes is 5-15 µm thick. The ridges of D (Nochtiella) tenuis are usually distinctive; they are relatively low and rounded, with a wavy, broken, and branching pattern. The space between each ridge is variable, and the height of each ridge varies. The external ridges can be absent even in a well-preserved section of D (Nochtiella) tenuis at some levels, but additional sections may reveal ridges.
At least 15 species of mosquitos serve as vectors for all species of Dirofilaria except for D (Nochtiella) ursi. Mosquito susceptibility varies within and between species. Temperature and the availability of breeding habitats affect the dynamics of parasite transmission. In North America, Aedes sierrensis, Aedes sollicitans, Aedes taeniorhynchus, and Anopheles bradleyi are well-known vectors. In Oceania, Aedes polynesiensis and Aedes samoanus are important vectors, and Aedes notoscriptus is the most important vector in Australia. The blackfly, Simulium species, especially Simulium venustum, is the vector for D (Nochtiella) ursi.
Adult members of the D (Nochtiella) subgenera live and reproduce in the subcutaneous tissues of their normal hosts. In humans, members of D (Nochtiella) subgenera usually die in the subcutaneous tissues. In rare instances, D (Nochtiella) repens migrate into the circulatory system, reach pulmonary vessels, and cause pulmonary dirofilariasis. Whether or not the worm survives to maturity, it almost invariably causes some dermal or subcutaneous injury.
Subcutaneous dirofilariasis is either a stationary or, less often, a migratory subcutaneous, flesh-colored to erythematous, variably tender nodule. Lesions may be painful and cause burning and itching. Common locations include the head, neck, breasts, arms, legs, or scrotum.
Histology
In patients with migratory lesions from living Dirofilaria species, missing the worm is easy; biopsy specimens are commonly taken from the area where the worm just left. These specimens reveal only normal epidermis and dermis and perhaps chronic inflammation suggestive of a foreign body reaction in the subcutaneous tissue.
Biopsy samples taken from nodules of subcutaneous dirofilariasis usually reveal a single, dead, or degenerating coiled worm. In an early nodule, where the worm has minimal degeneration, the zone immediately around the worm contains necrotic debris, and an abscess is around the debris. The predominant cells in the abscess are neutrophils and eosinophils. Worms in the subcutaneous fat provoke an eosinophilic panniculitis in the area surrounding the worm. Older lesions with a degenerated or partially calcified worm evoke granulomatous inflammation, consisting of epithelioid cells, giant cells, macrophages, lymphocytes, and eosinophils. The numbers of eosinophils is greatest in the involved periphery of the lesion. Uncommonly, patients with subcutaneous dirofilariasis develop an acute arthritis.
Diagnosis of subcutaneous dirofilariasis caused by D (Nochtiella) species is made by identifying the worm within the biopsy specimen or, less commonly, from recovering the worm extracted from a lesion.
Treatment and prevention of dirofilariasis
The only method of treatment of human dirofilariasis is surgical removal of the lesion or extraction of the worm. (Ivermectin is the treatment of choice for dogs with heartworm.) Routine methods for avoiding mosquito and fly bites help prevent infection. Deworming pets, especially pet dogs, is protective against D (Dirofilaria) immitis and D (Nochtiella) immitis infection in humans.
Multimedia
 | Media file 1: Third stage larvae of Onchocerca in proboscis of Simulium. |
 | Media file 2: Subcutaneous nodule on hip caused by encysted Onchocerca volvulus. |
 | Media file 3: Man blinded by microfilariae of Onchocerca volvulus. |
 | Media file 4: Movable, nontender subcutaneous nodule of Onchocerca volvulus. |
 | Media file 5: Bleeding on skin from scratching itchy skin of onchodermatitis. |
 | Media file 6: One anatomic quarter of body (leg) markedly affected by edema and papule formation of onchodermatitis. |
 | Media file 7: Skin with an aged appearance in a patient with chronic onchodermatitis. Note the subcutaneous nodule. |
 | Media file 8: Chronic onchodermatitis skin demonstrates a loss of elasticity. |
 | Media file 9: Skin of a West African person with leopard spot depigmentation. |
 | Media file 10: Skin of a Latin American child with erisípela de la costa. |
 | Media file 11: Patient from Cameroon with sowdalike lesions. |
 | Media file 12: Microfilariae, most numerous in upper dermis. |
 | Media file 13: Intraepidermal abscess containing microfilariae of Onchocerca volvulus. |
 | Media file 14: Loss of melanin pigment in basal layer of leopard skin. |
 | Media file 15: Thin epidermis with a few small rete ridges in elephantoid onchodermatitis. |
 | Media file 16: Very thin undulating epidermis lacking rete ridges in a patient with lizard skin onchodermatitis. |
 | Media file 17: Hyperkeratosis, focal parakeratosis, and follicular plugging in hyperreactive skin of a patient with sowda onchodermatitis. |
 | Media file 18: North American patient with subcutaneous abscess containing zoonotic Onchocerca. Note the very pronounced transverse ridges. |
 | Media file 19: Bancroftian filariasis, causing edema (left) and elephantiasis (right). |
 | Media file 20: Nodular and hyperplastic changes cause massive distortion to leg of an Indian man with bancroftian filariasis. |
 | Media file 21: Hydrocele in patient with bancroftian filariasis. |
 | Media file 22: Urine from patient with bancroftian filariasis demonstrating chyluria. |
 | Media file 23: Foot with verrucous skin change in patient with bancroftian filariasis. |
 | Media file 24: Vector for Loa loa, Chrysops, feeding on human skin. |
 | Media file 25: Angioedema causing swelling of face in woman with Loa loa infection. |
 | Media file 26: Focal abscess in hernia sac caused by degenerating adult Mansonella perstans. |
 | Media file 27: Microfilariae of Mansonella perstans in peripheral blood smear. |
 | Media file 28: Anterior end of microfilariae of Mansonella streptocerca in collagen layers of skin. |
 | Media file 29: Posterior end of microfilariae of Mansonella streptocerca in collagen layers of skin. |
 | Media file 30: Hypopigmented macules of streptocerciasis. |
 | Media file 31: Skin biopsy of Mansonella streptocerca dermatitis. |
 | Media file 32: No reaction to healthy adult female Mansonella streptocerca. |
 | Media file 33: Abscess formation around degenerating adult Mansonella streptocerca following diethylcarbamazine treatment. |
 | Media file 34: Skin reaction to diethylcarbamazine therapy in a patient with streptocerciasis. |
 | Media file 35: Microfilariae of Mansonella ozzardi. |
 | Media file 36: Cuticle of Dirofilaria (Nochtiella) repens demonstrating thick 3-layered cuticle with prominent external longitudinal ridges. Note the acute inflammatory cells responding to the infection. |
 | Media file 37: Biopsy of skin abscess shows a degenerating adult Loa loa in a Calabar swelling. |
Keywords
filarial parasites, lymphatic filariasis, onchocerciasis, mansonellosis, dirofilariasis
The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Brian OL Duke, MD, ScD (Cantab), FRCP, DTM&H †, to the development and writing of this article.
More on Filariasis |
| References |
| Further Reading |
References
Grove DI. Selective primary health care: strategies for the control of disease in the developing world. VII. Filariasis. Rev Infect Dis. Sep-Oct 1983;5(5):933-44. [Medline].
Lowenberger CA, Ferdig MT, Bulet P, Khalili S, Hoffmann JA, Christensen BM. Aedes aegypti: induced antibacterial proteins reduce the establishment and development of Brugia malayi. Exp Parasitol. Jul 1996;83(2):191-201. [Medline].
Higazi TB, Filiano A, Katholi CR, Dadzie Y, Remme JH, Unnasch TR. Wolbachia endosymbiont levels in severe and mild strains of Onchocerca volvulus. Mol Biochem Parasitol. May 2005;141(1):109-12. [Medline].
Kipp W, Bamuhiiga J, Rubaale T. Simulium neavei-transmitted onchocerciasis: HIV infection increases severity of onchocercal skin disease in a small sample of patients. Trans R Soc Trop Med Hyg. May-Jun 2003;97(3):310-1. [Medline].
Sallo F, Eberhard ML, Fok E, Baska F, Hatvani I. Zoonotic intravitreal Onchocerca in Hungary. Ophthalmology. Mar 2005;112(3):502-4. [Medline].
Beaver PC, Horner GS, Bilos JZ. Zoonotic onchocercosis in a resident of Illinois and observations on the identification of Onchocerca species. Am J Trop Med Hyg. Jul 1974;23(4):595-607. [Medline].
Takaoka H, Yanagi T, Daa T, Anzai S, Aoki C, Fukuda M. An Onchocerca species of wild boar found in the subcutaneous nodule of a resident of Oita, Japan. Parasitol Int. Mar 2005;54(1):91-3. [Medline]. [Full Text].
Duerr HP, Raddatz G, Eichner M. Diagnostic value of nodule palpation in onchocerciasis. Trans R Soc Trop Med Hyg. Feb 2008;102(2):148-54. [Medline].
Connor DH, Gibson DW, Neafie RC, Merighi B, Buck AA. Sowda--onchocerciasis in north Yemen: a clinicopathologic study of 18 patients. Am J Trop Med Hyg. Jan 1983;32(1):123-37. [Medline].
Mitsui Y, Tanimori H, Kitagawa T, Fujimaki Y, Aoki Y. Simple and sensitive enzyme-linked immunosorbent assay for ivermectin. Am J Trop Med Hyg. Mar 1996;54(3):243-8. [Medline].
Burnham G. Onchocerciasis. Lancet. May 2 1998;351(9112):1341-6. [Medline].
Boussinesq M, Chippaux JP. A controlled prospective trial of the prophylactic effect of a single dose of ivermectin against Onchocerca volvulus. Parasite. Sep 2001;8(3):255-9. [Medline].
Awadzi K, Opoku NO, Addy ET, Quartey BT. The chemotherapy of onchocerciasis. XIX: The clinical and laboratory tolerance of high dose ivermectin. Trop Med Parasitol. Jun 1995;46(2):131-7. [Medline].
Cooper PJ, Awadzi K, Ottesen EA, Remick D, Nutman TB. Eosinophil sequestration and activation are associated with the onset and severity of systemic adverse reactions following the treatment of onchocerciasis with ivermectin. J Infect Dis. Mar 1999;179(3):738-42. [Medline].
Abiose A. Onchocercal eye disease and the impact of Mectizan treatment. Ann Trop Med Parasitol. Apr 1998;92 Suppl 1:S11-22. [Medline].
Whitworth JA, Morgan D, Maude GH, Downham MD, Taylor DW. A community trial of ivermectin for onchocerciasis in Sierra Leone: adverse reactions after the first five treatment rounds. Trans R Soc Trop Med Hyg. Jul-Aug 1991;85(4):501-5. [Medline].
Pacque, Munoz B, Greene BM, Taylor HR. Community-based treatment of onchocerciasis with ivermectin: safety, efficacy, and acceptability of yearly treatment. J Infect Dis. Feb 1991;163(2):381-5. [Medline].
Taylor HR, Pacque M, Munoz B, Greene BM. Impact of mass treatment of onchocerciasis with ivermectin on the transmission of infection. Science. Oct 5 1990;250(4977):116-8. [Medline].
Duke BO. Onchocerciasis. In: Current Opinion in Infectious Diseases. Vol 1. 1988:695-699.
Shu EN, Okonkwo PO. Community-based ivermectin therapy for onchocerciasis: comparison of three methods of dose assessment. Am J Trop Med Hyg. Sep 2001;65(3):184-8. [Medline].
Brown KR. Changes in the use profile of Mectizan: 1987-1997. Ann Trop Med Parasitol. Apr 1998;92 Suppl 1:S61-4.
Duke BO, Zea-Flores G, Castro J, Cupp EW, Munoz B. Effects of three-month doses of ivermectin on adult Onchocerca volvulus. Am J Trop Med Hyg. Feb 1992;46(2):189-94. [Medline].
Kläger S, Whitworth JA, Post RJ, Chavasse DC, Downham MD. How long do the effects of ivermectin on adult Onchocerca volvulus persist?. Trop Med Parasitol. Dec 1993;44(4):305-10. [Medline].
Gardon J, Gardon-Wendel N, Demanga-Ngangue, Kamgno J, Chippaux JP, Boussinesq M. Serious reactions after mass treatment of onchocerciasis with ivermectin in an area endemic for Loa loa infection. Lancet. Jul 5 1997;350(9070):18-22. [Medline].
Horton J, Witt C, Ottesen EA, Lazdins JK, Addiss DG, Awadzi K, et al. An analysis of the safety of the single dose, two drug regimens used in programmes to eliminate lymphatic filariasis. Parasitology. 2000;121 Suppl:S147-60. [Medline].
Hoerauf A, Mand S, Adjei O, Fleischer B, Buttner DW. Depletion of wolbachia endobacteria in Onchocerca volvulus by doxycycline and microfilaridermia after ivermectin treatment. Lancet. May 5 2001;357(9266):1415-6. [Medline].
Awadzi K, Boakye DA, Edwards G, Opoku NO, Attah SK, Osei-Atweneboana MY, et al. An investigation of persistent microfilaridermias despite multiple treatments with ivermectin, in two onchocerciasis-endemic foci in Ghana. Ann Trop Med Parasitol. Apr 2004;98(3):231-49. [Medline].
Ackerman SJ, Kephart GM, Francis H, Awadzi K, Gleich GJ, Ottesen EA. Eosinophil degranulation. An immunologic determinant in the pathogenesis of the Mazzotti reaction in human onchocerciasis. J Immunol. May 15 1990;144(10):3961-9. [Medline].
Stingl P, Pierce PF, Connor DH, Gibson DW, Straessle T, Ross MA, et al. Does dexamethasone suppress the Mazzotti reaction in patients with onchocerciasis?. Acta Trop. Mar 1988;45(1):77-85. [Medline].
Zak F, Guderian R, Zea-Flores G, Guevara A, Moran M, Poltera AA. Microfilaricidal effect of amocarzine in skin punch biopsies of patients with onchocerciasis from Latin America. Trop Med Parasitol. Sep 1991;42(3):294-302. [Medline].
Poltera AA, Zea-Flores G, Guderian R, Striebel HP, Moran M. Longterm follow-up of onchocerciasis patients in Latin America after treatment and retreatment with amocarzine. Preliminary results. Trop Med Parasitol. Sep 1991;42(3):308-13. [Medline].
Guderian RH, Proaño R, Beck B, Mackenzie CD. The reduction in microfilariae loads in the skin and eye after nodulectomy in Ecuadorian onchocerciasis. Trop Med Parasitol. Dec 1987;38(4):275-8. [Medline].
Langworthy NG, Renz A, Mackenstedt U, Henkle-Dührsen K, de Bronsvoort MB, Tanya VN, et al. Macrofilaricidal activity of tetracycline against the filarial nematode Onchocerca ochengi: elimination of Wolbachia precedes worm death and suggests a dependent relationship. Proc Biol Sci. Jun 7 2000;267(1448):1063-9. [Medline].
Drobniewski FA. The safety of Bacillus species as insect vector control agents. J Appl Bacteriol. Feb 1994;76(2):101-9. [Medline].
Duke BO. Onchocerciasis (river blindness)-can it be eradicated?. Parasitology Today. 1990;6:82-84.
Lammie P, Liese B, Molyneux D, and the Global Alliance Team. The Global Alliance to Elliminate Lymphatic Filariasis. The Global Alliance to Elliminate Lymphatic Filariasis. Available at http://www.filariasis.org/. Accessed February 2, 2009.
O' Connor FW. The etiology of the disease syndrome in Wuchereria bancrofti infections. Trans Royal Soc Trop Med Hyg. 1932;26:13-33.
Fischer P, Supali T, Maizels RM. Lymphatic filariasis and Brugia timori: prospects for elimination. Trends Parasitol. Aug 2004;20(8):351-5. [Medline].
Hoerauf A. New strategies to combat filariasis. Expert Rev Anti Infect Ther. Apr 2006;4(2):211-22. [Medline].
Lammie PJ. The promise of wolbachia-targeted chemotherapy as a public health intervention for lymphatic filariasis and onchocerciasis. Clin Infect Dis. Apr 15 2006;42(8):1090-2. [Medline].
Stolk WA, de Vlas SJ, Habbema JD. Anti-Wolbachia treatment for lymphatic filariasis. Lancet. Jun 18-24 2005;365(9477):2067-8. [Medline].
Taylor MJ, Makunde WH, McGarry HF, Turner JD, Mand S, Hoerauf A. Macrofilaricidal activity after doxycycline treatment of Wuchereria bancrofti: a double-blind, randomised placebo-controlled trial. Lancet. Jun 18-24 2005;365(9477):2116-21. [Medline].
Eberhard ML, Hightower AW, Addiss DG, Lammie PJ. Clearance of Wuchereria bancrofti antigen after treatment with diethylcarbamazine or ivermectin. Am J Trop Med Hyg. Oct 1997;57(4):483-6. [Medline].
Dreyer G, Noroes J, Amaral F, Nen A, Medeiros Z, Coutinho A, et al. Direct assessment of the adulticidal efficacy of a single dose of ivermectin in bancroftian filariasis. Trans R Soc Trop Med Hyg. Jul-Aug 1995;89(4):441-3. [Medline].
Dreyer G, Addiss D, Noroes J, Amaral F, Rocha A, Coutinho A. Ultrasonographic assessment of the adulticidal efficacy of repeat high-dose ivermectin in bancroftian filariasis. Trop Med Int Health. Aug 1996;1(4):427-32. [Medline].
Ottesen EA. Efficacy of diethylcarbamazine in eradicating infection with lymphatic-dwelling filariae in humans. Rev Infect Dis. May-Jun 1985;7(3):341-56. [Medline].
Cicatelli G. The World Bank Group Press Release no. 98/1623. World Bank, SmithKline Beecham, and WHO to Cooperate on Elephantiasis elimination. 1998.
Singh SN, Bhatnagar S, Fatma N, Chauhan PM, Chatterjee RK. Antifilarial activity of a synthetic marine alkaloid, aplysinopsin (CDRI Compound 92/138). Trop Med Int Health. Jun 1997;2(6):535-43. [Medline].
Rom WN, Vijayan VK, Cornelius MJ, Kumaraswami V, Prabhakar R, Ottesen EA, et al. Persistent lower respiratory tract inflammation associated with interstitial lung disease in patients with tropical pulmonary eosinophilia following conventional treatment with diethylcarbamazine. Am Rev Respir Dis. Nov 1990;142(5):1088-92. [Medline].
Karnad DR, Meisheri YV. Mebendazole with levamisole in tropical pulmonary eosinophilia: an alternative in diethylcarbamazine allergy. Trop Doct. Jul 1992;22(3):136-7. [Medline].
Herrero-Morin JD, Fernandez Gonzalez MN, Gonzalez Rodriguez F, Garcia Lopez E, Diaz Arguelles M. [Ocular filariasis due to Loa-loa. An emerging tropical parasitosis in Europe?]. An Pediatr (Barc). Aug 2006;65(2):168-70. [Medline].
Nutman TB, Kradin RL. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 1-2002. A 24-year-old woman with paresthesias and muscle cramps after a stay in Africa. N Engl J Med. Jan 10 2002;346(2):115-22. [Medline].
Pion DS, Gardon J, Kamgno J, Gardon-Wendel N, Chippaux JP, Boussinesq M. Structure of the microfilarial reservoir of Loa loa in the human host and its implications for monitoring the progr,ammes of Community-Directed Treatment with Ivermectin carried out in Africa. Parasitology. Nov 2004;129(Pt 5):613-26. [Medline].
Develoux M. [Ivermectin]. Ann Dermatol Venereol. Jun-Jul 2004;131(6-7 Pt 1):561-70. [Medline].
Anosike JC. Studies on filariasis in Bauchi State, Nigeria. V. The distribution and prevalence of mansonellosis with special reference to clinical signs. Appl Parasitol. Sep 1994;35(3):189-92. [Medline].
Fischer P, Tukesiga E, Büttner DW. Long-term suppression of Mansonella streptocerca microfilariae after treatment with ivermectin. J Infect Dis. Oct 1999;180(4):1403-5. [Medline].
Ottesen EA, Campbell WC. Ivermectin in human medicine. J Antimicrob Chemother. Aug 1994;34(2):195-203. [Medline].
Gonzalez AA, Chadee DD, Rawlins SC. Ivermectin treatment of mansonellosis in Trinidad. West Indian Med J. Dec 1999;48(4):231-4. [Medline].
Duong TH, Kombila M, Ferrer A, Nguiri C, Richard-Lenoble D. Decrease in Mansonella perstans microfilaraemia after albendazole treatment. Trans R Soc Trop Med Hyg. Jul-Aug 1998;92(4):459. [Medline].
Bregani ER, Rovellini A, Mbaidoum N, Magnini MG. Comparison of different anthelminthic drug regimens against Mansonella perstans filariasis. Trans R Soc Trop Med Hyg. May 2006;100(5):458-63. [Medline].
[Best Evidence] Coulibaly YI, Dembele B, Diallo AA, et al. A randomized trial of doxycycline for Mansonella perstans infection. N Engl J Med. Oct 8 2009;361(15):1448-58. [Medline].
Simon F, Lopez-Belmonte J, Marcos-Atxutegi C, Morchón R, Martin-Pacho JR. What is happening outside North America regarding human dirofilariasis?. Vet Parasitol. Oct 24 2005;133(2-3):181-9. [Medline].
Abbas KF, El-Monem SG, Malik Z, Khan AM. Surgery still opens an unexpected bag of worms! An intraperitoneal live female Dirofilaria worm: case report and review of the literature. Surg Infect (Larchmt). Jun 2006;7(3):323-5. [Medline].
Huang SL, Liu YH, Chen W. Subcutaneous dirofilariasis caused by Dirofilaria immitis mimicking a large epidermal cyst. J Eur Acad Dermatol Venereol. Apr 2006;20(4):477-8. [Medline].
Abanobi OC, Edungbola LD, Nwoke BE, Mencias BS, Nkwogu FU, Njoku AJ. Validity of leopard skin manifestation in community diagnosis of human onchocerciasis infection. Appl Parasitol. Feb 1994;35(1):8-11. [Medline].
Baird JK, Neafie RC, Lanoie L, Connor DH. Adult Mansonella perstans in the abdominal cavity in nine Africans. Am J Trop Med Hyg. Nov 1987;37(3):578-84. [Medline].
Bradshaw H. Onchocerciasis and the Mectizan Donation Programme. Parasitology Today. 1989;5:63-64.
Browne SG. Rare skin lesions in African onchocerciasis. Dermatol Int. Oct-Dec 1968;7(4):191-5. [Medline].
Burchard GD, Brattig NW, Kruppa TF, Horstmann RD. Delayed-type hypersensitivity reactions to Onchocerca volvulus antigens in exposed and non-exposed African individuals. Trans R Soc Trop Med Hyg. Jan-Feb 1999;93(1):103-5. [Medline].
Burr WE Jr, Brown MF, Eberhard ML. Zoonotic Onchocerca (Nematoda:Filarioidea) in the cornea of a Colorado resident. Ophthalmology. Aug 1998;105(8):1494-7. [Medline].
Buxton BA, Mullen GR. Field isolations of Dirofilaria from mosquitoes in Alabama. J Parasitol. Feb 1980;66(1):140-4. [Medline].
Center Watch Clinical Trial Listings Service. Stromectol (Ivermectin). 2000;. Available at: http://centerwatch.com/patient/drugs/dru250.html. Accessed November 27, 2001. [Full Text].
Chandrashekar R, Curtis KC, Weil GJ. Molecular characterization of a parasite antigen in sera from onchocerciasis patients that is immunologically cross-reactive with human keratin. J Infect Dis. Jun 1995;171(6):1586-92. [Medline].
Corman LC. Acute arthritis occurring in association with subcutaneous Dirofilaria tenuis infection. Arthritis Rheum. Dec 1987;30(12):1431-4. [Medline].
de la Herran Herrera A, Gonzalez Garrido EA, Pila Perez R, Leon Díaz R. [Myocardiopathy in a patient with loaiasis. Presentation of a case]. Rev Cubana Med Trop. Sep-Dec 1981;33(3):201-6. [Medline].
Dreyer G, Brandao AC, Amaral F, Medeiros Z, Addiss D. Detection by ultrasound of living adult Wuchereria bancrofti in the female breast. Mem Inst Oswaldo Cruz. Jan-Feb 1996;91(1):95-6. [Medline].
Eberhard ML, Dickerson JW, Tsang VC, Walker EM, Ottesen EA, Chandrashekar R, et al. Onchocerca volvulus: parasitologic and serologic responses in experimentally infected chimpanzees and mangabey monkeys. Exp Parasitol. May 1995;80(3):454-62. [Medline].
Edeson JF, Wilson T, Wharton RH, Laing AB. Experimental transmission of Brugia malayi and B. pahangi to man. Trans R Soc Trop Med Hyg. May 1960;54:229-34. [Medline].
Erttmann KD, Buttner DW, Gallin MY. Molecular cloning, expression, and localization of E1, an Onchocerca volvulus antigen with similarity to brain ankyrin. J Biol Chem. Jan 19 1996;271(3):1645-50. [Medline].
Fischer P, Kilian AH, Bamuhiiga J, Kipp W, Büttner DW. Prevalence of Mansonella perstans in western Uganda and its detection using the QBC-fluorescence method. Appl Parasitol. Jan 1996;37(1):32-7. [Medline].
Gilbert HM, Hartman BJ. Short report: a case of fibrosing mediastinitis caused by Wuchereria bancrofti. Am J Trop Med Hyg. Jun 1996;54(6):596-9. [Medline].
Gutierrez Y. Diagnostic features of zoonotic filariae in tissue sections. Hum Pathol. Jun 1984;15(6):514-25. [Medline].
Hawking F. The distribution of human filariasis throughout the world. Part III. Africa. Trop Dis Bull. Aug 1977;74(8):649-79. [Medline].
Hay RJ, Mackenzie CD, Guderian R, Noble WC, Proano JR, Williams JF. Onchodermatitis--correlation between skin disease and parasitic load in an endemic focus in Ecuador. Br J Dermatol. Aug 1989;121(2):187-98. [Medline].
Kilian HD, Nielsen G. Cell-mediated and humoral immune responses to BCG and rubella vaccinations and to recall antigens in onchocerciasis patients. Trop Med Parasitol. Dec 1989;40(4):445-53. [Medline].
Klion AD, Eisenstein EM, Smirniotopoulos TT, et al. Pulmonary involvement in loiasis. Am Rev Respir Dis. Apr 1992;145(4 Pt 1):961-3. [Medline].
Marty AM, Neafie RC. Two patients with zoonotic onchocerciasis acquired in the United States. In: American Society of Tropical Medicine and Hygiene. Washington, DC: Armed Forces Institute of Pathology, Infectious and Parasitic Disease Department; 1997.
Meyers WM, Moris R, Neafie RC, Connor DH, Bourland J. Streptocerciasis: degeneration of adult Dipetalonema streptocerca in man following diethylcarbamazine therapy. Am J Trop Med Hyg. Nov 1978;27(6):1137-47. [Medline].
Meyers WM, Neafie RC, Moris R, Bourland J. Streptocerciasis: observation of adult male Dipetalonema streptocerca in man. Am J Trop Med Hyg. Nov 1977;26(6 Pt 1):1153-5. [Medline].
Morel L, Delaude A, Girard M, Bouzekri M. [Eosinophilic pulmonary infiltrates in filariasis of the Loa loa type]. Poumon Coeur. 1967;23(6):685-94. [Medline].
Murdoch ME, Abiose A, Garate T, Hay RJ, Jones BR, Maizels RM, et al. Human onchocerciasis in Nigeria: isotypic responses and antigen recognition in individuals with defined cutaneous pathology. Am J Trop Med Hyg. Jun 1996;54(6):600-12. [Medline].
Negesse Y, Lanoie LO, Neafie RC, Connor DH. Loiasis: "Calabar" swellings and involvement of deep organs. Am J Trop Med Hyg. May 1985;34(3):537-46. [Medline].
Nutman TB, Miller KD, Mulligan M, Ottesen EA. Loa loa infection in temporary residents of endemic regions: recognition of a hyperresponsive syndrome with characteristic clinical manifestations. J Infect Dis. Jul 1986;154(1):10-8. [Medline].
Orihel TC. The tail of the Mansonella streptocerca microfilaria. Am J Trop Med Hyg. Nov 1984;33(6):1278. [Medline].
Osamulia-Soendjojo N, Prens EP, Sluiters JF, Naafs B. Psoriasis and filariasis. Br J Dermatol. Nov 1994;131(5):723-4. [Medline].
Owen HB, Hennessey RS. A note on some ocular manifestations of helminthic origin occurring in natives of Uganda. Trans R Sco Trop Med Hyg. 1932;25:267-273.
Paleologo FP, Neafie RC, Connor DH. Lymphadenitis caused by Loa loa. Am J Trop Med Hyg. May 1984;33(3):395-402. [Medline].
Pampiglione S, Candiani G, Del Maschio O, Pagan V. [Human pulmonary dirofilariasis. A third case in Italy]. Pathologica. Jan-Feb 1991;83(1083):21-7. [Medline].
Parker BM. Variation of mosquito (Diptera: Culicidae) relative abundance and Dirofilaria immitis (Nematoda: Filarioidea) vector potential in coastal North Carolina. J Med Entomol. Mar 1993;30(2):436-42. [Medline].
Puente S, Subirats M, Martinez ML, Lago M, Bru F, Gonzalez-Lahoz JM. [Depigmented cutaneous lesions in a Equatorial-Guinean woman]. Enferm Infecc Microbiol Clin. May 1995;13(5):313-4. [Medline].
Rakita RM, White AC Jr, Kielhofner MA. Loa loa infection as a cause of migratory angioedema: report of three cases from the Texas Medical Center. Clin Infect Dis. Oct 1993;17(4):691-4. [Medline].
Roberts JM, Neumann E, Göckel CW, Highton RB. Onchocerciasis in Kenya 9, 11 and 18 years after elimination of the vector. Bull World Health Organ. 1967;37(2):195-212. [Medline].
Russell RC. The relative importance of various mosquitoes for the transmission and control of dog heartworm in south-eastern Australia. Aust Vet J. May 1990;67(5):191-2. [Medline].
Russell RC, Geary MJ. The susceptibility of the mosquitoes Aedes notoscriptus and Culex annulirostris to infection with dog heartworm Dirofilaria immitis and their vector efficiency. Med Vet Entomol. Apr 1992;6(2):154-8. [Medline].
Samarawickrema WA, Kimura E, Sones F, Paulson GS, Cummings RF. Natural infections of Dirofilaria immitis in Aedes (Stegomyia) polynesiensis and Aedes (Finlaya) samoanus and their implication in human health in Samoa. Trans R Soc Trop Med Hyg. Mar-Apr 1992;86(2):187-8. [Medline].
Sauerman DM, Nayar JK. A survey for natural potential vectors of Dirofilaria immitis in Vero Beach. Florida Mosq News. 1983;43:222-225.
Schwartz DA, Brandling-Bennett AD, Figueroa H, Connor DH, Gibson DW. Sowda-type onchocerciasis in Guatemala. Acta Trop. Dec 1983;40(4):383-9. [Medline].
Scoles GA, Dickson SL, Blackmore MS. Assessment of Aedes sierrensis as a vector of canine heartworm in Utah using a new technique for determining the infectivity rate. J Am Mosq Control Assoc. Mar 1993;9(1):88-90. [Medline].
Shenefelt PD, Esperanza L, Lynn A. Elusive migratory subcutaneous dirofilariasis. J Am Acad Dermatol. Aug 1996;35(2 Pt 1):260-2. [Medline].
Van Dellen RG, Ottesen EA, Gocke TM, Neafie RC. Loa loa. An unusual case of chronic urticaria and angioedema in the United States. JAMA. Apr 5 1985;253(13):1924-5. [Medline].
Vuong PN, Bain O, Cabaret J, Petit G, Prod'hon J, Ranque P, et al. Forest and savanna onchocerciasis: comparative morphometric histopathology of skin lesions. Trop Med Parasitol. Jun 1988;39(2):105-10. [Medline].
Zuidema PJ. Renal changes in loiasis. Folia Med Neerl. Aug-Sep 1971;14(4):168-72. [Medline].
Keywords
filarial parasites, lymphatic filariasis, onchocerciasis, mansonellosis, dirofilariasis
