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Lymphatic filariasis: Treatment and prevention

Lymphatic filariasis: Treatment and prevention
Literature review current through: Jan 2024.
This topic last updated: Aug 24, 2022.

INTRODUCTION — Filariasis is caused by nematodes (roundworms) that inhabit the lymphatics and subcutaneous tissues. Three species cause lymphatic filariasis: Wuchereria bancrofti, Brugia malayi, and Brugia timori. Infection is transmitted by mosquito vectors; humans are definitive hosts. Lymphatic filariasis is a major cause of disfigurement and disability in endemic areas, leading to significant economic and psychosocial impact.

The treatment and prevention of lymphatic filariasis will be reviewed here. The epidemiology, diagnosis, and clinical features of lymphatic filariasis and other filarial infections (including onchocerciasis, loiasis, and mansonellosis) are discussed separately. (See "Lymphatic filariasis: Epidemiology, clinical manifestations, and diagnosis" and "Onchocerciasis" and "Loiasis (Loa loa infection)" and "Mansonella infections".)

TREATMENT — The approach to treatment of lymphatic filariasis requires an understanding of antimicrobial agent mechanisms as well as attention to the possibility of coinfection. The clinical approach is described below, followed by a discussion of data related to individual antimicrobial agents.

Clinical approach — The treatment of choice for lymphatic filariasis is diethylcarbamazine (DEC); however, this agent is contraindicated in patients coinfected with onchocerciasis and must be used with caution in patients with loiasis, since severe adverse events can occur in individuals with high microfilarial loads (table 1). In addition, variability in individual responses to DEC have been described [1]. (See "Loiasis (Loa loa infection)", section on 'Treatment'.)

Doxycycline, which targets the intracellular endosymbiont, Wolbachia, is an alternative first-line antifilarial therapy for nonpregnant adults and children >8 years of age with lymphatic filariasis. Doxycycline has activity against adult worms and no effect on L. loa. Based on the available data in the literature, we favor the clinical approach discussed in the following sections.

Individual treatment

Monoinfection — Patients with lymphatic filariasis (in the absence of onchocerciasis or loiasis) should receive single-dose treatment with DEC (6 mg/kg), regardless of whether clinical symptoms or microfilaremia are present [2-4]. Patients with tropical pulmonary eosinophilia due to W. bancrofti infection are an exception; these patients should be treated with 14 to 21 days of DEC (6 mg/kg/day). Early lymphatic changes may be present before the onset of symptoms, and reversal of early lymphatic dysfunction has been observed following DEC treatment [5].

The addition of doxycycline (200 mg/day for four to six weeks) is also appropriate based on data demonstrating that doxycycline has macrofilaricidal activity and reduces pathology in mild to moderate disease [6-8]. Treatment is generally warranted even in the setting of advanced disease to kill any remaining adult parasites, although clinical improvement may be limited.

For cases in which DEC is not available or contraindicated, doxycycline (200 mg/day for four to six weeks) can also be used as an alternative first line therapy.

Concomitant infection — DEC is contraindicated in patients coinfected with onchocerciasis and/or patients with loiasis who have high microfilarial loads due to the risk of severe adverse events.

Onchocerciasis — DEC is contraindicated in patients with onchocerciasis, due to the potential for severe adverse events related to killing of microfilariae in the eye and/or skin (Mazzotti reaction) (table 1). Therefore, treatment of onchocerciasis with ivermectin (150 mcg/kg single dose) should be administered to clear O. volvulus microfilariae in the skin and eyes prior to standard treatment of lymphatic filariasis. (See 'Monoinfection' above.)

Based on kinetic studies of microfilarial clearance from the skin following ivermectin administration, it seems prudent to wait approximately one month between administration of ivermectin and initiation of DEC treatment [9,10]. In patients with ocular involvement, the length of time needed to prevent exacerbation of eye disease with DEC is unknown. Consequently, alternative therapy with doxycycline (200 mg orally once daily for four to six weeks) followed by ivermectin (150 mcg/kg orally single dose) is reasonable for treatment of both infections; however, the efficacy of this regimen compared with standard therapy for treatment of lymphatic filariasis is not known. (See "Onchocerciasis", section on 'Treatment'.)

Loiasis — DEC is the treatment of choice for patients with L. loa coinfection and low or undetectable levels of circulating microfilariae. However, as the microfilarial load increases, the incidence of severe adverse effects (including fatal encephalopathy) related to the rapid killing of microfilariae also increases (table 1). For patients with lymphatic filariasis who are coinfected with L. loa but have <2500 L. loa microfilariae/mL of blood, DEC therapy using the standard regimen for loiasis (8 to 10 mg/kg/day for 21 days) should be administered. (See "Loiasis (Loa loa infection)", section on 'Treatment'.)

For patients with higher levels of L. loa microfilaremia (but less than 20,000 microfilariae/mL), ivermectin pretreatment can be used to reduce the microfilarial load prior to administration of DEC [11,12]. Patients with L. loa microfilarial loads greater than 20,000 microfilariae/mL should be treated with doxycycline (200 mg orally once daily for four to six weeks), which has no effect on L. loa. Albendazole (200 to 400 mg with fatty meal twice daily for 21 days) also has no direct effect on L. loa microfilariae and is a reasonable alternative in patients who cannot take doxycycline. Issues related to management of high-level Loa microfilaremia are discussed further separately. (See "Loiasis (Loa loa infection)", section on 'Treatment'.)

Mass treatment — Mass drug administration reduces the bloodborne reservoir of microfilariae to a level below that required for sustained transmission by local mosquito vectors (figure 1 and figure 2). The period of microfilaremia has been estimated to be four to six years, corresponding with the reproductive lifespan of the adult parasite. W. bancrofti has been designated as a target for elimination since there are no animal hosts. Elimination of Brugian filariasis is not feasible since this infection has a large domestic and wild animal reservoir. (See "Lymphatic filariasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Epidemiology'.)

Mass drug administration using various regimens of DEC (single dose and medicated salt), ivermectin, and albendazole had been in place in some countries for more than 20 years prior to 2000, when the Global Program for the Elimination of Lymphatic Filariasis was launched with drug company donations of ivermectin and albendazole.

Since that time, mass drug administration programs have been implemented in more than 60 countries, with more than 5 billion doses of antifilarial therapy administered by 2014 (figure 3) [13,14]:

In areas where lymphatic filariasis is endemic (in the absence of onchocerciasis or loiasis), management consists of a three-drug combination regimen consisting of ivermectin, diethylcarbamazine, and albendazole (single dose) or a two-drug combination regimen of diethylcarbamazine plus albendazole (administered once yearly for three years) [15-17].

This approach is supported by a randomized trial including more than 180 adults in Papua New Guinea with W. bancrofti microfilaremia treated with a single dose of the three-drug regimen, a single dose of the two-drug regimen, or the two-drug regimen administered once a year for three years [16]. Administration of the three-drug regimen was associated with clearance of microfilaremia for three years in 98 percent of participants; it was superior to the two-drug regimen administered once and noninferior to the two-drug regimen administered once a year for three years. There were no serious adverse events.

In areas where lymphatic filariasis and onchocerciasis are coendemic (in the absence of loiasis), management consists of combination therapy with yearly ivermectin and albendazole; presence of onchocerciasis precludes use of diethylcarbamazine [18,19].

In areas where lymphatic filariasis and loiasis are coendemic, management consists of albendazole monotherapy twice yearly [15,20]; unless onchocerciasis is hyperendemic, in which case the benefits of ivermectin for onchocerciasis are felt to outweigh the risk of serious adverse events from ivermectin treatment of loiasis, and combination therapy with yearly ivermectin and albendazole is recommended.

Suppression of transmission to <1 percent (the predicted threshold for elimination) has been achieved in several countries, including Egypt, Togo, and 12 Asian and Pacific Island countries. A number of challenges remain; these include availability of funds for drug distribution and monitoring, the persistence of hot spots of transmission [21], difficulties reaching populations in remote areas and areas of conflict, and the occurrence of treatment-related encephalopathy in areas endemic for loiasis [11,22]. Human immunodeficiency virus (HIV) coinfection does not appear to affect response to mass therapy with ivermectin and albendazole [23].

Antimicrobial agents — Selection of therapy for treatment of lymphatic filariasis requires an understanding of the microfilaricidal and macrofilaricidal activity of therapeutic agents. The epidemiology of other filarial diseases is also important; in regions where loiasis and onchocerciasis may coexist with lymphatic filariasis, additional consideration is important for minimizing the likelihood of adverse effects.

Most of the studies regarding the efficacy of various regimens are derived from data from mass chemotherapy programs. These data are helpful in determining the relative efficacy of the drugs and combinations in terms of microfilaricidal and macrofilaricidal activity but do not necessarily provide optimal data on management of infected individuals, particularly those who live outside of endemic areas [24].

Diethylcarbamazine — DEC, a piperazine derivative, is a potent microfilaricidal and macrofilaricidal agent with activity against W. bancrofti, B. malayi, and B. timori [25]. The mechanism of action is uncertain; it is thought to alter microfilarial surface membranes or inhibit filarial release of immunomodulatory eicosanoids, thereby enhancing destruction via host immune responses [26,27]. DEC also has macrofilaricidal activity, likely via hyperpolarization leading to immobilization of adult worms. Estimates suggest DEC kills approximately 50 percent of adult worms, and its effect on adult worms in turn decreases the microfilarial burden [28].

Adverse effects of DEC include fever, headache, anorexia, nausea, and arthralgias. These effects are likely attributable to the host response following death of microfilariae (systemic reactions) and damage to adult worms (local reactions). Dying microfilariae probably release lipopolysaccharide-like proteins from endosymbiotic Wolbachia organisms within the filariae [29,30]. Management consists of administration of antipyretic and/or anti-inflammatory agents. Since post-DEC reactions are more severe in onchocerciasis and loiasis, evaluation for these coinfections should be pursued prior to administering DEC. (See "Onchocerciasis" and "Loiasis (Loa loa infection)".)

DEC should be avoided in pregnancy. Animal studies have not demonstrated teratogenicity. It is not excreted in breast milk and is considered safe during lactation.

DEC is not commercially available in the United States but can be obtained from the United States Centers for Disease Control and Prevention (CDC) under an Investigational New Drug protocol (CDC Drug Service, Atlanta, GA 30333; telephone 404-718-4745) [31].

Doxycycline — A promising alternative approach to attacking the worm directly is to focus treatment against Wolbachia, an intracellular bacterial symbiont of filarial parasites that is present in microfilariae and adult worms of W. bancrofti and both Brugia species [32]. (See "Lymphatic filariasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Wolbachia'.)

Doxycycline has both microfilaricidal and macrofilaricidal activity and has demonstrated efficacy in both W. bancrofti and B. malayi infections [33,34]:

In a randomized trial including 72 Tanzanian patients with Bancroftian filariasis, patients who received doxycycline (200 mg daily for eight weeks) had elimination of microfilaremia and diminished detectability of adult worms compared with patients who received placebo (22 versus 88 percent, respectively) [35]. Subsequent trials have demonstrated the efficacy of shorter regimens (four or six weeks may also be sufficient) [24,36,37] and that the addition of albendazole may enhance microfilarial clearance by doxycycline [38].

In a randomized trial including 161 Indonesian patients with Brugian filariasis, a six-week course of doxycycline reduced the prevalence of microfilaremia compared with placebo (77 versus 27 percent) [39].

There is also convincing evidence that doxycycline treatment, alone and in combination with DEC, reduces clinical pathology, including lymph vessel dilation and hydrocele in affected individuals [6,7]. A subsequent trial in 162 Ghanaian patients with lymphedema demonstrated that doxycycline (200 mg/day for six weeks) was effective in reducing lymphedema regardless of infection status as assessed by circulating antigen assay [8].

Tetracycline antibiotics may cause permanent tooth discoloration for children <8 years if used repeatedly. However, doxycycline binds less readily to calcium than other tetracyclines and may be used for ≤21 days in children of all ages [40].

Ivermectin — Ivermectin has microfilaricidal activity [41-43] but does not have significant macrofilaricidal activity [44-47]. Therefore, the reduction in microfilaremia is not sustained without repeat dosing. The clinical benefit of ivermectin is uncertain given the lack of activity against adult worms, which play an important role in the pathogenesis of lymphangitis and lymphedema. Ivermectin may have some effect in reducing the fertility of worms (in addition to its microfilaricidal activity).

Ivermectin is at least as effective as DEC in reducing microfilaremia due to Bancroftian filariasis [48,49]; a single dose has been shown to reduce microfilaremia by approximately 90 percent even one year after treatment [41,42]. One study in South India demonstrated that a single dose of ivermectin (150 microgram/kg) was approximately equivalent to a 12-day course of DEC in suppressing microfilaremia for three to six months [50].

Ivermectin is the treatment of choice for onchocerciasis and should be used as part of the regimen to treat patients with concomitant lymphatic filariasis and onchocerciasis but is contraindicated in patients with loiasis and high levels of L. loa microfilariae in the blood due to the risk of posttreatment encephalopathy. (See "Loiasis (Loa loa infection)", section on 'Ivermectin'.)

Albendazole — Albendazole has no direct effect on microfilariae but leads to a slow decline in microfilaremia due to macrofilaricidal activity against the adult worms. Consequently, side effects due to rapid killing of microfilariae are not seen, and albendazole can be used in patients with concomitant loiasis or onchocerciasis.

In one study in the Democratic Republic of Congo, biannual administration of single-dose albendazole (400 mg) led to microfilarial clearance in 37 percent of subjects at 12 months [51] and a 94 percent reduction in the prevalence of microfilaremia after three years [52]. In addition, results from two cohort studies of repeated albendazole administration in Central Africa demonstrated a close relationship between adherence to therapy and clearance of microfilariae, further supporting this approach [53].

Although most studies have demonstrated enhanced suppression of microfilaremia with albendazole and ivermectin as compared with ivermectin alone, albendazole does not appear to increase the microfilaricidal efficacy of DEC. In a small study that examined the effects of albendazole and DEC on adult worm killing as assessed by scrotal ultrasound, combination therapy was less effective than DEC alone [54].

Management of chronic pathology — The most common chronic complications of lymphatic filariasis are recurrent lymphangitis or cellulitis, lymphedema, elephantiasis, and hydrocele. Chyluria is relatively infrequent but does occur.

Lymphatic pathology — Individuals with lymphedema should wash affected areas twice daily, use antibacterial creams on small abrasions, keep nails clean, and wear shoes. The affected limb should be exercised regularly to promote lymph flow and should be elevated at night. Complex decongestive physiotherapy can also be effective in some cases. The National Lymphedema Network provides a listing of certified lymphedema therapists in the United States who have expertise in treating chronic lymphedema [55]. (See "Clinical staging and conservative management of peripheral lymphedema".)

Secondary infections (especially bacterial) are contributing determinants of worsening lymphedema and elephantiasis, particularly in individuals with late-stage disease. Aggressive treatment of secondary infections and close attention to hygiene is critical. Antibiotic prophylaxis should be considered in patients who experience recurrent infections despite appropriate local care. (See "Acute cellulitis and erysipelas in adults: Treatment".)

Reconstructive surgery involving lymphatic-venous anastomoses have been attempted to improve lymphatic drainage, but the long-term benefit is still unclear.

Hydrocele — The role of surgery depends upon the individual anatomy and local surgical expertise. Drainage of hydroceles may give some immediate relief but is almost always followed by reaccumulation of fluid. Hydrocelectomies can be helpful; among 301 patients with filariasis in Nigeria, hydrocelectomy was performed safely even in a rural area [56].

Chyluria — Chyluria may be associated with secondary nutritional deficiency. In such cases, low-fat, high-protein diets supplemented with medium-chain triglycerides can be helpful.

PREVENTION — The focus of disease control has been mass drug administration programs [25,57,58]. (See 'Mass treatment' above.)

Vector control with insecticide-treated bed nets is also a valuable tool for W. bancrofti elimination in areas where anopheline mosquitoes transmit the parasite [59] along with other personal protection measures against mosquitoes (eg, repellents). (See "Prevention of arthropod and insect bites: Repellents and other measures".)

There is no vaccine available; attempts to develop effective vaccination are underway [60].

SUMMARY AND RECOMMENDATIONS

Patients with lymphatic filariasis (in the absence of onchocerciasis or loiasis) should receive treatment with diethylcarbamazine (DEC), regardless of whether clinical symptoms or microfilaremia are present. The addition of doxycycline (200 mg/day for four to six weeks) following DEC treatment is also appropriate based on data demonstrating that doxycycline has macrofilaricidal activity and reduces pathology in mild to moderate disease. Doxycycline (200 mg/day for four to six weeks) can also be used as an alternative first line therapy in cases where DEC is not available or contraindicated. (See 'Monoinfection' above.)

Patients with coinfection due to lymphatic filariasis and onchocerciasis (in the absence of evidence for eye involvement) should undergo treatment of onchocerciasis first, with ivermectin (150 mcg/kg single dose) alone, followed by standard treatment for lymphatic filariasis (table 1). In patients with eye involvement, doxycycline (200 mg orally once daily for four to six weeks) followed by ivermectin (150 mcg/kg orally single dose) can be used, although the relative efficacy of this regimen compared with the standard DEC-containing regimen is not known. (See 'Onchocerciasis' above.)

The approach to patients with concomitant infection due to lymphatic filariasis and loiasis depends on the level of circulating L. loa microfilaremia (table 1). For patients with <2500 L. loa microfilariae/mL of blood, DEC therapy using the standard regimen for loiasis (8 to 10 mg/kg/day for 21 days) should be administered. For patients with >2500 but <20,000 L. loa microfilariae/mL of blood, ivermectin can be used to decrease the L. loa mf load prior to DEC treatment. For patients with >20,000 L. loa microfilariae/mL of blood, doxycycline (200 mg orally once daily for four to six weeks), which has no effect on L. loa, is the treatment of choice for the lymphatic filariasis. Albendazole (200 to 400 mg with fatty meal twice daily for 21 days) has no direct effect on L. loa microfilariae and is a reasonable alternative in patients who cannot take doxycycline. Issues related to management of high-level Loa microfilaremia are discussed further separately. (See 'Loiasis' above and "Loiasis (Loa loa infection)".)

Management of chronic complications of lymphatic filariasis is an important component of therapy. Secondary (often bacterial) infections are contributing determinants of worsening lymphedema and elephantiasis, particularly in individuals with late-stage disease. Aggressive treatment of secondary infections and close attention to hygiene is critical. Individuals with lymphedema should wash affected areas twice daily, use antibacterial creams on small abrasions, keep nails clean, and wear shoes. The affected limb should be exercised regularly to promote lymph flow and should be elevated at night. Prophylactic antibiotics may be necessary in some cases. Hydrocelectomy can be useful in reducing morbidity in affected patients. (See 'Management of chronic pathology' above.)

Mass drug administration reduces the bloodborne reservoir of microfilariae to a level below that required for sustained transmission by local mosquito vectors. Programs have been initiated in more than 60 countries and use various combinations of albendazole, ivermectin, and DEC. These programs have led to suppression of transmission to <1 percent (the predicted threshold for elimination) in several countries; many challenges remain. (See 'Mass treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dr. Karin Leder, who contributed to earlier versions of this topic review.

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Topic 5680 Version 34.0

References

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