Lymphatic Filariasis

Edward Mitre, MD
Thomas B. Nutman, MD
Address
National Institutes of Health, Building 4, Room B1-09,
Bethesda, MD 20892, USA.
E-mail: emitre@[Link]
Current Treatment Options in Infectious Diseases 2001, 3:337–344
Current Science Inc. ISSN 1523-3820
Copyright © 2001 by Current Science Inc.

Opinion statement
The proper treatment of lymphatic filariasis requires an understanding of the complex
interactions between the parasite and host and of the variety of clinical manifesta-
tions that may result from these interactions. Diethylcarbamazine (DEC) remains the
anthelmintic of choice because of its partial macrofilaricidal activity. Recent studies
have demonstrated the added importance of proper local hygiene and treatment
of bacterial superinfections in preventing the progression of lymphedema to
elephantiasis. Agents that target the endosymbiotic intracellular Wolbachia bacteria
may play a large role in the future treatment of this disease.

Introduction
Named Slipada (sli = elephant, pada = leg) by the W. bancrofti infection show that most patients who were
Indian physician Susruta in the 6th Century BC [1], previously categorized as having asymptomatic infec-
lymphatic filariasis continues to be a crippling disease. tion have subclinical but demonstrable abnormalities
It is estimated that 2% of the world's population is of their lymphatic systems; urinalyses of these patients
infected [2]. Wuchereria bancrofti, which is endemic reveal that almost 50% have hematuria or proteinuria,
throughout the tropics, causes 90% of the infections. findings consistent with subclinical glomerular disease
Brugia malayi and Brugia timori, which are limited to [8]. These results suggest that all patients with micro-
Southeast Asia, are responsible for the rest. filaremia or other indicators of patent infection should
The lymphatic filariae require two hosts: humans be treated regardless of their clinical status.
and mosquitoes. Humans become infected after being Although unavailable for brugian infections, circu-
bitten by a mosquito carrying the infective (L3) stage lating filarial antigen tests have been developed that are
larvae. The infective larvae penetrate the skin at the site more sensitive than blood smear for the definitive diag-
of the bite and then migrate to the lymphatics where, nosis of W. bancrofti infection [9,10]. Additional advan-
over 3 to 4 months [3], they mature into adult worms. tages to these antigen tests include high specificity, the
These worms can live for more than 10 years [4], during ability to use blood collected at any time of day, safety,
which time the male and female forms mate in the and minimal equipment requirements. Any untreated
lymph nodes and produce microfilariae that circulate in patient with a positive circulating filarial antigen test is
the bloodstream. The life cycle is completed when a likely an adult worm carrier and should be treated.
permissive mosquito host ingests the microfilariae, Careful bacteriologic, clinical, and histologic evalua-
which then develop into L3 larvae. tions reveal that recurrent febrile episodes of lymphangitis
The interactions between the parasite and host are (filarial fever) are comprised of two discrete clinical
complex and result in varying clinical presentations. entities: acute dermatolymphangioadenitis (ADLA)
Recent advances in diagnosis and pathophysiology of caused by bacterial infections and acute filarial lymphan-
lymphatic filariasis have changed the target treatment gitis (AFL) presumably caused by inflammatory reactions
population, the type and extent of preventive treatment, to adult worms [11•,12]. ADLA occurs much more
and the medications used. frequently than AFL does and contributes to progressive
Studies have demonstrated abnormalities in patients lymphatic destruction [13,14]. Consequently, prevention
previously thought to be unaffected by their infection. and treatment of bacterial infections play a major role in
Ultrasonography [5,6] and lymphoscintigraphy [7] in the treatment of lymphatic filariasis.

337
338 Parasitic Infections

Ultrasound and histologic studies show that DEC sites, including W. bancrofti and B. malayi [21,22]. Tetra-
has only partial macrofilaricidal effect [15,16] and that cycline treatment of infection with B. pahangi results in
ivermectin, whether administered as a single dose [17] degeneration of the endosymbiotic bacteria and inhibi-
or repeatedly at high doses [18], has no activity against tion of embryo development in the adult worms [23].
adult worms. Adding ivermectin to DEC does not An initial human study has shown that 6 weeks of doxy-
improve its macrofilaricidal effect [19]. These findings cycline treatment for patients with onchocerciasis
highlight the need to develop a more effective macro- results in more than a 90% decrease in endosymbiont
filaricidal agent. The partial macrofilaricidal effect of carriage and in abnormal embryogenesis in adult
DEC makes it the drug of choice for lymphatic filariasis. worms [24••]. Human trials are in progress to deter-
The endosymbiotic Wolbachia bacteria are essential mine whether this approach is more effective than the
for filarial life. Wolbachia are obligate intracellular current standard of treatment for lymphatic filariasis.
bacteria in the family Rickettsiacea that have a mutualis- Taking into account these new insights, the following
tic relationship with filarial nematodes [20]. These is a list of the various clinical manifestations of lymphatic
endosymbionts have been found in many filarial para- filariasis with the treatment recommendations for each.

Acute manifestations
Tropical pulmonary eosinophilia (TPE)
• Tropical pulmonary eosinophilia is typically accompanied by nocturnal
cough, dyspnea, fever, and wheezing. This syndrome is a rare manifestation
of lymphatic filariasis, occuring in fewer than 1% of infected patients [25],
that is the result of immunologic hyperresponsiveness to the microfilariae.
Therefore, this syndrome does not occur until the infective larvae have
matured into fertile adults. Because microfilariae are almost never isolated
in the blood, the diagnosis is made on clinical grounds and supported
by laboratory evidence of peripheral hypereosinophilia, elevated serum IgE,
elevated titers of antifilarial antibodies, and—in half the patients—the
presence of adult worms by ultrasonography or circulating filarial antigen.
Therapeutic response to DEC is necessary for the diagnosis of TPE [26].
• There are no comparative trials elucidating the ideal treatment regimen for
TPE. The recommended therapy is DEC at 6 mg/kg/d for 21 days.

Acute filarial lymphangitis (AFL)

• AFL presents as a circumscribed inflammatory nodule or cord with
descending lymphangitis. It is likely caused by an inflammatory response
to adult worms and is uncommon, occurring in approximately 3% of
patients with lymphatic filariasis [11•].
• The goal of therapy is to relieve acute symptoms and includes rest, leg
elevation, analgesics, and antipyretics. Treatment with anthelmintics does
not shorten the duration of AFL, although treatment with DEC after the
acute attack is warranted if the patient has microfilaremia by concentrating
techniques (ie, Knott's concentration or Nuclepore [Whatman, Newton,
MA] filtration) or is circulating antigen positive [27••].

Acute dermatolymphangioadenitis (ADLA)

• ADLA can be a common clinical feature of lymphatic filariasis. A bacterial
cellulitis or lymphangitis, ADLA presents as plaque-like lesions with diffuse
cutaneous inflammation and ascending lymphangitis; it is frequently asso-
ciated with systemic symptoms such as fever and chills [11•]. Concomitant
findings can include adenopathy, an entry lesion, and edema distal to the
 Lymphatic Filariasis Mitre and Nutman 339

area of inflammation. ADLA worsens lymphedema, which in turn predis-

poses patients to additional episodes of ADLA [14]. Preventing these
episodes helps halt the progression of lymphedema to frank elephantiasis.
• The most important factor in preventing recurrent ADLA is diligent foot and
limb care [28]. Proper hygiene involves regularly cleaning lymphedematous
limbs with soap and water, ensuring the toenails are clipped and the affected
limbs dry, and applying local antibiotic and antifungal creams to the sides of
the feet and between the toes.
• Acute attacks of ADLA should be treated with systemic antibacterials that
cover typical skin flora. Neither ivermectin nor DEC shortens or prevents
the occurrence of these episodes [29].

Chronic manifestations
Microfilaremia
• Microfilaremia can be diagnosed by blood smear, concentration (Knott's) tech-
niques, or membrane filtration on appropriately timed blood samples [30].
• Anthelmintic therapy should be administered to all patients with micro-
filaremia to prevent sustained and progressive lymphatic damage by the
adult worms and, in endemic regions, to decrease community transmission
rates by breaking the life cycle of the parasite. Ivermectin and DEC in single
doses result in sustained, long-term reductions in microfilaremia [31].
When compared with the classic 12-day course of DEC (6 mg/kg/d × 12
days), a one-time dose of 6 mg/kg of DEC clears microfilaremia less
rapidly in the first 6 months after treatment. However, by year 1, its
effect is equivalent, with both regimens resulting in approximately a 95%
decrease in average microfilarial concentration [32].
• Administering a combination of single dose ivermectin (400 mg/kg) plus
DEC (6 mg/kg) results in a greater decrease in microfilarial concentration
than either drug alone [33]. While albendazole by itself has been shown to
be effective only when given for 3 weeks [34], giving it as a single dose with
DEC [35] or ivermectin [36] results in enhanced and prolonged micro-
filarial suppression. Because of these findings, yearly single dose combina-
tion therapy has become the preferred modality for community-wide
elimination campaigns.
• Because of its parital macrofilaricidal activity, DEC is the treatment
of choice in microfilaremic individuals. The standard 12-day regimen
is optimal, although data suggest that single dose treatment is an
acceptable alternative.
• Regardless of the initial regimen chosen to treat lymphatic filariasis, the
key to effective treatment is careful follow-up. In all regimens, a substantial
percentage of patients remain microfilaria positive at 1 year after treatment.
Thus, patients should be reevaluated for microfilaremia and retreated
every 6 to 12 months as necessary for the first few years after diagnosis.

Adult worm infection without microfilaremia

• Use of ultrasonography and antigen detection assays makes it possible to
identify patients with living adult worms despite the absence of micro-
filaremia. Because the adult worms can cause lymphatic disease, treatment
of this manifestation with DEC is recommended [27••].
340 Parasitic Infections

Lymphedema/elephantiasis
• Efforts to improve lymphedema and elephantiasis should no longer
be seen as futile. Significant improvement in the degree of lymphedema
has been attained through the diligent use of local measures such as
rigorous hygiene, decongestive physiotherapy, application of local anti-
biotics, and treatment of bacterial superinfections [11•].
• In a few severe recalcitrant cases, lymphedema has been improved
surgically via a lymphonodovenous shunt, with or without excisional
surgery [37,38], although results using this approach have been variable.

Hydrocele
• The most frequent chronic complication of lymphatic filariasis, hydrocele,
is a major cause of physical and psychosocial suffering [39]. Definitive
treatment is surgical correction. However, sclerotherapy, which is
less invasive and has a 1-year cure rate of almost 90% [40,41], should
be considered. Several sclerosing agents, including antazoline and
polidocanol, have been used succesfully. However, use of tetracycline
should be avoided because 50% of the patients experience mild to
severe scrotal pain after use [42].

Treatment
Pharmacologic treatment
Diethylcarbamazine
Standard dosage For microfilaremia or adult worm carriers, 6 mg/kd/d orally for 12 days.
For single dose therapy, 6 mg/kg for 1 day. For TPE, 6 mg/kg/d orally for 21 days.
Contraindications Coinfection with onchocerciasis or microfilaremic loiasis must be excluded if a
patient is from an area endemic for these other filariae because treatment
with DEC can result in severe posttreatment reactions, including death. Pregnancy
because of possible abortifacient effect. Children < 18 months.
Main drug interactions None.
Main side effects Usually well tolerated. Fever, headache, nausea, vomiting, and arthralgias can occur.
Special points Some experts recommend slowly increasing DEC dosage when treating patients
in whom the microfilarial level cannot be obtained. For example, administering
50 mg on day 1, 50 mg three times on day 2, 100 mg three times on day 3,
and then 6 mg/kd/d for the following 11 days.
Cost effectiveness Because it is no longer produced in the United States, DEC is provided by the
Centers for Disease Control and Prevention (phone: 404-639-3757) free of charge
under an IND.

Ivermectin
Standard dosage One dose of 400 mg/kg.
Contraindications Conditions associated with an impaired blood-brain barrier because penetration
into the CNS can cause lethargy, ataxia, tremors, and death.
Main drug interactions None.
Main side effects Usually well tolerated. Fever, itching, dizziness, and edema can occur, mainly
related to the death of the microfilariae. Can precipitate a serious reaction in
patients coinfected with onchocerciasis.
Special points Not approved for use in children < 5 years old and pregnant women. Is excreted in
low concentrations in breast milk and thus should be avoided in nursing mothers
because safety in infants has not been established.
Cost effectiveness $50 for five 6-mg tablets (a one time dose for a 75-kg person) [43].
 Lymphatic Filariasis Mitre and Nutman 341

Albendazole
Standard dosage 400 mg orally twice daily for 3 weeks as single agent. 400 to 600 mg orally as one
dose in combination with DEC or ivermectin.
Contraindications Pregnancy because albendazole is teratogenic in animal studies.
Main drug interactions Although pharmacokinetic studies do not show a change in theophylline levels
when administered with albendazole, the manufacturer recommends that plasma
concentrations of theophylline be monitored during treatment with albendazole
because it can induce cytochrome P450 1a.
Main side effects All rare with single dose therapy. Scrotal nodules in patients with Wuchereria
bancrofti have been seen. Other reactions include epigastric pain, nausea,
vomiting, diarrhea, and headache. Increased liver enzyme levels, leukopenia,
and alopecia have been reported with prolonged use.
Special points Not a first-line agent. Best when used in combination with DEC or ivermectin.
Cost effectiveness $2.20 for a single dose of 400 mg.
$92.40 for a 3-week course [43].

Procedures
Injection sclerotherapy
Standard procedure [40,41] Using sterile technique, an 18-guage intravenous cannula is inserted into an
avascular area on the cranial portion of the scrotum. All fluid from the hydrocele
is aspirated through the cannula, and then 2 to 4 mL of a sclerosing agent (such as
50 mg/mL antazoline or 2%–3% polidocanol) is injected. A suspensory bandage
can be placed, and if available, plastic pants should be provided. Patients should
then be observed clinically. If there is recurrence, the procedure can be repeated
two or three times.
Contraindications If a patient has an episode of ADLA involving the scrotum, the procedure should
be delayed until the bacterial cellulitis and lymphangitis is cleared.
Complications Pain and inflammation after the procedure occur in up to 10% of the patients.
Hematoma occurs in 1% to 2%.

Surgery
Hydrocelectomy
Standard procedure There are various techniques of hydrocelectomy. All involve dissection and
mobilization of the hydrocele sac. The Lord technique [44], which involves
opening the hydrocele sac and bringing out the testicle with some eversion
of the parietal vaginalis, has been shown to be superior to techniques that involve
dissection or excision of the vaginalis [45].
Complications Scrotal edema occurs in 10%. Hematoma and wound infection can also occur.

Lymphonodovenous shunt
Standard procedure [37] An incision is made starting at the saphenofemoral junction and extended for
10 cm along the long saphenous vein. The long saphenous vein and a lymph node
selected for anastomosis are dissected. A fleshy lymph node is preferable over
a fibrotic one. The long saphenous vein is divided 7 cm to 8 cm from the
saphenofemoral junction. One third of the superficial surface of the lymph node
is shaved off and an end-to-side, end-to-end, or side-to-side anastomosis is made
between the end of the vein and the horizontally transected node. The long
saphenous vein is not divided in side-to-side anastamoses.
Contraindications Infection or ulceration of the overlying skin.
Complications Bleeding, hematoma, wound infection.
Special points Possible recurrence. Has not been proven to be better than decongestive physiotherapy.
342 Parasitic Infections

Lifestyle factors and prevention

• Use of insect repellants and mosquito netting can decrease one's risk of
becoming infected when visiting an endemic region.
• A daily dose of 500 mg of DEC administered for 2 consecutive days every
month has been shown to decrease the rate of microfilaria positivity in
people living in endemic areas [46].
• Yearly single dose combination anthelmintic therapy (DEC/ivermectin,
ivermectin/albendazole, or DEC/albendazole) has been advocated by
the World Health Organization for control and elimination of lymphatic
filariasis as a public health problem. If coverage of a community is great
and distribution is sustained over a 5- to 10-year period, data suggest that
filarial transmission may be interrupted with rates of disease decreasing
dramatically in endemic areas [47].

Emerging therapies
• Human studies evaluating the macrofilaricidal effect of prolonged therapy
with tetracyclines and rifampin are commencing.
• Various benzopyrone [48], polyamine [49], and UMF-078 [50] derivatives
have been shown to have macrofilaricidal effects in animal models.

References and Recommended Reading

Papers of particular interest, published recently, are highlighted as:
• Of importance
•• Of major importance
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