Lymphatic filariasis

 

Salient features

 

·       Filariasis is an infection of the lymphatic system by tissue nematodes (roundworms) acquired via mosquito vectors

 

·       There are acute, chronic, and asymptomatic forms of filariasis

 

·       Manifestations of the acute phase include lymphangitis and orchitis

 

·       Chronic disease is characterized by the sequelae of lymphatic obstruction, e.g. lymphedema, elephantiasis, hydroceles, and chyluria; associated skin findings include hyperkeratosis, verrucous changes, soft tissue hypertrophy, and fibrosis

 

Introduction

 

Lymphatic filariasis is an infection of the lymphatic system caused by two genera of filarial nematodes (roundworms). Several species of mosquitoes act as vectors. Cutaneous findings during the acute and chronic stages include lymphangitis and lymphedema accompanied by changes of elephantiasis. The single largest cause of lymphedema worldwide is lymphatic filariasis.

 

Epidemiology

 

Incidence and prevalence

There are two major forms of filariasis, Bancroftian (due to Wuchereria bancrofti), causing 90% of infections, and Malayan (due to Brugia malayi and B. timori); Brugia malayi accounts for only 10% of all cases. Infections caused by B. timori are rare. The areas with the highest incidence of infection are South‐East Asia and sub-Saharan Africa. W. bancrofti is found worldwide, whereas B. malayi is restricted to South- East Asia. The distribution of B. timori is limited to certain Indonesian islands.

A number of mosquito species act as vectors for filarial nematodes. The most important ones for W. bancrofti are Culex quinquefasciatus, Anopheles gambiae, Anopheles funestus, Aede spolynesiensis, Aedes scapularis, and Aedes pseudoscutellaris. Both B. malayi and B. timori are transmitted by Anopheles barbirostris. B. malayi can also be transmitted by several species of Aedes and Mansonia mosquitoes.

The adult worms reside within the afferent lymphatic vessels (and/or the lymph nodes) while their larvae, the microfilariae, circulate within the peripheral blood and are able to infect mosquito vectors as they feed, facilitating transmission to other human hosts. The adult female worm may survive for more than a decade and is able to release thousands of fully formed microfilariae into the lymphatic circulation of the host every day.

Lymphatic filariasis is first acquired in childhood, often with as many as one-third of children in endemic areas infected before the age of 5. However, the characteristic symptoms typically occur years after infection and the prevalence of clinical disease increases after age 20 in endemic areas. Adult worms live an average of 10–15 years, and microfilariae probably 6–12 months. Symptoms and sequelae can persist after the death of all parasites.

  

Pathophysiology

 

The clinical manifestations of lymphatic filariasis reflect a complex interplay of the pathogenic potential of the parasite, the immune response of the host, and secondary bacterial and fungal infections.

 

The presence of adult worms in the lymphatics with the resulting inflammatory response is the cause of the main pathological feature – lymphatic obstruction. Leakage of lymph may contribute to tissue damage. Circulation of microfilariae in the bloodstream has remarkably little effect, although their entrapment in the lungs may cause tropical pulmonary eosinophilia.

The filarial parasites specifically target the lymphatics and impair lymph flow, which is critical for the maintenance of fluid balance and physiological interstitial fluid transport.

Lymphedema may occur as a result of live adult worms within lymphatic vessels in the lower limbs and pelvic region. The live worms secrete irritant toxins that cause dilatation of the lymph vessels surrounding the worm. This causes a reduction in lymphatic flow. The subsequent edema promotes fibrosis. Lymphedema is further aggravated by secondary bacterial and fungal infections that arise as a result of impaired immune surveillance within the lymphoedematous region.

Lymphatic damage and subsequent lymphedema may also occur as a direct result of dead adult worms within the lymphatic vessels (worm death due to old age or treatment). The presence of dead worms induces an intense inflammatory reaction with granulomatous changes and necrosis, which leads to lymphatic outflow obstruction within the vessel and subsequent lymphedema.

 

Most filarial species that infect people co-exist in mutualistic symbiosis with Wolbachia bacteria, which are essential for growth, development, and survival of their nematode hosts. These endosymbionts contribute to inflammatory disease pathogenesis and are a target for doxycycline therapy, which delivers macrofilaricidal activity, improves pathological outcomes, and is effective as monotherapy. Wolbachia also stimulates an innate and adaptive immune response that leads to expression of vascular endothelial growth factors (VEGFs) that promote lymphangiogenesis, lymphatic endothelial proliferation, and dilation of lymphatic vessels.

 

Predisposing factors

 

People residing for prolonged periods in areas where lymphatic filariasis is endemic are at the greatest risk for infection. Repeated mosquito bites over several months are required in order to acquire LF. Visiting tourists have a very low risk of acquiring LF.

 

Life cycle

 

 

The disease is transmitted by many species of anthropophilic mosquitoes of the genera Culex, Aedes, Mansonia and Anopheles. The mosquito acquires microfilariae during a human blood meal in which sheathed microfilariae are present. The organisms lose their sheaths in the mosquito's stomach, and in less than 24 h have entered the thoracic muscles. Metamorphosis proceeds and mature larvae migrate to the labella 10 days after infection of the insect. Here they are ready to be transmitted to humans when the mosquito takes its next blood‐meal and larva enters skin by biting. Once transmitted to humans, the larvae take approximately 6–12 months to mature into adult worms.

In humans, larvae pass through peripheral lymphatics, develop and migrate centrally and eventually grow into adults, which mate in the lymphatics proximal to the lymph nodes. Fertilized females discharge their sheathed microfilariae, which leave the lymphatic system and appear in peripheral blood 12 months after the initial infection. The discharge is cyclical and occurs principally at night. These microfilariae can pass the placental barrier. The adults are found coiled up in dilated lymphatics. The female filaria reaches a length of up to 10 cm. The microfilarias are 0.2–0.3 mm long.

 

Clinical features

 

The incubation period is usually 5–18 months. Clinical manifestations may be acute, chronic, and asymptomatic. The most common presentation of LF is with acute adenolymphangitis (ADL) in adolescence. ADL is characterized by sudden‐onset fever, painful enlargement of lymph nodes, particularly the inguinal group, recurrent lymphangitis with characteristic retrograde progression (beginning in the affected lymph node and moving distally) and transient edema. Involvement of the genitals appears to occur exclusively with W. bancrofti infection, such as orchitis and epididymitis. Acute adenolymphangitis (ADL) typically recurs 6–10 times per year, with each episode lasting 3–7 days. The affected body part clinically appears normal between early episodes, although during the resolution of the acute phase of W. bancrofti filariasis, there may be extensive exfoliation of the skin of the affected limb. Intermittent fever and adenolymphangitis can recur for the lifetime of the adult worm. Another disease manifestation is acute dermato lymphangio-adenitis characterized by cutaneous or subcutaneous inflammatory plaques associated with ascending lymphangitis, regional lymphadenitis, and fever; this may result from a bacterial or fungal super infection, often with an interdigital entry point. Acute symptoms, which are thought to reflect a lack of tolerance to filarial antigens, are most common in recently infected young adults and older patients; children residing in endemic areas are often asymptomatic until they reach puberty, when they typically develop chronic manifestations.

After 10 to 15 years of infection, the clinical features of chronic disease, i.e. the sequelae of lymphatic obstruction due to both adult worms and granulomatous inflammation, are noted. These include lymphedema, elephantiasis, hydroceles, and chyluria. Hydroceles are the result of accumulation of clear, straw‐coloured lymphatic fluid within the tunica vaginalis as a result of obstruction of lymphatic vessels draining the retroperitoneal and subdiaphragmatic areas. The diameter of the hydroceles may be significant, reaching up to 30 cm.

Lymphedema occurs as a result of the accumulation of lymphatic fluid within tissues following lymphatic vessel damage. The lower extremity, scrotum, and penis are most commonly affected, and less frequently the upper extremity, breast, and vulva are involved. Initially the lymphedema is intermittent and pitting in nature, but over time it becomes persistent and fibrotic. It is accompanied by gross skin changes referred to as elephantiasis – the skin over the involved area can become hypertrophic, verrucous, and fibrotic with soft tissue hypertrophy and redundant skin folds. Fissures, ulceration and gangrene may also occur. Secondary bacterial and fungal infections are very common.

Although anti parasitic treatment does not reverse the late findings of scarring and lymphatic obstruction, a 6 week course of doxycycline can reduce mild to moderate lymphedema independent of active filarial infection by reducing vascular endothelial growth factor.

Chyluria is a rare complication of LF and is the result of the presence of chyle (intestinal lymph) within the urinary tract. It occurs as a result of impaired drainage of retroperitoneal lymph below the cisterna chyli with subsequent reflux and flow of the lymph directly into the renal lymphatic vessels, which may rupture and permit flow of chyle into the urinary tract. The urine appears milky white in color. Serious nutritional deficiencies may occur as a result of the loss of fat and protein within the urine.

There are two major reasons for the predilection of filariasis for the lower extremities and genitalia: (1) the female mosquito flies near the ground, thus it is more likely to bite the lower limbs, which is followed by retrograde involvement of the inguinal region; and (2) due to gravitational forces, the legs are at greater risk for venous hypertension and valvular incompetency and therefore more susceptible to the development of chronic lymphedema.

 

Tropical pulmonary eosinophilia syndrome may occur in some patients with filarial infections due to W. bancrofti or B. malayi. They develop respiratory wheeze and a paroxysmal nocturnal cough, similar to asthma. Chest radiographs demonstrate nodular or diffuse pulmonary infiltrates. Other features of this syndrome include elevated peripheral blood eosinophilia and high levels of serum immunoglobulin E. If untreated, the patient may develop restrictive lung disease with interstitial fibrosis. Treatment with diethylcarbamazine is effective.

 

Diagnosis

 

In endemic areas, adults with lower limb lymphedema and/or male genital involvement are likely to have LF.

 

Detection of circulating filarial antigen is now the preferred method for diagnosis of Bancroftian filariasis; immunochromatographic card tests or test strips are typically utilized. Similar tests are not currently available for Malayan filariasis, which can be diagnosed using a dipstick test for IgG4 antibody specific for the Brugia antigen BmR1. Alternatively, the diagnosis can be established by the demonstration of microfilariae in the blood, urine, or other body fluids and tissues, or by the identification of adult worms.

 

A definitive diagnosis can be made by detection of the adult parasitic worm within the lymphatic vessels or accessible lymph nodes. Doppler ultrasound may detect motile adult worms within the scrotum. Biopsy of an enlarged lymph node may be diagnostic.

Microfilariae are demonstrated in the blood especially in acute cases, either in a thick blood film (stained with Giemsa or haematoxylin and eosin or by passing heparinized blood through a millipore filter with a pore size of 3 microns, which retains the microfilariae, which can then be seen easily under the microscope. As the parasite exhibits a nocturnal periodicity in humans, 10 p.m. to 2 a.m. is the optimal time period for blood collection.

An alternative procedure is to repeat blood films 1 h after a single dose of DEC 100 mg. This releases more microfilariae into the circulation. However, parasite detection is not a particularly reliable method because many symptomatic patients are amicrofilaremic. Inguinal lymph node ultrasound may show active microfilariae (“filarial dance sign”), more commonly seen in men than in women.

++A polymerase chain reaction (PCR) based test has been applied to the detection of W. bancrofti genomic DNA in blood.

 

Treatment

 

The World Health Organization (WHO) launched the Global Programme to Eliminate Lymphatic Filariasis (GPELF) which aims to stop the spread of LF. Two phases of their programme have been developed: parasite elimination and morbidity control. Parasite elimination is only possible if the entire at‐risk population is treated by mass drug administration for a prolonged period of time to ensure a reduction in the blood levels of microfilariae to a level where transmission can no longer be sustained. The following drug regimens have been recommended by the WHO to be administered once a year for at least 5 years, with a coverage of at least 65% of the total at‐risk population: (i) 6 mg/kg diethylcarbamazine citrate (DEC) in combination with 400 mg albendazole; or (ii) 150 μg/kg ivermectin in combination with 400 mg albendazole (in areas where onchocerciasis is prevalent, in order to avoid adverse drug reactions with DEC).

The drug of choice for individual patient is diethylcarbamazine, which is active against microfilariae but has a limited effect on adult worms. The usual course is 6 mg/kg/day for 12 days. Doxycycline (200 mg/day for 4–8 weeks) targeting the Wolbachia endosymbiont can also eliminate microfilariae, kill adult worms and improve lymphatic drainage. During the treatment period, antihistamines and glucocorticoids may be useful in decreasing the allergic reaction that may result from massive disintegration of microfilariae. Because severe reactions may follow the administration of diethylcarbamazine in patients who have loiasis or onchocerciasis, it is important to exclude other helminthic diseases before instituting therapy.

Side effects of DEC occur and include anorexia, nausea, vomiting, giddiness, headache, drowsiness and acute allergic reactions due to destruction of microfilariae and adult filariae.

Ivermectin is also effective in lymphatic filariasis. The drug works more rapidly than DEC, and microfilaraemia is reduced to 14–30% of pretreatment levels 6 months after therapy. There are also similar adverse reactions to ivermectin in patients with this condition. The dose is usually 400 μg/kg. Ivermectin does not kill adult worms, so recurrence of microfilaraemia is common and further treatments are often necessary.

Morbidity control is approached through a combination of lower limb exercise, compression stockings and elevation of affected limbs, other anti-inflammatory drugs, and protection of the affected area from trauma. There is evidence that this can reduce limb swelling considerably, even in late stages. Surgical approaches may improve the appearance of affected limbs either in the early stages by creating a lymph node to venous shunt, or by removing subcutaneous tissue and grafting of split‐skin onto a muscle bed (Charles operation) in established elephantiasis. Males with hydroceles benefit from hydrocelectomy procedures to achieve volume reduction.

 

Lifestyle management

 

Lifestyle measures can reduce the bacterial and fungal load that contributes to worsening lymphedema. These include regular washing with soap and water, use of footwear and access to antibiotics and lymphedema treatment. Prevention of infection can be achieved by avoidance of mosquito bites. Lifestyle measures include sleeping under a mosquito net, using mosquito repellent on exposed skin and wearing long sleeves and trousers.

 

Therapeutic ladder

First line

·        Diethylcarbamazine 200 mg PO every 12 h × 12 days, repeat 10 days later. Note: contraindicated in patients co‐infected with onchocerciasis. In patients with both diseases, a severe inflammatory response can occur

Second line

·        Ivermectin 0.15–0.2 mg/kg PO × 1 dose (treatment of choice for patients with concurrent onchocerciasis)