Lymphatic Filariasis (Elephantiasis)

Epidemiology and Etiology

Epidemiology

• 120 million patients infected worldwide as of 2019
• Geographic distribution:
  • Wuchereria bancrofti: 
    • Etiology for 90% of lymphatic filariasis
    • Most prevalent in sub-Saharan Africa, Southeast Asia, Indian subcontinent, Pacific islands, and Caribbean and South American tropical and subtropical climates
  • Brugia malayi: Southeast Asia, China, India, and Pacific islands
  • B. timori: Timor island of Indonesia
• Most patients in endemic areas were exposed in their 30s or 40s.
• Lymphatic filariasis has a 10:1 predilection for men over women.

Etiology

Lymphatic filariasis is caused by nematodes.

Causative species:

• W. bancrofti
• B. malayi
• B. timori

General characteristics:

• Nematode (roundworm)
• Eukaryotic
• Thread-like, nuclei do not appear at the end of the tail
• Anaerobic
• Reproduce by sexual reproduction

Stages of life:

• Microfilariae:
  • Found in the peripheral blood of the human host
  • Produced by adult nematodes
  • Ingested by a mosquito during a blood meal
• Larvae:
  • Microfilariae that lose their sheaths
  • In the mosquito, microfilariae mature into larvae inside the mosquito: L1 (1st stage) larvae to L3 (3rd stage) larvae
  • L3 larvae travel to the mosquito’s proboscis, and human infection occurs during a blood meal.
  • In the infected human, larvae migrate to the bloodstream and lymphatics.
  • Maturity reached in 6–9 months
• Adults:
  • Mature from L3 larvae in the regional lymphatics 
  • Adult female Wuchereria worms: 80–100 mm in length and 0.24–0.30 mm in diameter
  • Adult male Wuchereria worms: about 40 mm by 0.1 mm
  • Adult female Brugia worms: 43–55 mm in length
  • Adult male Brugia worms: 13–23 mm in length

Transmitted to mosquitoes:

• W. bancrofti:
  • Aedes
  • Anopheles
  • Culex
  • Mansonia
  • Coquillettidia
• Brugia: 
  • Aedes
  • Mansonia

Pathophysiology

Transmission

• The primary reservoir for filariasis is humans, and the vector is mosquitos. 
• Transmission from human to human occurs via mosquito bites.

Life cycle

1. Mosquitos deposit L3 larvae into a human’s skin, which burrow through the bite wound to the bloodstream.
2. L3 larvae migrate to the lymph nodes and regional lymphatics and mature into adults, which have a predilection for inguinal lymph nodes.
3. Adult worms undergo sexual reproduction, with females birthing microfilariae that migrate actively through lymph and blood.
4. A mosquito ingests the microfilariae during a blood meal. 
5. After ingestion, the microfilariae work their way through the wall of the mosquito’s midgut and reach the thoracic muscles. 
6. Within the mosquito, the microfilariae develop into L1 larvae.
7. L1 larvae subsequently develop into L2 then L3 infective larvae.
8. The L3 larvae migrate to the mosquito’s proboscis, where they can infect a human during the mosquito’s next blood meal.

Disease process

• After mating, the adult female lays thousands of microfilariae daily:
  • In most areas, W. bancrofti microfilariae are in circulation (found in the bloodstream) during nocturnal hours.
  • In the South Pacific, the microfilariae are found in the circulation all day.
• Acute infection:
  • Filarial antigens trigger increased cytokines and immunoglobulins (IgE and IgG4).
  • Molting, dying, or dead adult worms produce pathologic changes:
    • Dilatation of lymphatics
    • Hyperplasia of vascular endothelium
    • Lymphangitis (infiltration of eosinophils, lymphocytes in the lymphatics, and thrombi formation)
• Chronic and repeated infections lead to:
  • Granuloma formation
  • Fibrosis of lymphatic vessels and the surrounding connective tissue
• Effects:
  • Contractile dysfunction and lymphatic occlusion, causing lymphedema and prohibiting lymphatic drainage
  • Susceptibility of the human host to bacterial and fungal infections, which further contribute to tissue damage
• Adult filaria can survive inside humans for up to 9 years. 
• Adult worms also carry Wolbachia (endosymbiotic bacteria) in their gut, which appear to benefit the worms.

Clinical Presentation

Symptoms may take 9 months up to 1 year to manifest after the initial infection. Children or individuals in endemic areas often remain asymptomatic (subclinical infection), while others show acute and/or chronic signs and symptoms.

Acute manifestations

• Filarial fever:
  • Typically low-grade fever, self-limiting
  • May have myalgias
  • +/– Lymphadenopathy
• Acute adenolymphangitis (ADL):
  • Fever and lymphadenopathy
  • Lymphangitis (inflammation spread distally to the lymph node), with lymphatic vessels in the leg(s) becoming warm, enlarged, red, and tender
  • Commonly seen in inguinal lymph nodes but can also affect the genitalia (epididymitis in males)
  • Lasts a few days then resolves, but recurs periodically
• Acute dermatolymphangioadenitis (DLA):
  • Fever, chills
  • Edematous plaques (commonly interdigital) that are believed to be entry lesions and caused by bacteria
  • Lymphedema (worsens with recurrent episodes)
  • Seen in endemic areas
• Tropical pulmonary eosinophilia (TPE):
  • Immune reaction to microfilariae trapped in the lungs
  • Restrictive lung disease, which can progress to interstitial pulmonary fibrosis
  • Wheezing
  • Shortness of breath
  • Bloody sputum
  • Eosinophilia

Chronic manifestations

• Lymphedema:
  • Chronic swelling of the limb from chronic inflammation of the lymphatic vessels
  • Graded based on the extent and progression of the symptoms:
    • Grade 0: subclinical
    • Grade I: pitting edema of the extremities, reversible (↓ with limb elevation)
    • Grade II: pitting or nonpitting edema of the extremities, nonreversible
    • Grade III: nonpitting edema with skin thickening and overgrowths, nonreversible  (elephantiasis)
• Hydrocele:
  • Lymphatic disease involving the scrotum
  • Unilateral or bilateral
• Renal involvement:
  • Chyluria (milky urine): 
    • Normally, lymphatic vessels have no communication with the urinary tract.
    • In filariasis, fluid with intestinal lymph and chylomicrons leak into the urine intermittently.
    • Leads to protein loss
  • Hematuria and proteinuria also seen (but with unclear mechanism)

Diagnosis

Laboratory tests

• Peripheral blood smear:
  • Thick and thin smears
  • Venipuncture or finger/heel stick
  • Taken between 10 pm and 2 am (microfilaria have nocturnal periodicity)
  • Giemsa or Wright stains
• Circulating filarial antigen (W. bancrofti): 
  • Detects antigens of adult filarial worms
  • May be positive even in those without microfilariae
• Antifilarial antibody tests:
  • Elevated levels of antifilarial IgG4 in the blood 
  • Used mostly for travelers (who are not from endemic areas)
• PCR for antigen detection
  • Used in research
  • Assay not approved for commercial use
• Biopsy: tissue from cutaneous lesions
• Additional laboratory tests:
  • In areas endemic for onchocerciasis (Onchocerca volvulus) or loiasis (Loa loa), co-infection has to be determined, as management will differ.
  • CBC showing eosinophilia and elevated IgE noted in TPE

Imaging

• Ultrasonography:
  • Reveals adult worms moving in lymphatic vessels
  • The “filarial dance sign”—an irregular worm movement pattern—may be detected on Doppler.
• Lymphoscintigraphy:
  • Assess lymphatic drainage
  • Can detect preclinical lymphedema
• Chest X-ray:
  • To evaluate for TPE
  • Diffuse interstitial lesions and pronounced bronchoalveolar markings

Management

Treatment

Filariasis without co-infection:

• Diethylcarbamazine (DEC): 
  • 1st-line therapy
  • Single dose
  • 2–3 weeks of treatment for TPE due to W. bancrofti
• Doxycycline: 
  • In addition to DEC or an alternative therapy
  • For nonpregnant adults and children > 8 years of age
  • Effective against Wolbachia

Filariasis with loiasis:

• DEC intake increases the risk of life-threatening encephalopathy in co-infection as microfilarial load increases.
• Medication will vary depending on the load:
  • < 2500 L. loa microfilariae/mL: DEC
  • > 2500–8000 microfilariae/mL: ivermectin to decrease the microfilarial load, then DEC
  • > 8000 microfilariae/mL: doxycycline for 4–6 weeks

Filariasis with onchocerciasis:

• DEC intake worsens eye disease (↑ risk of blindness).
• Treatment options:
  • Treat onchocerciasis 1st with ivermectin, followed by DEC. 
  • For those with eye disease, give doxycycline followed by ivermectin.

Surgical treatment:

• Skin debulking and lymphovenous anastomosis for drainage improvement
• Surgical excision of hydrocele

Long-term management to reduce lymphedema progression:

• Skin hygiene
• Wearing comfortable shoes
• Compressive bandages
• Limb elevation
• Cold and heat therapy
• Antibiotic and antifungals to prevent flares

Prevention

• Avoid mosquito bites:
  • Sleep in an air-conditioned room or under mosquito nets.
  • Use mosquito repellent.
  • Wear long sleeves and trousers.
• Mosquito control with insecticide spraying
• Global Program for the Elimination of Lymphatic Filariasis:
  • Launched to eliminate spread and reduce morbidity
  • Consists of an annual mass drug administration (for at least 5 years) implemented using various regimens with:
    • DEC
    • Ivermectin
    • Albendazole

Complications and prognosis

Occult filariasis is a filarial infection that extends into tissues, without any evidence in the blood. This leads to chronic complications, such as:

• TPE
• Filarial arthritis
• Filaria-associated immune complex glomerulonephritis
• Filarial breast abscesses

Prognosis:

• When diseases is diagnosed and treated early, the prognosis is good. 
• As symptoms may present later in adulthood, lymphedema and, subsequently, elephantiasis are associated with disability and morbidity.

Differential Diagnosis

• Onchocerciasis: infection caused by the filarial nematode Onchocerca volvulus. also called river blindness: The vector for O. volvulus is the black fly from the Simulium genus. Manifestations involve the eye (keratitis, uveitis, chorioretinitis, optic atrophy), skin (subcutaneous nodules, dermatitis), and nervous system (seizures). Diagnosis is by skin snip biopsy. Treatment is with ivermectin.
• Loiasis: infection caused by the filarial nematode Loa loa. Loiasis is also known as the African eye worm. Transmission is via a bite of the Chrysops fly. Infected individuals can be asymptomatic, but the disease can manifest with subcutaneous swellings (Calabar swelling) and the subconjunctival migration of the adult worm. Diagnosis is through peripheral blood smear (microfilariae seen) or identification of a migrating worm in the eye or subcutaneous tissue. Treatment is with DEC if microfilarial load is low. With elevated levels of microfilariae, reduction of the load is required before treatment with DEC.
• Other testicular conditions: Other testicular infections may include varicocele or dilatation of the pampiniform venous plexus, which is connected to the internal spermatic or gonadal vein. Varicoceles present with a painless “bag of worms” appearance upon exam. Hydrocele or extra fluid in the tunica vaginalis leading to a swollen scrotum can be congenital or can be from trauma. Spermatocele, or epididymal cyst, commonly arises from the head of the epididymis and usually presents as a painless, incidental scrotal mass on exam.
• Other etiology of lymphedema: abnormal interstitial fluid accumulation from lymphatic obstruction. Primary lymphedema is from impaired lymphatic function or anomalous development due to genetic disorder(s). Secondary lymphedema has an underlying disease or treatment that led to the swelling. Causes include malignancy (and treatment), infection, trauma, or inflammatory conditions. The diagnostic approach involves a thorough history and examination, with workup dependent on clinical suspicion.