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Internal Medicine

Lymphatic filariasis (LF)

Vector-borne disease of tropical & subtropical countries due filarial worm infections, which invade the lymphatics of humans initiating pathological changes leading to later filarial disease manifestations.

Lymphatic filariasis, commonly known as elephantiasis, is a painful and profoundly disfiguring disease. It is caused by infection with parasites classified as nematodes (roundworms) of the family Filariodidea that are transmitted through the bites of infected mosquitos. Mosquito-transmitted larvae are deposited on the skin from where they can enter the body. The larvae then migrate to the lymphatic vessels where they develop into adult worms, thus continuing a cycle of transmission. | Lymphatic filariasis (Elephantiasis). (2020). Retrieved 19 November 2020, from https://www.who.int/health-topics/lymphatic-filariasis#tab=tab_1

Introduction

Vector-borne disease of tropical & subtropical countries due filarial worm infections, which invade the lymphatics of humans initiating pathological changes leading to later filarial disease manifestations.

  • #2 leading infectious cause of disability worldwide (after leprosy)
  • M/C cause of lymphedema in endemic countries
Wuchereria bancrofti. Contributed From the Center of Disease Control and Prevention (CDC; Public Domain) Image courtesy: https://en.wikipedia.org/wiki/Wuchereria_bancrofti#/media/File:Wuchereria_bancrofti_1_DPDX.JPG

Epidemiology

Lymphatic filariae (nematodes/roundworms):

Vectored by arthropods; mature and mate in specific host tissues; and produce microfilariae.
  • Wuchereria bancrofti (bancroftian fialriasis) (90% cases)
  • Brugia malayi (10% cases)
  • Brugia timori
Differentiation of different species of microfilariae on the basis of presence or absence of caudal nuclei (CN) and sheath (SH)

Life cycle:

Adult female worms produce microfilariae. Feeding vector mosquitoes ingest microfilariae from the bloodstream. In the mosquito the microfilariae mature to infective larvae, which migrate to the mosquito’s mouth-parts, enter a new host via the vector’s puncture wound, migrate to the lymphatics, mature, and mate.
  • Man (definitive host)
  • Mosquito (intermediate host):
    • Brugia spp. filariasis: Mansonia and Aedes
    • W. bancrofti: Aedes spp., Anopheles spp., Culex spp., Mansonia spp., and Coquillettida juxtamansonia
During a blood meal, an infected mosquito introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound (1). They develop in adults that commonly reside in the lymphatics (2). The female worms measure 80-100 mm in length and 0.24-0.30 mm in diameter, while the males measure about 40 mm by 1 mm. Adults produce microfilariae measuring 244-296 μm by 7.5-10 μm, which are sheathed and have nocturnal periodicity, except the South Pacific microfilariae which have the absence of marked periodicity. The microfilariae migrate into lymph and blood channels moving actively through lymph and blood (3). A mosquito ingests the microfilariae during a blood meal (4). After ingestion, the microfilariae lose their sheaths and some of them work their way through the wall of the proventriculus and cardiac portion of the mosquito’s midgut and reach the thoracic muscles (5). There the microfilariae develop into first-stage image larvae and subsequently into third-stage infective larvae (6). The third-stage infective larvae migrate through the hemocoel to the mosquito’s prosbocis image and can infect another human when the mosquito takes a blood meal (8). | CDC – Lymphatic Filariasis – Biology. (2020). Retrieved 19 November 2020, from https://www.cdc.gov/parasites/lymphaticfilariasis/biology.html

Host types:

  • Endemic normals (EN): Subjects living in endemic areas but free of infection and not showing any symptoms of the disease
  • Chronic (CH): Individuals with chronic sequelae of the disease such as elephantiasis, hydrocele or both for more than four years
  • Asymptomatic carriers (AS): Individuals with microfilaremia and antigenemia not showing any clinical symptoms

Pathophysiology

Lymphatic remodeling during filariasis:

Filarial lymphedema is associated with characteristic alterations of the lymphatic system, including the dilation of lymphatics with extensive collateral formation, loss of functional valves and retrograde lymph flow in response to an inflammatory disease state
Different stages of lymphatic vessel remodeling and modulation of lymphatic flow during progression of filarial infection. A. Normal lymphatic collecting vessel showing normal flow patterns and lymphatic drainage regulated by the unidirectional valves in the absence of filarial parasitic infection. B. Onset and progression of acute filarial infection with microfilariae and adult worms lodged within the vessel. Normal host immune response is initiated. Slight hypertrophy of the lymphatic muscle cell layers is observed with a partial impairment of lymph flow. C. Chronic filarial infection results in a major host immune response due to toxins released by dead or live parasites. Various immune cells are observed at the site of infection leading to a strong inflammatory reaction. Secondary infections with bacteria harboring Wolbachia exacerbates the condition leading to a chronic infection state or elephantiasis. The lymphatic vessels exhibit largely dysfunctional valves, vessel dilation, impaired lymphatic muscle contractility and insufficient drainage. The resultant fluid accumulation and retrograde lymph flow associated with severe lymphedema. Activation and remodeling of lymphatic endothelial cells during this chronic stage could potentially result in either endothelial dysfunction or promote lymphangiogenesis. | Chakraborty, S., Gurusamy, M., Zawieja, D. C., & Muthuchamy, M. (2013). Lymphatic filariasis: perspectives on lymphatic remodeling and contractile dysfunction in filarial disease pathogenesis. Microcirculation (New York, N.Y. : 1994), 20(5), 349–364. https://doi.org/10.1111/micc.12031

Host-parasite interaction:

Filarial parasite associated modulation of the immune response in microfilaremic patients which promotes the development of physiologic abnormalities of the lymphatic vasculature.
Schematic showing the synergetic roles of a plethora of signaling molecules and pathways that contribute to the onset and progression of filariasis. A. Complex interplay of cytokines and chemokines and associated immune cells triggered by different stages of the worm maintain the balance between a filaricidal or antifilaricidal host response. B. Specific parasitic toxins or excretory secretory products act through yet unidentified receptors on lymphatic muscle and endothelial cells to impair lymphatic contractile function. | Chakraborty, S., Gurusamy, M., Zawieja, D. C., & Muthuchamy, M. (2013). Lymphatic filariasis: perspectives on lymphatic remodeling and contractile dysfunction in filarial disease pathogenesis. Microcirculation (New York, N.Y. : 1994), 20(5), 349–364. https://doi.org/10.1111/micc.12031

Clinical features

While severe manifestations do not develop in the majority of infections, LF is a potentially highly disfiguring and disabling disease. The most prominent clinical feature is the development of severe lymphedema of the limbs (“elephantiasis”) and occasionally genitalia (hydrocele) due to dysfunction of lymphatic vessels. Affected limbs become grossly swollen; the skin may become thick and pitted, and secondary infection are frequent due to lymphatic dysfunction. Scrotal hydrocele is also seen in some infected males. Lymphangitis, lymphadenopathy, and eosinophilia may accompany infection in the early stages.

Acute Acute dermato-lymphangio-adenitis (ADLA):

M/C acute clinical manifestations in LF as a result of host immune response to antigens released by dying worms
  • Repeated bouts of sudden-onset fever and painful lymphadenopathy
  • Genitourinary symptoms:
    • Painful epididymitis (in males)
    • Chyluria (lymphatic fluid leaks into the kidneys and turns the urine milky white)
Urine from a patient with filarial chyluria. | Sham Sunder, Rajesh Jayaraman, Himanshu Sekhar Mahapatra, Satyanand Sathi, K. Venkataramanan, K. Prabhu, Anurag Gupta, and Suman Sethi – “Analysis of case series of milky urine: A single center and departmental clinical experience with emphasis on management perspectives: A prospective observational study” DOI: 10.4103/0974-7796.141002, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=59055580

Filarial fever:

Episodes of self-limiting fever without any associated lymphadenopathy

Tropical pulmonary eosinophilia (TPE):

Chronic syndrome associated with involving eosinophilic pulmonary infiltrate, peripheral hypereosinophilia, wheezing, chest pain, splenomegaly, and bloody sputum.
  • Repeated bouts of dry nocturnal cough & wheeze
  • Chest pain and bloody sputum

Lymphedema:

M/C chronic presentation that develops over a long period due to chronic lymphatic damage
  • Characteristically presents with swelling of upper limbs (axillary lymphatic vessels) or lower limbs (inguinal lymphatic vessels)
  • Pitting edema (early stages) → Brawny non-pitting type

Elephantiasis:

M/severe type of lymphedema
  • Characterized by severe swelling of the limbs, genitalia, and breasts.
  • Hyperpigmentation & hyperkeratosis of skin.
Elephantiasis of leg caused by chronic infection with the filarial nematode Wuchereria bancrofti. (Courtesy of Shoyei Yamauchi, Honolulu, HI.)

Unilateral/bilateral hydrocele:

Very large, reaching up to 40 cm

Diagnosis

Lab studies:

  • Diethylcarbamazine (DEC) provocation test: DEC induces microfilaria to move into peripheral circulation during daytime for collection
  • Night blood examination (to detect mf)
  • Immuno-chromatographic-card test (ICT) (for filarial antigenemia)

Ultrasonography:

For locating the adult worms; It is usually negative once lymphedema is established
  • Filarial dance sign: Filariasis in scrotum

Chest X-ray:

  • Tropical pulmonary eosinophilia (TPE): Increased bronchovascular markings, discrete opacities or diffuse miliary mottling
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Chest X-rays of tropical filarial pulmonary eosinophilia before (A) and after (B) treatment with diethylcarbamazine. | Akuthota, P., & Weller, P. F. (2012). Eosinophilic pneumonias. Clinical Microbiology Reviews, 25(4), 649–660. https://doi.org/10.1128/CMR.00025-12

Lymphoscintigraphy:

Assess structural and functional changes in the lymphatics

Management

Diethylcarbamazine (DEC) remains the mainstay of treatment

Very effective as a microfilaricidal agent, it kills only around 50% of adult worms

ADLA management:

  • Mild ADLA: Bed rest, elevation of affected limb and symptomatic treatment + local antibiotics/antifungals
  • Moderate/severe attacks: Oral/parenteral antibiotics + analgesic/anti-inflammatory agents

Lymphoedema management:

  • Elasto-crepe bandage or tailor made stockings while ambulant
  • Limb elevation at night, after removing the bandage
  • Regular exercising (affected limb)
  • Regular light massage (affected limb): Stimulate lymphatics and promote flow of lymph towards larger patent vessels
  • Intermittent pneumatic compression (affected limb)
  • Heat therapy (wet heat or hot ovens)

Surgical management:

Even after surgery the local care of the limb should be continued for life, so that ADLA attacks and recurrence of the swelling are prevente
  • Lymph nodo-venous shunts
  • Omentoplasty
  • Excision with skin grafting

Summary:

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