Case 12 Andrea De Mesa

Case Description MG, a native from Leyte, was brought to Manila and admitted to your hospital because of swelling of both lower extremities and scrotal edema, noted for the past 2 weeks. MG, a native from Leyte, was brought to Manila and admitted to your hospital because of swelling of both lower extremities and scrotal edema, noted for the past 2 weeks.

Filariasis

Diagnosis Filariasis Filariasis Caused by very small worm Caused by very small worm * Wuchereria bancrofti * Wuchereria bancrofti * Brugia malayi * Brugia malayi Endemic in the southern part of the country Endemic in the southern part of the country MOT: skin penetration MOT: skin penetration

ELEPHANTIASIS Massive swelling, esp. of the genitalia and lower extremities, resulting from obstruction of lymphatic vessels, for example by filarial parasites, malignancies, neurofibromatosis, or a familial congenital disease (Milroy's disease). Prolonged swelling can cause an increase in interstitial fibrous tissue and skin puckering or breakdown. In patients with parasitic elephantiasis (i.e, the filarial diseases, which are common in the tropics), single-dose therapy with ivermectin or ivermectin plus albendazole destroys immature but not adult worms Massive swelling, esp. of the genitalia and lower extremities, resulting from obstruction of lymphatic vessels, for example by filarial parasites, malignancies, neurofibromatosis, or a familial congenital disease (Milroy's disease). Prolonged swelling can cause an increase in interstitial fibrous tissue and skin puckering or breakdown. In patients with parasitic elephantiasis (i.e, the filarial diseases, which are common in the tropics), single-dose therapy with ivermectin or ivermectin plus albendazole destroys immature but not adult worms

Lymphatic filariasis Lymphatic filarial worms Lymphatic filarial worms Wuchereria bancrofti Wuchereria bancrofti Brugia malayi & timori Brugia malayi & timori In tropical areas: In tropical areas: SE Asia, India, Indonesia, China, South Pacific, Central America, Caribbean 120 million infected 120 million infected Vectored by various mosquitoes Vectored by various mosquitoes Show different periodicity Show different periodicity Larval stages (microfilaria) circulate in blood at Larval stages (microfilaria) circulate in blood at different times, corresponding to times when different times, corresponding to times when vector feeds vector feeds

Generalized life cycle 1 st stage larvae (microfilaria=mf) circulating in blood of human ingested as mosquito takes blood meal 1 st stage larvae (microfilaria=mf) circulating in blood of human ingested as mosquito takes blood meal Develop over 1-3wks in mosquito to infective 3 rd stage larvae, deposited onto skin and enter blood stream Develop over 1-3wks in mosquito to infective 3 rd stage larvae, deposited onto skin and enter blood stream Mature in lymphatics, mate, produce mff Mature in lymphatics, mate, produce mff

Morphology Adults Adults Females mm long, males half Females mm long, males half White, threadlike, in lymphatics White, threadlike, in lymphatics Females bear live young (mff) Females bear live young (mff) Microfilaria Microfilaria Sheathed Sheathed In blood In blood Sheath

Lymphatic Microfilaria Wuchereria bancrofti Brugia spp μm Pointed tail Nuclei stop short of tip Nuclei discrete, not smudged μm Tapered tail w/nuclei to tip A constriction separates last 2 nuclei (subterminal & terminal) Sheath of B. malayi stains pink w/ Giemsa

Lymphatic Filariasis Initially asymptomatic until mechanical damage caused by highly motile adult worms in lymphatic channels induce an inflammatory response Initially asymptomatic until mechanical damage caused by highly motile adult worms in lymphatic channels induce an inflammatory response Inflammation leads to valve damage, flow inhibition, fibrosis, collateral channel development Inflammation leads to valve damage, flow inhibition, fibrosis, collateral channel development Bancroftian filariasis usually in inguinal, epitrochlear, axillary, testicular areas Bancroftian filariasis usually in inguinal, epitrochlear, axillary, testicular areas Brugian filariasis usually in inguinal or axillary area, affecting distal extremities Brugian filariasis usually in inguinal or axillary area, affecting distal extremities Early disease Early disease Retrograde lymphangitis, fever, chills, malaise for 3-15 days, occurring several times/year Retrograde lymphangitis, fever, chills, malaise for 3-15 days, occurring several times/year Lymph node abscesses in brugian type Lymph node abscesses in brugian type Can get marked eosinophilia (1000->2500 cu mm) Can get marked eosinophilia (1000->2500 cu mm)

Tropical Pulmonary Eosinophilia Sequestration of mff in lungs, no microfilaremia Sequestration of mff in lungs, no microfilaremia Allergic response Allergic response Recurring episodes of wheezing or nocturnal paroxysmal cough Recurring episodes of wheezing or nocturnal paroxysmal cough Persistent hypereosinophilia (>3000/ cu mm), high IgE levels, miliary lesions on xray Persistent hypereosinophilia (>3000/ cu mm), high IgE levels, miliary lesions on xray Lasts for weeks Lasts for weeks Tx as for bancroftian filariasis Tx as for bancroftian filariasis

Chronic disease Prolonged infection leads to obstructive disease Prolonged infection leads to obstructive disease Chyluria w/ obstruction of renal lymphatics Chyluria w/ obstruction of renal lymphatics Hydrocele most common complaint in genital area Hydrocele most common complaint in genital area Lymphadema & elephantiasis most common in extremities (full leg w/ bancroftian, lower leg w/ brugian) Lymphadema & elephantiasis most common in extremities (full leg w/ bancroftian, lower leg w/ brugian)

Elephantiasis of Extremities

LABORATORY EXAMS

Thick blood Smear Thick blood smear – most commonly used for detection of microfilaremia Thick blood smear – most commonly used for detection of microfilaremia - taken 8pm-4am (filarial species have nocturnal periodicity) - taken 8pm-4am (filarial species have nocturnal periodicity)  In many chronic infections, microfilariae may not be demosntrable in the peripheral blood. Among the reasons include: a. low intensity infection a. low intensity infection b. dead worms b. dead worms c. obstructed lymphatics c. obstructed lymphatics

For low infections, perform filtration using Nucleopore filter or Knott’s method For low infections, perform filtration using Nucleopore filter or Knott’s method Ultrasonography – may be able to demonstate live worms in the lymphatics Ultrasonography – may be able to demonstate live worms in the lymphatics Contrast lymphangiography and Lymphscintigraphy using radiolabelled albumin or dextran – may be able to demonstrate obstructed lymphatics Contrast lymphangiography and Lymphscintigraphy using radiolabelled albumin or dextran – may be able to demonstrate obstructed lymphatics

MANAGEMENT & PHARMACOKINETICS The most useful nonspecific procedure in swelling of both lower limbs is pressure bandaging using 6-inch strips of bath toweling, covering with cotton elastic bandage and an outer muslin bandage to keep out dirt. The most useful nonspecific procedure in swelling of both lower limbs is pressure bandaging using 6-inch strips of bath toweling, covering with cotton elastic bandage and an outer muslin bandage to keep out dirt. Exercise is required to prevent cyanosis and hasten reduction of the lymphedema Exercise is required to prevent cyanosis and hasten reduction of the lymphedema

Diethylcarbamazine DEC for treatment of infections with these parasites, given its high order of therapeutic efficacy and lack serious toxicity. DEC for treatment of infections with these parasites, given its high order of therapeutic efficacy and lack serious toxicity. Synthetic piperazine derivative, given at dose of 6mg/kg/BW, orally for 12 days, given preferably in divided doses after meals. Synthetic piperazine derivative, given at dose of 6mg/kg/BW, orally for 12 days, given preferably in divided doses after meals. Rapidly absorbed in GIT Rapidly absorbed in GIT Peak plasma level is reached within 1-2 hrs Peak plasma level is reached within 1-2 hrs

Plasma half-life is 2-3 hrs in presence of acidic urine but about 10 hrs if urine is alkaline. Plasma half-life is 2-3 hrs in presence of acidic urine but about 10 hrs if urine is alkaline. Drug rapidly equilibrates with all tissue except fat Drug rapidly equilibrates with all tissue except fat It is excreted, principally in the urine unchanged It is excreted, principally in the urine unchanged It immobilized microfilariae (which results in their displacement in tissues) and alters their surface structure, making them more susceptible to destruction by host defense mechanisms. It immobilized microfilariae (which results in their displacement in tissues) and alters their surface structure, making them more susceptible to destruction by host defense mechanisms. Mode of action against adult worm is unknowm Mode of action against adult worm is unknowm

Ivermectin Semisynthetic macrocyclic lactone Semisynthetic macrocyclic lactone Derived from the soil actinomycete, Steptomyces avermitilis Derived from the soil actinomycete, Steptomyces avermitilis Given orally at μg/kg for 12 days Given orally at μg/kg for 12 days The drug is rapidly absorbed, reaching maximum plasma concentration at 4 hrs The drug is rapidly absorbed, reaching maximum plasma concentration at 4 hrs Has a wide tissue distribution Has a wide tissue distribution Half life is 11 hrs Half life is 11 hrs Excretion is almost exclusively in the feces Excretion is almost exclusively in the feces

Ivermectin By opening glutamate-gated chloride channels (found only in invertebrates) and increasing chloride conductance By opening glutamate-gated chloride channels (found only in invertebrates) and increasing chloride conductance Thru binding to a novel allosteric site on the acetylcholine nicotinic receptor to cause an increase in transmission leading to motor paralysis. Thru binding to a novel allosteric site on the acetylcholine nicotinic receptor to cause an increase in transmission leading to motor paralysis. Side effects include: skin rashes, fever, giddiness, headaches and pain in muscles, joints and lymph gland Side effects include: skin rashes, fever, giddiness, headaches and pain in muscles, joints and lymph gland In general, the drug is well tolerated In general, the drug is well tolerated

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