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FILARIASIS.pptx
- 1. FILARIASIS
- 2. Learning objectives • Somatic nematodes • Difference between various filarial nematodes • Lymphatic Filariasis • Loiasis • Onchocerciasis
- 4. Differences between various filarial nematodes
- 9. WUCHERERIA BANCROFTI Epidemiology • Southeast Asia accounts for highest burden; comprises of 50% of globally infected lymphatic Filariasis (LF) cases. • India – It is estimated that about 650 million people are at risk, residing in 256 districts of 21 states in India; accounting for 40% of global burden. • Highly endemic states are Uttar Pradesh, Jharkhand, Bihar and West Bengal, which account for two-thirds of the lymphatic Filariasis burden in India
- 10. Morphology-Adult worm • Long, slender, creamy-white thread like, filariform shaped with tapering ends. • Females are viviparous and they directly discharge larvae without any eggs.
- 11. Morphology-Larva • First stage larva is called as microfilaria. • The third stage larva is called as filariform larva; which is the infective form to humans.
- 12. Morphology-Larva • Microfilariae are the diagnostic forms, found in the blood vessels. • The nuclei are present throughout the body except near the head and the tail end. • Nuclei are also absent in few places which represent various primordial organs like nerve ring, excretory pore, anal pore and genital cells
- 13. Comparison of microfilariae of various filarial worms
- 14. Comparison of microfilariae of various filarial worms
- 15. Cultivation • Cell line: W. bancrofti and B. malayi can be cultivated in mosquito cell line (like Aedes togoi and Anopheles maculatus) grown in modified RPMI-1640 medium or medium-TC199 supplemented with 20% newborn calf serum and LLC-MK2 cells.
- 16. Life Cycle Host: W. bancrofti completes its life cycle in two hosts. • Definitive host: Man is the definitive host and also the only reservoir host. • Intermediate host: Mosquito named Culex quinquefasciatus is the principle vector worldwide. • Infective form: Third stage filariform larvae • Mode of transmission: Filariform larvae get deposited in skin by the mosquito bite.
- 17. Life cycle
- 18. Pathogenesis and pathology • Tissue alterations related to migration of live adult worms such as lymphatic dilatation and thickening of the vessel walls • Tissue alterations related to antigen and toxic metabolites released from dead adult worm • Secondary bacterial and fungal infections • Host’s inflammatory response to both live and dead parasite
- 19. Host Immune Response • Both cellular and humoral immune response are altered. • Antigens of both adult worms and microfilariae are processed by the antigen presenting cells (macrophages) and presented to T helper cells (TH cells). • TH cells are stimulated and differentiated into TH 1 cells and or TH 2 cells.
- 20. Clinical Features • Incubation period is about 8–16 months. • Clinical manifestations can be categorized into: o Lymphatic Filariasis o Tropical pulmonary eosinophilia (TPE)/(Occult Filariasis) o Immune complex mediated manifestations.
- 21. Lymphatic Filariasis • Endemic normal -normal people residing in endemic area. • Asymptomatic microfilaremia – o Microfilaremia demonstrated in their peripheral blood o Microscopic hematuria and/or proteinuria o Dilated and tortuous lymphatics (visualized by imaging) o Filarial dance sign (ultrasound showing motile adult worm in scrotal lymphatics).
- 22. Lymphatic Filariasis (cont..) Acute Filariasis (acute adenolymphangitis) - Recurrent episodes of: • Filarial fever (high-grade fever) • Lymphatic inflammation (lymphangitis and lymphadenitis): Lower extremities are more commonly affected than the upper limbs • Transient local edema • Dermatolymphangitis
- 23. Lymphatic Filariasis (cont..) Chronic Filariasis: • Severe lymphatic obstruction and pedal edema • Hydrocele • Elephantiasis • Chronic funiculitis and epididymitis • Chyluria Elephantiasis Hydrocele
- 24. Differences between classical & occult Filariasis
- 26. Thick blood smears stained with Giemsa showing microfilaria of (A) Wuchereria bancrofti; (B) Brugia species (A) (B) Laboratory Diagnosis
- 27. Treatment • DEC • DOXYCYCLINE • Albendazole • MANAGEMENT OF LYMPHEDEMA
- 28. Elimination of Lymphatic Filariasis (ELF) • Global programme to eliminate lymphatic Filariasis (LF) is launched by WHO in 2000 aiming at global elimination by the year 2020. • Strategy: WHO recommends yearly single dose of DEC + albendazole in all endemic areas except o In oncocerciasis endemic areas where ivermectin+ albendazole is given. o In Loa loa endemic area (albendazole twice per year given) o Recently in 2018, WHO recommended IDA regimen (combination of ivermectin, DEC and albendazole) under elimination program. It is yet to be implemented.
- 29. ELF in India • In India, ELF is in operation since 2004 in parallel with global strategy. • Twin Strategies employed: Comprises of (1) annual mass drug administration (MDA) of DEC + Albendazole; (2) Home based management for lymphedema cases and up scaling of hydrocele operations. • Dosage: DEC is given at dose of 100mg for 2-5 years, 200mg 6-14 years and 300mg for ≥15 years age and albendazole is given 400mg for all age group >2 years. • Indication: MDA is indicated in all high risk population of 256 endemic districts of India; except in children <2 years, pregnant women and severely ill. • Duration: MDA should be continued annually for minimum five years; with a target of >65% coverage of at risk population.
- 30. ELF • Filariasis elimination: After four years of post MDA surveillance, the area is declared as having achieved elimination status. • Elimination status: As of 2018, five states (Assam, Tamil Nadu, Goa, Puducherry, Daman & Diu) stopped MDA after achieving elimination status and observing post MDA surveillance activities.
- 31. BRUGIA MALAYI Epidemiology- • There is considerable overlapping in the geographical distribution of Brugian Filariasis and Bancroftian Filariasis. • B. malayi occurs primarily in eastern India, Indonesia, Malaysia, Thailand and Philippines
- 32. Morphology-Adult worm • The adult worms are essentially similar to that of W. bancrofti except they are smaller in size; males (3.5 cm × 0.1 mm) and females (5–6 cm × 0.1 mm).
- 34. Clinical Features • Both lymphatic Filariasis and tropical pulmonary eosinophilia syndrome are observed in Brugian Filariasis. • Clinical features are similar to Bancroftian Filariasis except: o More frequent episodes of acute adenolymphangitis, adenitis (femoral nodes), and filarial abscesses o Chronic manifestations (lymphedema and elephantiasis) occur less frequently o The genital involvement is not seen o Elephantiasis: Swelling is limited to leg below the knee o Chyluria does not occur.
- 35. Laboratory Diagnosis As in Bancroftian Filariasis, the diagnosis of Brugian Filariasis depends on: • Microscopy: Microfilaria in blood can be detected by Giemsa stained peripheral blood smear examination. • Antibody detection methods: ICT (Brugia Rapid) is available detecting parasite-specific IgG-4 antibodies • Molecular methods
- 36. TREATMENT AND PREVENTION • Treatment for Brugian Filariasis is same as for Bancroftian Filariasis except that frequency of adverse effects following DEC medication is more; therapy should be started with lower dose. • Prevention- Same as for Bancroftian Filariasis (i.e both chemoprophylaxis and vector control).
- 37. LOA LOA Morphology • Adult worms (females, 50–70 mm long and 0.5 mm wide; males, 30–35 mm long and 0.3 mm wide) • Live in subcutaneous tissues • Microfilariae circulate in the blood with a diurnal periodicity Loa loa microfilaria
- 38. Life Cycle • Life cycle is similar to that of W. bancrofti except the vector is female Chrysops species (deer flies, mango flies, red flies or tabanid flies) • Mode of transmission infective (L3 ) larvae are transmitted by the bite of female Chrysops species during the blood meals in the daytime
- 39. Pathogenesis and Clinical Feature • Calabar Swellings - most common form of Loiasis, also called as fugitive swelling. It is a subcutaneous swelling developing on the extremities • Ocular Manifestations - conjunctival granuloma, edema of the eye lid leading to proptosis (bulging). • Complications- Meningoencephalitis
- 41. Laboratory Diagnosis • Microscopy - Definite diagnosis of Loiasis requires Detection of microfilariae in the peripheral blood • Molecular Methods - Nested PCR-based assays for the detection of L. loa DNA in blood • Antibody Detection - Lateral flow assay (ICT)
- 42. Treatment • DEC • Albendazole • Apheresis
- 43. ONCHOCERCA VOLVULUS • Onchocerca volvulus is the causative agent of “river blindness” in man • Endemic area: The majority of individuals infected with O. volvulus live in the rural poor region of Sub-Saharan Africa, particularly West Africa.
- 44. Morphology • Adult Worm - long, thin, tapering at both the ends. They bear transverse striations on the cuticle with annular and oblique thickening. This helps in differentiating from other filarial worms • Microfilaria - skin dermis Microfilariae; Adult worms Transverse section
- 45. Life Cycle • Life cycle is similar to that of W. bancrofti, except the vector is Simulium (black flies).
- 46. Clinical Features Skin (Dermatitis) • Intense pruritus and generalized papular rashes are the most common manifestations. • Leopard skin: Skin may be hypo to hyper pigmented. • Lichenoid changes and hyperkeratosis may occur in late stages • Sowda: It is a chronic hyperreactive form of dermatitis
- 47. Clinical Features (cont..) Onchocercoma (Subcutaneous Nodules) • Subcutaneous nodules are firm, non-tender, variable in size containing the coiled adult worms and rarely microfilariae. Ocular Involvement • Bilateral blindness (river blindness) • Conjunctivitis with photophobia • Punctate keratitis: “snowflake opacities” • Sclerosing keratitis - Onchocercal blindness
- 49. Laboratory Diagnosis • Detection of the Microfilariae - Skin snips technique: Most common sites: Both iliac crests or sometimes from calves and the shoulders, scapula. • Detection of the Adult Worm - biopsy of the subcutaneous nodules, but it is less sensitive. • Serology- currently developed IgG4 specific dip stick assay detecting Ov16 antigen may indicate active infection. • Molecular Methods - PCR detecting onchocercal DNA in skin snips
- 50. SKIN SNIP BIOPSY Left: A physician takes a skin sample from a patient for a skin snip biopsy by elevating a piece of skin with a needle and shaving it off with a scalpel. Right: A physician takes a skin sample from a patient for a skin snip biopsy using a sclerocorneal biopsy punch.
- 52. MANSONELLA SPECIES • Mansonella perstans – Causes angioedema, urticaria, pruritus and Calabar-like swelling similar to that of Loa loa. • It also produces acute periorbital inflammation; known as bung-eye or bulge-eye • Treatment - DEC or albendazole are found to be effective; lowering the level of microfilaremia.
- 53. MANSONELLA SPECIES (cont..) • Mansonella Streptocerca - Many infected individuals are asymptomatic; few may develop inguinal lymphadenopathy, pruritus, dermatitis with hypo pigmented macule • DEC is effective for streptocerciasis.
- 54. MANSONELLA SPECIES (cont..) • Mansonella Ozzardi - Most infections are asymptomatic, but occasionally cause lymphadenopathy, urticaria, pruritus, pulmonary symptoms, arthralgia and keratitis • Treatment -Ivermectin is effective in lowering the level of microfilaremia. Use of DEC is controversial.
- 55. MANSONELLA SPECIES Microfilariae of Mansonella perstans (stained with Giemsa) Microfilaria of Mansonella streptocerca (stained with hematoxylin) Microfilaria of Mansonella ozzardi (Giemsa stain)
Editor's Notes
- Mansonia and Aedes- for Brugia malayi as per CDC
- Different species of the following genera of mosquitoes are vectors of W. bancrofti filariasis depending on geographical distribution. Among them are: Culex (C. annulirostris, C. bitaeniorhynchus, C. quinquefasciatus, and C. pipiens); Anopheles (A. arabinensis, A. bancroftii, A. farauti, A. funestus, A. gambiae, A. koliensis, A. melas, A. merus, A. punctulatus and A. wellcomei); Aedes (A. aegypti, A. aquasalis, A. bellator, A. cooki, A. darlingi, A. kochi, A. polynesiensis, A. pseudoscutellaris, A. rotumae, A. scapularis, and A. vigilax); Mansonia (M. pseudotitillans, M. uniformis); Coquillettidia (C. juxtamansonia).
- Tropical (pulmonary) eosinophilia, or TPE, is characterized by coughing, asthmatic attacks, and an enlarged spleen, and is caused by Wuchereria bancrofti, a filarial infection. It occurs most frequently in India and Southeast Asia. Tropical eosinophilia is considered a manifestation of a species of microfilaria. This disease can be confused with tuberculosis, asthma, or coughs related to roundworms. Tropical pulmonary eosinophilia is a rare, but well recognised, syndrome characterised by pulmonary interstitial infiltrates and marked peripheral eosinophilia. This condition is more widely recognised and promptly diagnosed in filariasis-endemic regions, such as the Indian subcontinent, Africa, Asia and South America. In nonendemic countries, patients are commonly thought to have bronchial asthma. Chronic symptoms may delay the diagnosis by up to five years. Early recognition and treatment with the antifilarial drug, diethylcarbamazine, is important, as delay before treatment may lead to progressive interstitial fibrosis and irreversible impairment. The condition of marked eosinophilia with pulmonary involvement was first termed tropical pulmonary eosinophilia in 1950. The syndrome is caused by a distinct hypersensitive immunological reaction to microfilariae of W. bancrofti and Brugia malayi. However, only a small percentage (< 0.5%) of the 130 million people globally who are infected with filariasis apparently develop this reaction. The clearance of rapidly opsonised microfilariae from the bloodstream results in a hypersensitive immunological process and abnormal recruitment of eosinophils, as reflected by extremely high IgE levels of over 1000 kU/L. The typical patient is a young adult man from the Indian subcontinent.
- Diethylcarbamazine (DEC) is the drug of choice in the United States. The drug kills the microfilariae and some of the adult worms. DEC has been used world-wide for more than 50 years. CDC gives the physicians the choice between 1 or 12-day treatment of DEC (6 mg/kg/day). One day treatment is generally as effective as the 12-day regimen. DEC is generally well tolerated. Side effects are in general limited and depend on the number of microfilariae in the blood. The most common side effects are dizziness, nausea, fever, headache, or pain in muscles or joints. DEC should not be administered to patients who may also have onchocerciasis as DEC can worsen onchocercal eye disease. In patients with loiasis, DEC can cause serious adverse reactions, including encephalopathy and death. The risk and severity of the adverse reactions are related to Loa loa microfilarial density. In settings where onchoceriasis is present, Ivermectin is the drug of choice to treat LF. Some studies have shown adult worm killing with treatment with doxycycline (200mg/day for 4–6 weeks). People with lymphedema and elephantiasis are unlikely to benefit from DEC treatment because most people with lymphedema are not actively infected with the filarial parasite. To prevent lymphedema from getting worse, patients should ask their physician for a referral to a lymphedema therapist so they can be informed about some basic principles of care such as hygiene, elevation, exercises,skin and wound care, and wearing appropriate shoes. Patients with hydrocele may have evidence of active infection, but typically do not improve clinically following treatment with DEC. The treatment for hydrocele is surgery. There is some evidence that suggests that a course of the antibiotic doxycycline may prevent lymphedema from getting worse.
- The treatment of loiasis is complex and is best undertaken after consultation with experts who have experience in the treatment of the disease and prevention of complications of treatment. Additionally, there may be times when it is best not to treat the infection. Surgical excision of migrating adult worms is an effective treatment for symptoms localized to the migrating worm and provides an opportunity for diagnosis. Surgery is not curative. Antiparasitic medication is required for cure. The drug of choice for the treatment of loiasis is diethylcarbamazine (DEC). Most patients will achieve cure, defined as resolution of symptoms, resolution of eosinophilia, and decreasing antifilarial antibody titers, with one or two courses of DEC. Some will require additional courses of DEC or a trial of albendazole. DEC is the treatment of choice because there is solid evidence that it kills both the microfilariae and the adult worms, resulting in quicker resolution of the infection. The risk of fatal encephalopathy or other severe adverse neurologic events is related to the microfilarial load. Quantitative blood smears are required before initiating treatment. Prophylactic DEC (300 mg once a week) can be used to prevent infection in long-term travelers to endemic areas. There is some evidence that albendazole given twice daily for 21 days may be an effective treatment for loiasis that is refractory to DEC treatment. It also may be used to reduce microfilarial load prior to initiation of DEC treatment. The response to albendazole is slow so close, frequent monitoring would be needed to determine when it is safe to treat with DEC. Albendazole does not appear to be prone to cause encephalopathy, though published data are limited. Treatment of loiasis with antiparasitic agents may result in a brief increase of symptoms, such as Calabar swelling or pruritus. Some authors suggest that these symptoms might be attenuated with the concomitant use of antihistamines or corticosteroids during the first seven days of treatment. There is also the risk of fatal encephalopathy with DEC treatment; this risk has not been shown to be eliminated by corticosteroid treatment. More details on this are given below the treatment table. Loa loa do not contain Wolbachia so doxycycline is not an effective treatment. Note on risk of fatal encephalopathy when treating loiasis: Available data demonstrate that the risk of fatal encephalopathy in patients treated with DEC with microfilarial loads <8,000 microfilariae per mL approaches zero. In those patients with microfilarial loads ≥8,000 microfilariae per mL, apheresis can be used in specialized centers to reduce the load below the 8,000 threshold prior to beginning treatment. Some authors suggest a more conservative threshold of 2,500 microfilariae per mL for the initiation of treatment of loaisis. This lower threshold would need to be balanced with the risk associated with apheresis. There are some data available that suggest treating the patient with albendazole, 200mg twice daily for 21 days, may reduce the microfilarial load to acceptable levels, though re-measurement of levels after albendazole treatment would be required prior to treatment with DEC. Note on treatment in patients with O. volvulus co-infection: DEC is contraindicated in persons with onchocerciasis because of the risk of blindness and/or severe exacerbation of skin disease.
- Sowda is an unusual form of onchocerciasis in Yemenites that differs from African onchocerciasis. Clinical and pathological studies were performed on 18 patients in Yemen Arab Republic (North Yemen). Biopsies of skin and lymph nodes were taken, and then processed at the Armed Forces Institute of Pathology, Washington, D.C. The most striking clinical features were swollen, darkened, pruritic, papular skin changes that were usually limited to one leg, more rarely to one arm, and large soft regional lymph nodes. Dermal changes were deeper and more diffuse than in African onchocerciasis, with many large fibroblasts and plasma cells. Microfilariae of Onchocerca volvulus were much rarer in skin from Yemenites with sowda. When patients were treated with diethylcarbamazine, the dermatitis became suddenly worse as the microfilariae degenerated and provoked acute inflammation. The dermatitis decreased after several days of treatment. Enlarged lymph nodes from sowda have shown follicular hyperplasia, in contrast to follicular atrophy and perivascular fibrosis that are characteristic of lymph nodes from cases of African onchocerciasis. Cell-mediated and humoral immunity may be more active in sowda than in African onchocerciasis.
- Diagnosis The gold standard test for the diagnosis of onchocerciasis remains the skin snip biopsy. The biopsy is performed using a sclerocorneal biopsy punch or by elevating a small cone of skin (3 mm in diameter) with a needle and shaving it off with a scalpel. This will result in the removal of around 2 mg of tissue. The tissue is then incubated in normal saline at room temperature for 24 hours to allow the microfilariae (larvae) to emerge. The microfilariae can then be identified microscopically. The sites for the skin snip are usually over the iliac crest, the scapula, and the lower extremities. Six snips provide the most diagnostic sensitivity. Although the skin snip is highly specific, its sensitivity can be limited in the pre-patent stage of infection, which can last 1 to 1.5 years, and in low intensity infections. Performing polymerase chain reaction (PCR) of the skin snip can increase the sensitivity in these two situations, though this is not commercially available. If a patient has skin nodules caused by onchocercal infection, nodulectomy allows for the identification of macrofilariae (adult worms) in the tissue. Slit lamp eye exam can be used to visualize microfilariae in individuals with eye disease. There are antibody tests that can assist in the diagnosis of onchocerciasis, though many are not available outside the research setting. There is a general screen for any filarial infection (including Wuchereria, Brugia, Loa, and Mansonella infections) that is available in some specialty diagnostic labs. Because the test is highly sensitive, it is useful in determining if an individual has had filarial infection, but it is not specific enough to identify which filarial infection. As with any antibody test, the results indicate only that the patient has been exposed to the disease, but it cannot determine if the patient has an active infection. This distinction is less important in symptomatic travelers, but it limits the usefulness of the test in persons from endemic areas. One advantage of the test is that it can pick up evidence of infection in the pre-patent stage of infection. There are several Onchocerca-specific serologic tests in existence, such as the OV-16 antigen antibody test and the OV luciferase immunoprecipitation system (LIPS) assay, but these are currently only available in the research setting and are not approved for diagnosis in the United States. In general the diagnosis of O. volvulus infection should be made with skin snip. However, when skin snips are negative and clinical suspicion of infection is high, the general antibody test could be used in an attempt to exclude infection. If the general antibody test were positive, then it might be necessary to consider performing additional skin snips and/or seeking additional diagnostic information by enlisting the assistance of researchers who perform antibody tests.
- Treatment General principles of treatment (see table below for dosing and precautions) The treatment of choice for onchocerciasis is ivermectin, which has been shown to reduce the occurrence of blindness and to reduce the occurrence and severity of skin symptoms. Ivermectin kills the microfilariae (larvae), but not the macrofilariae (adult worms). There is no evidence that prolonged daily treatment provides any benefit over annual treatment, as one dose results in a significant decrease in microfilarial load that lasts a year or more. Treatment with higher than recommended doses has an increased incidence of side effects and may even be harmful. Although ivermectin does not kill the macrofilariae, it does sterilize the females. There is evidence that treating people with ivermectin more frequently than once a year facilitates more rapid sterilization of the female and that treating a person who no longer lives in an endemic area more frequently, such as every 3 to 6 months, could result in a shorter duration of symptoms. Treatment for a patient who will not be returning to live in an endemic area should be given every 6 months (and dosing as frequent as every 3 months could be considered) for as long as there is evidence of continued infection. Evidence of continued infection would include skin symptoms such as pruritus, microfilariae in skin biopsies, and microfilariae on eye exam. Finding adult worms in nodules would not necessarily constitute evidence of the need for continued treatment, as the macrofilariae do not cause symptoms and ivermectin does not kill the macrofilariae. Treatment with ivermectin can cause mild symptoms associated with death of the microfilariae, such as increase itching, but there is no worsening of eye symptoms. Severe adverse reactions to ivermectin in the absence of Loa loa co-infection are rare. An evolving treatment is doxycycline, which has been shown in studies to kill Wolbachia, an endosymbiotic rickettsia-like bacterium that appears to be required for the survival of the O. volvulus macrofilariae and for embryogenesis. Treatment with a 6-week course of doxycycline has been shown to kill more than 60% of the adult female worms and to sterilize 80 to 90% of the females 20 months after treatment. Doxycycline does not kill the microfilariae, so treatment with ivermectin would be needed to result in a more rapid decrease of symptoms. Most protocols that have examined the effectiveness of doxycycline had given treatment with ivermectin 4 to 6 months after treatment with doxycycline, so the safety of simultaneous treatment is not known. Treating with ivermectin one week prior to starting doxycycline would be reasonable. As doxycycline does not result in the rapid death of the parasites and as most of the mild side effects of ivermectin treatment are thought to be related to rapid release of Wolbachia antigens, the side effect profile of the medication when used for the treatment of onchocerciasis does not appear to be different than that of its use for other indications. There are limited data to suggest that treatment of onchocerciasis with doxycycline in patients co-infected with Loa loa is safe, but this is limited to one randomized controlled trial where only people with Loa microfilarial loads < 8,000 per mL were treated and one community-based study of doxycycline treatment in co-endemic areas in which Loa microfilarial loads were not determined. Older treatments for onchocerchiasis, such as suramin and diethylcarbamazine should not be used. Suramin has multiple systemic toxicities that limit its use in the presence of other less toxic and effective therapies. Diethylcarbamazine accelerates the development of onchocercal blindness. Doxycycline is not standard therapy, but several studies support its use and safety. Treatment with ivermectin should be given one week prior to treatment with doxycycline in order to provide symptom relief to the patient. If the patient cannot tolerate 200 mg PO daily of doxycycline, 100mg PO daily is sufficient to sterilize female Onchocerca. Oral ivermectin is available for human use in the United States. Note on treatment in patients co-infected with Loa loa: Patients with Loa loa co-infection should not be treated for onchocerciasis without consulting an expert on loaiasis due to the risk of a fatal encephalitic reaction to ivermectin. Treatment of co-infected people with doxycycline has only been studied in persons with Loa counts of <8000 microfilariae per mL.