ESCMID Online Lecture Library © by Author ESCMID Online Lecture Library Filaria and Filariasis

Benznidazol Nifurtimox

Free radical formation upon metabolism Nifurtimox also for West African trypanosiomiasis (CNS stage)

© by author ESCMID Online Lecture Library Aldert Bart & Tom van Gool © by author ESCMID Online Lecture Library Case history 34-year old Nigerian male Applicant for asylum, arrival in Netherlands: sept 2009 No medical history Former occupation: farmer

Since 5 years: “Pepperish body” Worm-like movements in throat and stomach Itching skin, varying in duration and location

Additional information:© by author No unprotected sex (never tested for HIV) ESCMIDNo movements Online in his eye Lecture Library No skin lesions No intoxications Stable weight Physical examination No abnormalities, notably: No lymfadenitis No scrotal abnormalities No skin lesions

Additional tests Initial laboratory tests: all normal, notably: Haemoglobin 9.2 mmol/l, WBC 4.2 x 109/l, normal differentiation (no eosinophilia) Negative serology© for: byHIV, authorschistosomiasis and strongyloides QBC: no trypanosomiasis, but… ESCMID Online Lecture Library © by author ESCMID Online Lecture Library Filaria and filariasis

heterogeneous group of nematodes (draadwormen) blood/tissue parasites vector borne transmission imported disease spectrum of diseases (eosinophilia!) serological cross© reactions by author ESCMID Online Lecture Library Filaria

macrofilaria: adult worms, male or female take 1-2 year to develop, live up to >15 years 2-7 cm (Loa loa) to 50 cm (Onchocerca volvulus) in lymphatic system, subcutaneous, deep connective tissues or body cavities; may migrate microfilaria: larvae up to 1 year in host In blood, skin, urine,© lungs; by migrate author develop in vector (1-2 weeks) in infectious larvae ESCMID Online Lecture Library PERIODICITY nocturnal periodicity: largest number of microfilaria in the peripheral circulation occurs at night between 9 p.m. and 2 a.m. (W. bancrofti). diurnal periodicity: largest number of microfilaria found during daytime (Loa loa). aperiodic: (Mansonella perstans ). subperiodic or nocturnally subperiodic: microfilaria can be detected© by during author the day but at higher levels during late afternoon or at night (W. bancrofti, pacific region). ESCMID Online Lecture Library The basis of periodicity is unknown and when they are not in the peripheral blood, they are primarily in capillaries and blood vessels of the lungs. • Lymphatic filariasis – Wuchereria bancrofti – Brugia malayi – Brugia timori

• Onchocerciasis (river blindness) – Onchocerca volvulus

• Others: – Loa loa © by author – Mansonella perstans (formerly Dipetalonema perstans) – M. streptocerca ESCMID– M. ozzardi Online Lecture Library

• Zoonoses: Dirofilaria Geographical Site of adult in Parasite Discase caused Vector distribution body Wuchereria lymphatic filariasis Africa, Asia, mosquitos lymphatics bancrofti (Bancroftian) South America, Pacific lymphatic filariasis Brugia malayi Asia mosquitos lymphatics (Malayan) loaiasis Calabar Central and West Loa loa Chrysops subcutaneous swelling Africa Onchocerca Onchocerciasis Africa and Central Simulium subcutaneous volvulus 'river blindness' America Tetrapetalonema Central and West abdominal or pleural none Culicoides perstans Africa, South America mesenteries Tetrapetalonema none West Africa Culicoides subcutaneous streptocerca Mansonella abdominal or pleural none South America Culicoides ozzardi © by author mesenteries

The microfilariae of each species of filarial worms differ, and examination of microfilariaeESCMID is necessary Online to confirm the Lecture presence and identity Library of a particular parasitic infection. Genus and species of Geographic Location of Size in µm Sheath Head Tail Periodicity Vector Symptoms adult location distribution microfilaria length width Tropis and 1 subtropics Blood + Wuchereria bancrofti Tapered to point; Nocturnal, lymphatics Worldwide 230 - 300 7,5-10 Short no nuclei in end subperiodic Mosquitoes elephantiasis Tapered; terminal Southeast Asia, Brugia malayi Blood and subterminal Nocturnal, 2 West Pacific + lymphatics 170 - 260 5-6 Prolonged nuclei subperiodic Mosquitoes elephantiasis Tapered; nuclei West and Central Loa loa Blood irregularly spaced calabar swellings 3 Africa + subcutaneous 250 - 300 6-8 Short to end Diurnal Deer fly African eye worm Central and South Mansonella perstans America Tapered, bluntly Blood 4 body cavities, mesentery, - rounded; nuclei to Africa perirenal 150 - 210 4-5 Rounded end None Midge asymptomatic

Mansonella ozzardi Central and South America, Blood 5 subcutaneous, possible - Long, slender tail; Carribean body cavity 175 - 240 3-5 Rounded no nuclei to end None Midge asymptomatic Central and South © by author river blindness America onchodermatitis Skin 6 Onchocerca volvulus - Short, Tapered to point; None or femoral lymph Africa subcutaneous 250 - 300 5-9 rounded no nuclei in end minimal Black fly nodes

Tapered, bluntly West and Central Mansonella Skin rounded; nuclei to 7 Africa - streptocercaESCMID Online LectureRounded, end of tail. TailLibrary bent non pathogenic subcutaneous 150 - 240 2,5-3,5 slender in hook shape None Midge slight itching rash Lymphatic filariasis: elephantiasis

1.3 billion people at risk (20% world population)

30% India, 30% Africa, remainder Asia, Pacific, Americas

Bangladesh, Congo, India, Indonesia, Madagascar, Nigeria, Philippines most highly - endemic countries

70-120 million persons© infected by author 25ESCMID million genital diseaseOnline (hydrocoele) Lecture Library 15 million lymphoedema/elephantiasis of the leg © by author ESCMID Online Lecture Library Adults in lymphatic system Microfilaria in blood transmission by mosquitoes 78-130 million infected worldwide Wuchereria bancrofti

Brugia malayi © by author

BrugiaESCMID timori Online Lecture Library Distribution of lymphatic filariases

© by author ESCMID Online Lecture Library Adults in lymphatic system Microfilaria in blood transmission by mosquitoes 78 million infected worldwide Wuchereria bancrofti: periodic and non-periodic (islands of Eastern Pacific) Brugia malayi: periodic© by and author non-periodic (West Malaysia, S. Vietnam, Thailand, Philippines) BrugiaESCMID timori: IndonesiaOnline Lecture Library Bancroftian filariasis: I. Distribution and life cycle

maturation (~1 year)

lymph nodes, ~10 testis and days epididymis © by author ESCMID Online Lecture Library Adult male W. bancrofti ~4 cm females ~ 8–10 cm long © by author

OnESCMID maturation, the Online infective larvaeLecture copulate Library and the adult filariae become localised in lymph glands (e.g. in the groin). © by author ESCMID Online Lecture Library

Mosquito vectors: Culex, Mansonia, Aedes © by author ESCMID Online Lecture Library - Symptomless mf+ carriers - Amicrofilaremic patients adult (including - Lymphangitis endosymbiont Wolbachia) - Lymphadenopathy cause of disease through - Lymphadenitis inflammatory response © by author methylene-blue staining of Wolbachia endobacteria. (A, C). Wolbachia are ESCMID Online Lecture Libraryessential for growth, development, embryogenesis and survival of O. volvulus and lymphatic filaria - Symptomless mf+ carriers - Amicrofilaremic patients adult (including - Lymphangitis endosymbiont Wolbachia) - Lymphadenopathy cause of disease through - Lymphadenitis inflammatory response - Chronic Manifestations© by author in endemic areas : Hydrocoele ESCMIDOrchi-epididymitis Online Lecture Library Elephantiasis teenager from an Early elephantiasis due eastern Indian village Elephantiasis of the leg to Brugia malayi suffering from filarial and scrotum due to hydrocele. Wuchereria bancrofti in © by author Tahiti: requires radical surgery to remove the surplus tissue. ESCMID Online Lecture Library

Severe socio-economic consequences of lymphatic filariasis: shunning, decreased income, … Elephantiasis of the scrotum © by author

Urine containing lymph ESCMIDThe dilated lymph Online vessels rupture Lecture and Library discharge chyle into the urinary tract, thus producing the milky appearance known as chyluria. Control: mass drug administration

© by author ESCMID Online Lecture Library 1. ONCHOCERCIASIS Onchocerca volvulus Transmitted by Simulium (fly) Adults in nodules, microfilaria in the dermis: tropical Africa (99%), South America, Yemen. Symptomatology Symptomless but© mf+ by author Cutaneous lesions: nodules or onchocercoma, pruritis, dermatitis with lichenification, lizard or elephant skin ESCMIDOcular lesions: Online blindness Lecture Library © by author ESCMID Online Lecture Library

Geographical map of Onchocerca volvulus mainly a disease of riverine country © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library

Simulium or buffalo-fly with a humped back (larval stages in fast running water) © by author ESCMID Online Lecture Library

Onchocercal scabies © by author ESCMID Online Lecture Library

Subcutaneous nodule predominantely in the lower part of the body in Africa Macroscopic section of nodule

© by author ESCMID Online Lecture Library - 2. LOASIS Loa loa Transmission by Chrysops sp. Adults migrate, microfilaria in blood only in Central and West African rain forest. Symptomatology: Asymptomatic mf+ carriers Transient Calabar swellings© by author Almost constant pruritis Migration of adult under the skin and the conjunctiva Neurological,ESCMID cardiac Online and renalLecture complications Library © by author ESCMID Online Lecture Library

Geographical map of Loa loa from the Gulf of Guinea in the west of the Great Lakes east © by author ESCMID Online Lecture Library Loa loa cycle

Tabanid or deerfly or mango fly: Chrysops sp. in rain forests in west and central Africa © by author author by © feeding: very painful due bite the ton laceration stylet

Chrysops ESCMID Online Lecture Library Library Lecture Online ESCMID © by author ESCMID Online Lecture Library

Calabar swelling of the cheek lasts about 3 days: 12-13 million infected in Africa © by author ESCMID Online Lecture Library

Calabar swelling of the hands; marked associated Eo (60-90%) Loa loa infection

ESCMIDAdult Loa crossing Online the eye Lecture beneath the Libraryconjunctiva. The worms move at a speed of about 1 cm per minute. © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library

Adult Loa loa migrating under the skin 3. Mansonella streptocerca Transmission by Culicoides Africa : Ghana, Zaïre, Congo Often asymptomatic, can cause skin manifestations, including pruritus, papular eruptions and pigmentation changes. © by author ESCMID Online Lecture Library 4. Dracunculiasis (aka Guinea Worm Disease) Dracunculus medinensis Transmitted by cyclops mainly Africa (Sudan). Symptomatology Urticaria, blister on the ankles, knee joints, hands, buttocks, scrotum and emergence of the adult © by author Encystment, calcifications, radiological images ESCMIDEncystment, Onlineabcess, arthritis Lecture Library © by author ESCMID Online Lecture Library

Copepod (NL: watervlo) Intermediate host: Cyclops (transmission by drinking water containing infected copepods) © by author ESCMID Online Lecture Library

Guinea worm: radiological appearance © by author ESCMID Online Lecture Library

Guinea worm: adult under the skin © by author ESCMID Online Lecture Library

Larvae of Dracunculus medinensis © by author ESCMID Online Lecture Library Mansonella perstans: Africa, Latin America.

Mansonella ozzardi: Latin America

Blood Mf: Culicoides© by author (biting gnat) ESCMID Online Lecture Library Diagnosis

Phase of invasion: Eo 30 to 60%

Adult stage:© by Eo author rarely elevated ESCMID Online Lecture Library Blood - Diurnal or nocturnal periodicity: finger prick - Venous blood Microscopic detection of mf - Direct wet smears - Thin and thick blood smears (numeration of mf in loiasis) ; mf often at outer edges of film. - Concentration techniques:© by Knott,author saponine treatment, le ucoconcentration - Membrane filtration technique (read when wet) - ESCMIDQBC method (fluorescentOnline microscope)Lecture Library Urine: W. bancrofti (chyle), O. volvulus (after Tt), - Mf normally in blood (hematuria due to bilharziases) : L. loa, M. perstans, O. volvulus. Hydrocoele fluid Lymphatic filariasis, Loa, Onchocerca CSF Tuberculous meningitis, alteration of the meningeal barrier© (Loaby )author Eye Biomicroscope:ESCMID Online O. volvulus Lecture Library Identification : Coloration: Giemsa, RAL555, Delafield’s Hematoxylin

Counting of mf :

N°of mf/20mm3© (WHO) by author Calibration in thick blood smear ESCMIDCounting after Online dilution Lecture (Loa loa )Library © by author ESCMID Online Lecture Library

Sheathed Mf : Wuchereria bancrofti: distinct nuclei, graceful curves, no terminal nuclei © by author author by © , 2 terminal, nuclei and presence a of sheath

Mf Brugia malayi ESCMID Online Lecture Library Library Lecture Online ESCMID © by author ESCMID Online Lecture Library

Mf: Mansonella perstans (absence of sheath, knob like tail) © by author ESCMID Online Lecture Library

Mf: Loa loa (sheath not colored with Giemsa but with hematoxylin, terminal nucleus) © by author ESCMID Online Lecture Library

Mf Loa loa: note the sheath colored with hematoxylin and the terminal nucleus O. volvulus, M. streptocerca

- Skin snip (scleral punch tool of choice).

- Scarification of the dermis with a vaccino- style: method of Hooge (1st drop rich with mf). © by author - Slit-lamp examination of the eye to detect ESCMIDand visualize Online mf in the Lecture anterior chamberLibrary of the eye . Onchocerciasis: Diagnosis: skin snip

shoulders

hips

Small snips of skin are removed with scalpel or razor blade ESCMIDand placed inOnline saline at 37°C. Lecture After 4h and Library 24 hours, saline is investigated by microscopy. Onchocerciasis: II. Diagnosis

Actively moving microfilariae emerge from the skin ESCMIDand can Online be seen under Lecture a stereoscopic microscope. Library More than 50 microfilariae in a snip means that a person is heavily infected, and more than 15 seen in a snip taken from near the eye means that the person is in danger of later becoming blind. © by author ESCMID Online Lecture Library

Mf: Onchocerca volvulus (unsheathed) 1. Onchocerciases: nodules. 2. Lymphatic filariasis: accidental finding in lymph nodes. 3. Dracunculosis: adult under the skin, ectopic migrations. 4. Loasis: adult under the conjunctiva or the skin. © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library

Adulte female of Dracunculus medinensis -Detection of circulating filarial antigen (CFA) Immunochromatographic test (ICT) Binax, USA: specific for W. bancrofti: sensitive, easy of performance (10min), daytime application but expensive. Oncho-dipstick: urine and tears. Og4C3 ELISA for W. bancrofti (TroBio Pty, Australia): us ing monoclonal Abs, very sensitive. © by author ESCMID Online Lecture Library Detection of anti-filarial antibodies: o ELISA Bordier: (cross)reacts with all filaria o Immunofluorescence o Precipitation techniques o Luciferase immunoprecipitation assay (Loa and Onchocerca©) being by author developed at NIH o Cross reactions between filariae and other helminths oESCMIDSometimes absenceOnline of Lecture Abs whereas Library mf present Treatment 2 important drugs: DEC and ivermectin may used in combination with albendazole.

Albendazol: macrofilaricidal

DEC: mainly microfilaricidal, kills some of the adults 1-12 days orally, drug of choice for Wuchereria, Brugia, Loa loa risk of side effects Caution is needed with© bypatients author who may also have onchocerciasis and loiasis. DEC can worsen onchocercal eye disease and can cause serious adverse reactions in ESCMIDpatients with loiasis. Online These Lectureinclude fever, Library headache, rash, oedema in heavily infected (Mazzotti), encephalopathy and death. The risk and severity of the adverse reactions are related to Loa loa microfilarial density. Treatment (continued)

Ivermectin: microfilaricidal (and partly affecting adult female)

Adverse effects are mild and non-ocular, therefore drug of choice for onchocerciasis. Risk of serious adverse reaction in patients with high Loaloa infection.

Wolbachia endobacteria essential for fertility of O. volvulus and probably also survival Wolbachia related to severity© by of author symptoms Treatment Wolbachia with doxycycline for 6 weeks completeESCMID depletion Online Wolbachia Lecture for 11 months Library and inhibition of embryogenesis in female worms, possibly permanent.

Shorter / alternative therapy now searched for. © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library Back to our patient

Since 5 years: “Pepperish body” Worm-like movements in throat and stomach Itching skin, varying in duration and location

QBC: no trypanosomiasis, but…. Quantitative buffy coat: microfilariae Saponine concentration: loa loa 40 parasites/ml blood

Quantitative buffy coat: microfilariae Saponine concentration: loa loa 40 parasites/ml blood Ophtalmologic investigation: no parasites in anterior eye chamber Rule out Onchocerciasis co-infection higher risk of anaphylactic reaction (massive death microfilariae) Skin snips: no microfilariae© by author Treatment Determine parasite load (risk anaphylaxis upon treatment) ESCMIDStandard treatment: Online diethylcarbamazepine, Lecture 21 days.Library First 3 days: add prednisone (to prevent anaphylactic reaction)