ESCMID Online Lecture Library © by Author

Library TOXOCARIASIS IN PATIENTSLecture WITH SKIN DISORDERS author Carmen-MichaelaOnlineby Cretu “Carol Davila” University© of Medicine and Pharmacy Colentina Teaching Hospital Eco-Para-Diagnosis Bucharest - Romania ESCMID 21st ECCMID 27th ICC Milan, 7-11 May 2011 LARVA MIGRANS SYNDROME

LM Syndrome – migration of some nematode larvae,Library through the tissues of parathenic host, after invading the host either by digestive (ingestion of infective eggs), or subcutaneous penetration of the larvae. Lecture(Schantz şi Michelson, 1992) LMV est une migration prolongée et la longue persistance de larves de parasite, habituellement un nématode,author dans les organes internes d’une hôte anormale (paratenique). Onlineby (Petithory et al. 1994) © VLM - Toxocara canis - Spirometra spp. - Toxocara catii Etiology - Toxocara vitulorum ESCMID- Balysascaris spp. - Parascaris equorum - Gnathostoma spp. - Ascaris suum Morphology

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Lecture author Toxocara adults - dog Onlineby ©

ESCMID EM – Toxocara larvae Toxocara egg Life cycle

Eggs need soil development The diseaseLibrary is due to the larval stage in human tissues

Larvae are trapped in tissue granuloma during the migratory Lecturestage The life cycle remains unaccomplished, larvae wondering, authorand then remaining in tissues

Onlineby The pathology is due to the © antigenic stimulation produced by the migrating larvae and tissue granulomtous reaction

!! Congenitally transmission of ESCMID Toxocara larvae in dogs (puppies ar an important source of infection) Transmission

¾ Accidental ingestion of fertilized egg (vegetables,Library dirty hands, etc…)

(L T Glickman and J-F Magnaval, 1993. Zoonotic roundworm infections. Inf Dis Clin North America. 7(3): 717-731) ¾ Consumption of raw chicken liver, Lecturecattle meat, or rabbit giblets

(K Nakagura et al: 1989 Toxocariasis possible caused by ingesting raw chicken. J Infect Dis 160: 735- 736) author (D Sturchler et al: 1990 TransmissionOnlineby of toxocariasis. J Infect Dis 162: 571) (Espana et al: 1993. Secondary urti©caria due to toxocariasis: possibly caused by ingesting raw cattle meat. J Invest Allergol Clin Immunol. 3(1): 51-52)

(Y Morimatsu et al. 2006. A familial case of Visceral larva Migrans after ingestion of raw chicken liver: appearance of specific antibodies in BAL of the patients.ESCMID Am J Trop Med Hyg. 75(2):303-396) Toxocariasis epidemiology

Adult dog Library • Transplacentar transmission Puppies • Eggs in stool, by 2 weeks of age Environment Home Parks • Eggs in soil Lecture• Risk factors for zoonotic transmission -Pica Human - Puppy exposure infection author- Poor hygiene Larval migration through liver and lungs Onlineby © Epilepsy (?) Subclinical infection OLM VLM Asthma (?) Covert toxocariasis Neuropsichologic ( +/- eosinophilia)ESCMID (Glickman, 1993) Risk factors for VLM and OLM

Host associated risks EnvironmentalLibrary risks Visceral Larva Migrans

z Lower socio-economic status z Children z RuralLecture residence z Black race> white z Contact with puppies at home, z Pica/geophagy or with soil contaminated with T. canisauthor eggs Onlinezby Consumption of raw liver © Ocular Larva Migrans

z Contact with puppies at home, z Children ESCMID or with soil contaminated with z Pica/geophagia T. canis eggs (Glickman, 1993) Library

Lecture author Onlineby ©

ESCMID Patients With Toxocariasis Considering the Risk Factors (200 cases)Library

PROFESSIONAL PICA ALIMENTARY 2.7% UNKNOWN 4.6% 2.7% 23.6% Lecture author Onlineby © ANIMAL CONTACT 66.4% ESCMID (Creţu et al. 2002) “Urbanization” ?

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Lecture author Onlineby ©

ESCMID Toxocara Serology in Blood Donors (85 persons)Library

65.9% 80 Percentage 60 Lecture25.9 40 3.5% 4.7% 20 author 0 Serology E by IV Online IVE BTFUL GAT U© NE DO POSIT POSITIVE AK WE (Cretu et al. 2002)

About 2% oh the healthy people tested in UK had positive serology ESCMID (Rook & Straughton, Dermatologica, 1972) …Seropervelence 8,2% in psychiatric patients (Huminer et al, 1992) Soil samples examined for parasites eggs (200 samples)Library

50.00% 38.20% 45.00% 47.10% 40.00% 35.00% 24.50% 30.00% 20.60% 25.00% Lecture 20.00% 11.80% 15.00% Percentage 10.00% author 5.00% 0.00% Onlineby 37.50% s s p . le ra e p p p iu id p m h o s s ess a ic ic s Parasites eggs c s r cu ra b c a 37.50% e s tr m o ©oc v u c ' ac ti ri o x s a iu . l n g h i To e c A ch d N ri E Dog n T u ro 25% yg la P s u o du ar 0% 10% 20% 30% 40% z ESCMID Ha (Creţu et al. 2002) Clinical Aspects in Toxocariasis (200 cases) 120 Library No. of patients 62,7% 100

80 109 Lecture 60 According to: 11,8% author 14,6% - Parasitic burden 40 10,9% -Larval distribution Onlineby 20 22 - Repetition of infection ©16 9 0 29 - Host background 2 13 - Host immune response M VL LM Clinical forms O CT cs ESCMID ati Children Adults m pto ym (Cretu, 1998) As VLM - Clinical signs and symptoms

Percentage of patients Signs Harrison- Huntley Taylor LibraryGillespie Creţu Symptoms Snyder

Pica 100 90 - 10 4,6 Fever 55 80 33 39 10 Cough 20 80 Lecture68 46 51,8 Wheezing 20 63 51 28 38 Failure to thrive - 39 author- 4 - Anaemia 40 - - 4 38,2 Asymptomatic 0 0 - 12 9,1 Male 75 Online66by - 60 64,5 Eosinophilia 100 ©100 - 77 82,7 Hepatomegaly 85 65 26 15 16,4 Splenomegaly 40 - 8 11 12 Limphadenopaty - 8 62 21 17,3 Bronchospasm - 43 - 17 10 Skin lesions ESCMID- 22 5 5 69,1 Abdominal pain 0 0 63 32 16,4 (Gilespie 1993, Creţu 1998) VLM - Clinical and Biological Signs Clinical signs % Biological signs % Library Adults Child Adults Child E&K Creţu ren ren

Hepatomegaly 79 47 13,8 31,3 Hypereosinophilia 100 82,7 Respiratory 72 42 46,8 81,3 Hyperleucocitosis 84 45,5 Fever 69 71 3,2 50LectureHipergamaglobulinemia 82 51,4 Malnourish 46 36 - - Heterophyle antibodies 74 - Digestive 44 60 11,7 43,8 ELISA toxocara pozitiv 68 100 Splenomegaly 35 18 8,8 15 authorIsohemaglutinines 67 - Anorexia 31 30 - - Anemia 63 38,2 Pale 29 12 Online- by- Hypoalbuminemie 62 29,2 Skin signs 23 29 69,1© 68,8 Liver biopsy - larve 37 2 Lymphadenopathy 21 19 10,6 56,3 Hyper GGT - 78,1 Oedema 13 5 - - ESR - 75,5 Heart 11 10 4,3 - FG - 55,5 CNS 36 33 4,3 18,8 CRP - 51,8 Asthenia ESCMID38 63 - - LDH - 56,3 (Erhard şi Kernbaum, 1979; Creţu 1998) COVERT TOXOCARIASIS Clinical and Biological Signs

Clinical signs BiologyLibrary

9Asthenia 74% ELISA E/S positive 100% 9Allergic reactions Specific Ig E 78% - cutaneous 60% IncreaseLecture total Ig E 69% - neurologic (headache) 47% Hypereosinophilia 59% -lung+ URT 24% High ESR 36% -ocular 12% Hyperauthor GGT 31% (conjunctivitis) Onlineby Hiper Total Ig M 25% 9Digestive desorders 48%© Hiper Total Ig A 20% Hepatomegaly 5% Hiper Total Ig G 11%

ESCMID (Magnaval, 1989) Clinical Signs in Toxocariasis (200 patients) Library

No. patients 138 104

140 Lecture 120 100 33 35 33 author33 33 80 15 22 60 7 5 107 Stage 40 Onlineby 70 40 20 4 0 5 5© 9 2 27 33 Onset 0

s y y c s r y i S l i r e e r us it th N a t la iv n e o o d C g a u t g v t r pa e m c s i e a ne a o m u O e S F r a c n o e ig l pi t o e n h D a s u y d le R r e C M A p ne R os e ESCMIDt G pa e H (Creţu, 1998) Clinical Aspects in Children and Adults at the Onset Library

No patients

120 Lecture 100 118 80 80 35author 60 5 18 20 24 13 7 7 18 22 Ad 40 Onlineby ul 15 16 t 20 20 24 13 7 9 4 0 5 0 2 © C h 0 ildr s y r y e l ly ic is ic r en u r e h iv ra a t t S t a o a v t t e g a i a ul ne on a s n rd CN m a Fe op e me m a o t lm n ig Ge o eu c t Oc u e D n h io Cu P d le R mp A p M si s A to ESCMID a ep H (Creţu, 1998) Diagnosis Library 9 Epidemiology and Risk factors 9 Clinical symptoms/signs 9 Laboratory: positive ElISA E/SLecture antigens Avidity tests and WB WBC and Eo level,author RBC Total and specific IgE InflamatoryOnline biologicalby syndrome (CRP, ESR,Fg Liver and muscle© enzymes Gamma GT ECP 9 Pathology:ESCMID eosinophylic granuloma 9 Imagery: X Ray, US, CT Hipereosinophilia in Toxocariasis Library > 30% Eo <3% Eo 9% 17% Lecture author Onlineby 4-10% Eo © 12% 11-30% Eo 62% ESCMID (Creţu, 1998) Correlation of Hypereosinophilia With Clinical Manifestations Library

No.of 40 cases 35 30 19,8% 24,2% 25 Lecture 20 16,1% 9,9% 15 8,8% 12,1% 10 5,5% author 13,2 % 5 1,1% 16 3,3% 5,5% 33 0 2 9 15 5 by 27 40 Online9 M s 20 22 L c O r ve © Fe CNS gy syptomati lo A o aly t g a Rheumatics a gi Mycarditis ome erm n D Digestive Myal - monary Clinical ia ul atosple P ep sten manifestations ESCMID H A (Creţu, 1998) Skin disorders in VLM Library 9…22% of the patients with Toxocariasis presented skin lessions (Huntley et al. Pediatrics 1965, 36(4), 523 – 536)

9 .. 24% out of the patients with toxocariasis present cutaneous reactions (Erhard and Kernbaum,Lecture 1979, 77, 225-287 )

9…7-12% out of 221 patients with VLMauthor presented skin disorders -rash, eczema, urticaria (Taylor et al, The Lancet , 1988, March, 692-694) Onlineby 9 …20% of the patients with VLM© presented allergic reactions (Scaglia et al. 1989, 82, 410-421)

9 …64,7% out of patients with urticaria presented anti Toxocara antibodies, while 21 % in controle (Volfrom et al. Ann Dermatol Venerol,ESCMID 1996, 123:140-46) Skin disorders associated to VLM Library z Pruritus z Urticaria z Angioedema z Acute or chronic prurigo z Eczema Lecture z Atopic dermatitis z Dermographism z Acneea author z Skin rash z Eosinophilic cellulitisOnline (Wells’by syndrome) z Eosinophilic paniculitis© z Athypical erithema nodosum / hypodermal nodules z Purpura

Rook and Stroughton, 1971; Erhard and Kernbaum, 1979; Glickman et al.1987; Magnaval.ESCMID 1987; Scaglia, 1989; Humbert et al, 1995; hurni et al. 1997; Humbert et al. 2000; Cretu 1998; 2002) Library

Lecture

- Hematology (WBC + Eo and RBC) author - Inflamatory Syndrome Onlineby - Chest X Ray - Liver Function © - Thyroid function - Ex oto-rhyno- laringology - Coprology and serology for parasites - Tests for autoimmune disorders - Hepatitis markers B and C - Tests for malignancies ESCMID -Total IgE - Tests for allergies (digestive, respiratory) Library

Lecture author Onlineby

Pr. J. Sayac ©

ESCMID Library

Lecture author Onlineby ©

ESCMID Toxocariasis in atopic patients Library z “…la toxocarose aurais un effet amplificateur sur les manifestations allergiques des sugets atopiques” (Magnaval et al. 1994, 145, 611- 627) z Antibodies level of Toxocara ES is associated with high total and specific IgE and Eo z Asthma, is associated in 6,5-14% Lectureof cases of toxocariasis and urticaria between 7,2-25% (Magnaval et al. 1993, in Toxocaraauthor and Toxocariasis, Ed. Lewis and Maizels) z “Toxocara as environmental factorby play a role in the induction of allergen specific IgE andOnline promoting allergic diseases” ©(Buijs et al. 1994, A J Epidemiol, 140(9), 839-847 z “Toxocara stimulates allergic reactions, based on hereditary tendency for skewing to type 2 T-helper cell function and longevity of the parasite within the host.“ ESCMID (Buijs et al. 1997, Eur Respir J,, 10, 1467-1475) Library

Lecture author Onlineby ©

ESCMID Library

Lecture author Onlineby ©

ESCMID Urticaria & Angioedema

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Lecture

¾ 48 YO, male, atopic patient, with chronicauthor urticaria ¾ Developed angioedema, without any explanation ¾ WBC 11.000.cmm and EoOnline normal by ¾ Toxocara positive with AI specific© for a recent infection (less than 20 w) ¾ Liver function normal ¾ Muscle enzymes normal ¾ Total IgE increased ¾ Chest X-rayESCMID and abdominal US normal ¾ Tolerance of albendazole very good (Cretu & Berghea, 2010) Urticaria & Angioedema

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Lecture author Onlineby ©

ESCMID (Cretu & Berghea, 2010) Urticaria Library

Lecture author Onlineby ©

ESCMID (Cretu & Berghea, 2010) Library

Lecture -Great proportion of patients with IgG againsauthort Toxocara spp. have urticaria and prurigo

-Half of the patients with urticariaOnline andby TES ELISA were cured after the treatment of the parasites ©

-Non specific pruritic papules of prurigo are considered systemic skin reaction to parasitic antigenic stimulus ESCMID Library

Lecture author - 2% of healthy persons testedOnline for byToxocara are positive -Pruritus, rash, dry skin, dermal© oedema, simulating scleroderma,

followed by skin nodules, with Toxocara test positive and very good

response to DEC treatment ESCMID Skin rash & Prurigo Library

Lecture author Onlineby ©

ESCMID (Cretu & Cristodulo 2010) Library

Lecture author Onlineby

In patients sero-positives for© Toxocariasis, the risk to develop chronic urticaria is 6.9 times higher than in sero-negative patients

ESCMID 37 yo, Male constant dog contact Library z Urticaria z Dermal oedema z Pruritus Lecture z Fever z Thoracic pain author z WBC 9600/cmm Onlineby z Blood Eo normal © z ELISA ES Toxocara positive ESCMID Eo Pleurisy Library

Lecture author Onlineby II 2000 © IV 2000 WBC 6 800 – Eo 3% WBC 9 600 – Eo 2.9% ⇒ ABZ 14 days ⇒ ELISA Toxocara – Pleural fluid - Eo 25 % 2 courses ELISA ToxocaraESCMID positve negative Chest X ray -Pleurisy Chest X ray – sequels Eczema and VLM Library z Boy, 6 YO, rural residence z WBC 34 600/cmm z Animal contact (dogs, cats) z Eo 74,4% z Height and wait under limits z Total IgE 7788gIU/ml z Fever (38-390 C) zLectureCRP 9,10/mg/l z Dry cough, dispnoea z ESR 120mm/1 hour z Pruritus z Stool examination negative z Vesicular eruption z Ova/larvaeauthor parasites z Plantar edema z Liver function normal z Arthralgia Onlinebyz LDH, CK, CKMB increased z Nausea, vomiting © z HIV negative z Hepato-splenomegaly z Chest X Ray – interstitial pneumonia z Ocular ex normal z Toxocara IgG positive with low AI ESCMID Dishydrotic eczema Library

Lecture author Onlineby ©

ESCMID Imaging Library

Non homogenous HSM recent infection Lecture author Onlineby ©

ESCMID Prurigo

Library

Papular type ESCMID Eczema-like prurigo (Cretu & Popescu 2010) Skin Rash Dermographysm Library

ESCMID (Cretu & Popescu 2010) T.M., 29 YO, Vrancea county Dg. Chronic Prurigo Lung Toxocariasis December 1999 Library Abrupt onset: dry cough, fever, dyspnoea, pruritus Lecture DEC Dg. Acute diffuse Interstitial pneumonia author Respiratory flow reduced by 38% II 2000 XI 2000 WBC 19 6000, Eo normal Onlineby -WBC 6200 - Eo 9% NL 4300 – Eo 2 % ⇒ Antibiotics -BAL Eo 24.5% © ELISA ⇒ pruritus and skin lesions -ELISA Toxocara – Toxocara ⇒ corticosteroids Positive negativ New episode after coming home February 2000ESCMID – Inst Pneumology Cured Ex. BAL P. carinii -negativ DG: Chronic Prurigo Lung Toxocariasis Library

ESCMID (Cretu & Popescu 2010) Concomitant OLM & VLM 3 YO girl, Bacau County

• Atopic dermatitis ⇒ acute urticaria Library • Epigastric pain • Red eye • Photophobia • Decreased and blurred vision Lecture • Leucochoria • Fundus ex. Retinal granuloma • VBC 12.400/cmm - Eo 17% author Corticosteroids: localOnline systemicby • Liver function normal • Chest X ray normal © • Abdominal US non-homogenous HSM • Stool ex for parasites – negative • ELISA Toxocara negative •ToxoplasmaESCMID IgM & IgG – negative • WB positive for Toxocara 35 KDa 24 KDa Concomitant OLM & VLM

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OLM – US- retinal VLM – non homogenous liver, with detachment due to posterior hyperechoicESCMID areas corresponding granuloma and vitreal to Eo granulomas (old lessions) reaction associated OCULAR LARVA MIGRANS

Erhard & Molk Shields Ristea & Kernbaum (1983) (1984)Library Creţu (1979) (2000) Cr. endophtalmitis Cr. endophthalmitis Posterioar Mobile larvae Peripheral + retinochoroiditis Acute granuloma Retinal detachment Peripheral endophthalmitis Posterior Posterior granulomaLectureretinochoroiditis Chronic granuloma Peripheral granuloma Papillitis endophthalmitis Other forms authorEndophthalmitis Anterior chronic - hemorrages Pars-planitis Mobile larvae in uveitis -larvae Optic NeuritisOnlineby retinal layer Posterior embolization Keratitis © Unilateral granuloma - papilitis Uveitis-iritis diffuse -hyalitis Hypopion sub acute - iridocyclitis Mobile Larvae in neuroretinitis - cataract ESCMIDvitros cavity Keratitis - cheratitis Conjunctivitis - orbital lesions Lens opacities OCULAR TOXOCARIASIS RETINAL GRANULOMA Library

Lecture author Onlineby Fundus examination Fundus examination Active lesion © Sequels (Ristea and Creţu, 2000) (Ristea and Creţ u, 2000)

ESCMID

(Cretu & Vintila 2007) OCULAR TOXOCARIASIS Library

Lecture author Fundus examination Fundus examination Onlineby Vitreal reaction Mobile larvae © (Ristea and Cre ţu, (Ristea and Cre ţu, 2000) 2000) ESCMID Total uveitis (Ristea and Creţu, 2000) Toxocariasis – Infection Or Disease ?

INFECTION DISEASELibrary 9 Various and different intensity clinical signs 9 Asymptomatic considered as VLM, OLM 9 Hazardous discovered of Lectureor CT hipereosinophilia 9 Can induce differential 9 Specification of diagnosis authordiagnosis as they cam mimic neurological, heart, 9 Epidemiological studies to dermatological, detect toxocartiasisOnline by respiratory disturbances, prevalence © etc… !! TREATAMENT – NOT NECESSARY !! NECESSARY TREATMENT Taylor et al, 1987, 1988 Beaver et al, 1952 Magnaval,ESCMID 1994 Glickman and Shantz, 1981, 1987 Bass et al, 1987 Taylor et al, 1987 TREATMENT Library ¾ Specific medication

- Diethilcarbamazine - Albendazole Lecture - Ivermectine author - Flubendazole Onlineby -Thiabendazole© ¾ Antiallergic medication ¾ Steroid and non-steroid anti-inflammatory ESCMID medication

O DIETHYLCARBAMAZINE C H 2 5 N N H3C C N C H (DEC) 2 5 Action Library • Piperazine derivate, very efficient on mf. Toxocara larvae • Decrease the muscular activity and block of the organism by the hiperpolarisation effect of the medication • Changes on the parasite surface Lecturemembrane which become vulnerable to the host defense mechanisms • Inhibition of the prostaglandine productionauthor • Increase the neutrophilsOnline and eosinophilsby citotoxicity Side effects © • Transitory hiperleucocitosis şi hipereozinophilia • Transitory anorexia, nausea,headache Posology: BANOCIDEESCMID®, HETRAZAN ®, NOTEZINE® 3-4 mg/kg/day – 21 days // 6 mg/kg/day – 8-21 days N ALBENDAZOLE H7C3 S NH COO CH3 (ABZ) N Action: H • Selective depletion of cytoplasmic tubules at Librarythe digestive epithelium level and parasite cuticle • Decrease glucose intake → glicogen depletion Side effects: • Abdominal pains, headache, nausea,Lecture vomiting, alopecia • Leucopenia, anaemia • Elevated transaminases author • To be avoided in pregnantOnline womanby and children under 12 months © Posology: ZENTEL®, DUADOR ® - 200 mg/tb ESKAZOLE ® - 400 mg/Tb ESCMID 10-15 mg/kg/day, 5-21 days, according to the clinical status and location Clinical score after DEC Treatment Library

Number of 40 2 patients 35 6 30 25 Lecture 8 4 20 5 32 1 15 3 2 author 10 1 1 1 2 3 19 17 16 5 11 8 2 6 5 by 7 4 6 4 0 Online 3 a s a © i es is rs egal Fever Cough isorders ymptom d Pruritus nom ocardit isorde a - Mialgi Arthralgia e enopathi i Wheesing d s i d M S en spl A t o CN eneral As at G Clinical sign s Digestive disordersep Cutaneous H ESCMID (Cretu, 1998) Clinical score after ABZ Treatment Library

40 1

35 3

30 7 2 1 25 Lecture 1 20 10 6 4 author 2 15 1 6 6 1 6 1 2 10 1 Online1 by 15 1 1 4 1 1 11 10 11 5 1 2 © 2 1 1 1 5 1 5 4 3 2 2 2 0 1

a s h s ers itus lgia ers ers m r ialgi oug rd Fever arditi C pto isord M isord Pru rthra diso A Wheesing sym a - Adenopathy Myoc us d ni ve d ral sti CNS ne sthe ige Ge utaneo A D C ESCMID Hepatosplenomegalia (Cretu, 1998) Biologic score after DEC Treatment

Number of 50 3 3 Library 8 45 6 9 patients 7 14 40 15

35 13 4 12 1 2 30 2 3 3 5 7 Lecture 4 25 2 2 5 41 2 6 20 38 36 32 32 author 15 29 28 27 29 25 4 24 6 25 10 Onlineby 19 18 19 11 5 © 9 8

ESCMID Investigation First course Second course Third course (Cretu, 1998) Biologic score after ABZ Treatment

Number of cases Library

7 4 5 40 3 5 3 35 7

7 10 30 2 10 1 6 4 2 Lecture 25 5 5 10 2 20 4 2 1 1 2 2 4 4 15 24 author 1 3 1 1 1 21 3 19 20 2 3 3 18 4 18 10 1 17 2 2 3 2 14 15 Online3 by 4 1 11 5 8 1 8 8 8 6 5 © 4 3 0

o g P l E L F R H s H PK M gG gE IC g gG N C S in PT T e s D C g I I C C I V ob G A in ne L I A gl a- S m li S o m /A u u I m m T lb ob EL e a A A gl H G L a- A m am ESCMID G First course Second course Third course Fourth course More than 4 courses (Cretu, 1998) Library

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