Toxocariasis-associated cardiac diseases—A systematic review of the literature

Accepted Manuscript Title: Toxocariasis-associated cardiac diseases – a systematic review of the literature Author: Esther Kuenzli Andreas Neumayr Matthew Chaney Johannes Blum PII: DOI: Reference:

S0001-706X(15)30151-0 http://dx.doi.org/doi:10.1016/j.actatropica.2015.11.003 ACTROP 3772

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Acta Tropica

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17-6-2015 5-11-2015 7-11-2015

Please cite this article as: Kuenzli, Esther, Neumayr, Andreas, Chaney, Matthew, Blum, Johannes, Toxocariasis-associated cardiac diseases ndash a systematic review of the literature.Acta Tropica http://dx.doi.org/10.1016/j.actatropica.2015.11.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Toxocariasis-associated cardiac diseases – a systematic review of the literature Esther Kuenzli1,2a* [email protected], Andreas Neumayr1b [email protected], Matthew Chaney1b [email protected], Johannes Blum1,3b [email protected] 1

Swiss Tropical and Public Health Institute, Basel, Switzerland

2

Division for Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel,

Switzerland 3

a

University of Basel, Basel, Switzerland

Swiss Tropical and Public Health Institute, Socinstrasse 57, P.O. Box, 4002 Basel, Switzerland &

Division for Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland. b

Swiss Tropical and Public Health Institute, Socinstrasse 57, P.O. Box, 4002 Basel, Switzerland.

*

Corresponding author at: Swiss Tropical and Public Health Institute, Socinstr. 57, 4051 Basel,

Switzerland, Tel.: 0041 61 284 82 55; Fax: 0041 61 284 81 83.

Highlights      

Toxocariasis is a mostly oligo- or asymptomatic infection Toxocariasis may present with unusual complications Diagnosis is based on clinical presentation, eosinophilia and serological findings Toxocara spp. can cause endocarditis, myocarditis and pericarditis Tamponade, endocardial thrombosis or heart failure can complicate cardiac toxocariasis Severe disease may warrant prolonged treatment with albendazole and corticosteroids

Abstract Toxocariasis, caused by Toxocara canis or Toxocara catis, is a worldwide occurring parasitic disease, reaching high prevalences especially in tropical and subtropical countries. The clinical presentation can range from asymptomatic seropositivity to life threatenting disease, depending on the organ system involved. Cardiac involvement, one of the possible manifestations of human Toxocara spp. infection, is rarely reported in case reports. As far as we know, no systematic reviews of clinical presentations have been published till now and no clear recommendations regarding the treatment of Toxocara spp. infection involving the heart exist. In a systematic review of the literature, 24 published cases of Toxocara spp. infection involving the heart were identified. The cardiac entities described included myocarditis, pericarditis, and Loeffler’s endocarditis. The clinical presentation ranged from asymptomatic or mild disease to life threatening myocarditis/pericarditis with heart failure or cardiac tamponade, leading to death. In most cases, the diagnosis was based on a combination of clinical, laboratory and radiological findings. Only in three of the nine cases in which histological analysis was performed (either pre- or post-mortem), granulomas or remnants of the parasite were detected. In the other six cases, findings were nonspecific; the damage of the heart was equally caused by direct invasion of the larvae and by immunological reactions, either caused by the systemic hypereosinophilia or by the presence of the larvae in the tissue. The treatment regimen described mostly consisted of anthelmintic drugs in combination with corticosteroids. Even though dosage and duration of treatment varied widely, ranging from days to months, most patients were treated successfully. Cardiac involvement in Toxocara spp. infection is a rare but potentially life-threatening complication of a very common disease. The therapeutic regimens vary widely especially with regard to the duration of therapy, however the combination of an anthelmintic drug and a corticosteroid appears to be a valuable option. For the daily clinical work, tissue manifestation by parasites should be considered in cases of unspecific organ manifestations, (i.e. heart, lungs, liver), accompanied by fever and eosinophilia with or without allergic skin rashes. Keywords: Toxocara spp.; toxocariasis; visceral larva migrans; cardiac involvment of toxocariasis; treatment of complicated Toxocara spp. infection

Introduction Multiple parasitic infections can cause cardiac disease. In Chagas disease, cardiac manifestations are the primary clinical entity, but for most parasites, including Toxocara spp., extra-cardiac manifestations dominate, and the involvement of the heart is either clinically less frequent or of minor clinical relevance (Blum et al., 2007; Blum et al., 2008; Hidron et al., 2010). Toxocariasis occurs worldwide. The highest prevalence rates are found in tropical and subtropical countries. Children are at highest risk of infection due to their exposure to contaminated environments like sandboxes and playgrounds (Despommier, 2003). Even though prevalence rates of 40% and more have been described (Centers for Disease Control and Prevention, 2013), the real rates might be higher, probably even exceeding other soil-transmitted helminth infections such as ascaris, trichuriasis, or hookworm infection (Hotez et al 2009), which are all considered neglected tropical disease according to the CDC (Centers for Disease Control and Prevention, 2011). Toxocara spp. affects dogs (Toxocara canis) and cats (Toxocara catis), which excrete invective ova in their faeces. Humans swallowing embryonated eggs, - from soil contaminated by the faeces of infected dogs or cats or by consumption of raw or undercooked meat from paratenic hosts - are accidental hosts in whom the parasite cannot complete its life cycle. The eggs hatch and larvae penetrate the intestinal wall in order to enter the circulation. Via the systemic circulation they can reach nearly every organ (liver, brain, lungs, eye, muscle, kidney, heart). In the respective organs, they cause a granulomatous (often eosinophilic) reaction, which inhibits their further migration but causes pathology by tissue destruction. The dormant larvae can stay alive there for many years (Despommier, 2003), with a potential for reactivation and further migration (Pawlowski, 2001). Originally, human toxocariasis was divided into Visceral Larva Migrans (VLM) (Beaver et al., 1952) and Ocular Larva Migrans (OLM) (Wilder, 1950). Symptoms and signs depend on the involved organ. Classical signs and symptoms of VLM include fever, hepatosplenomegaly, abdominal pain, vomiting, diarrhoea, respiratory signs, anorexia, weight loss, fatigue, neurological symptoms (including convulsions/epilepsy, hyperactivity and mental retardation), pallor, and allergic symptoms like urticaria, asthma and Loeffler syndrome (Despommier, 2003; Holland and Smith, 2006). Ocular

toxocariasis may lead to visual impairment or even blindness (Hotez, 1993). More recently, less severe syndromes have been described: covert toxocariasis (Bass et al., 1987; Bass et al., 1983; Taylor et al., 1987; Taylor et al., 1988) and common toxocariasis (Glickman et al., 1987), showing similar but less severe symptoms than VLM. Most seropositive subjects detected in population-based surveys are asymptomatic or only have nonspecific and mild symptoms and usually do not require treatment with anthelmintics (Pawlowski, 2001; Rubinsky-Elefant et al., 2010). In three cohorts of patients with VLM, pulmonary symptoms and findings (19-80%), hepatomegaly (11-50%) and fever (10-80%) dominated, whereas skin eruptions including urticaria (0-22%), neurological findings (0-22%), lymphadenopathy (2.5-8%), diarrhoea, abdominal pain and joint pain were less frequent (<10%). Cardiac involvement occurred in only one patient of these three cohorts with a total of 134 patients (Altcheh et al., 2003; Jacob et al., 1994; Noemi et al., 1984). However, in these studies no examinations were performed to rule out heart involvement. According to estimates based on animal studies, the percentage of heart involvement may reach up to 10-15% (Bolivar-Mejia et al., 2013). This systematic review intends to assess the clinical presentation of cardiac toxocariasis and its complications, the treatment and the outcome. Material and methods To begin with, a literature search was performed in PubMed (Medline) and Embase for case reports and case series, using the search terms (“Toxocara spp.” or “toxocariasis” or “visceral larva migrans” or “larva migrans” or “vlm”) AND (“heart” or “cardiac” or “myocard*” or “pericard*” or “endocard*”). The following languages were considered: English, French, German, Italian, Spanish and Portuguese. No limits regarding publication date were applied. Consecutively, the reference lists of the articles derived through the literature search were screened for additional cases or case series. All articles were reviewed by two of the authors independently and the decision on whether to include an article had to be unanimous. In case of disagreement, a third author was included in the decision.

The case definition for inclusion was based on clinical symptoms in accordance with cardiac disease AND one of the following criteria: A) detection of (i) parasite material or (ii) eosinophilic granuloma in histological sections of cardiac tissue OR (iii) a shared environment with a dog or a cat with a confirmed Toxocara spp. infection or B) cases fulfilling at least 2 of the following 3 criteria: (i) a positive serological titre, (ii) an increase or decrease of the titre during disease or treatment or (iii) eosinophilia (>500/µl). As exclusion criteria we considered (i) case series in which symptoms, clinical findings and treatment could not be attributed to one patient unambiguously and (ii) cases in which a aetiology other than toxocariasis as the cause of the symptoms appeared more likely. Results Twenty-eight articles, reporting cases of Toxocara spp. infection with cardiac involvement were found (Abe et al., 2002; Altcheh et al., 2003; Becroft, 1964; Borlot et al., 2006; Boschetti and Kasznica, 1995; Brill et al., 1953; Dao and Virmani, 1986; De Cock et al., 1998; Dent et al., 1956; Eicher et al., 2009; Enko et al., 2009; Farinha et al., 1997; Files et al., 2009; Friedman and Hervada, 1960; Haralambidou et al., 2005; Herry et al., 1997; Kawano et al., 2011; Kim et al., 2012; Leibetseder, 1981; Lemaire et al., 2013; Matsuki et al., 2007; Prunier et al., 2001; Rayes et al., 1999; Rugiero et al., 1995; Shrestha et al., 2012; Thomas et al., 2000; Traboulsi et al., 2006; Vargo et al., 1977). Seven of them were excluded following the exclusion criteria: Four articles describing case series were excluded from analysis, since it was not possible to clearly attribute history, clinical/paraclinical findings and treatment regimens to individual patients (Altcheh et al., 2003; Farinha et al., 1997; Rugiero et al., 1995; Shrestha et al., 2012). Three articles were excluded, because a different aetiology than Toxocara spp. appeared much more likely: •

A patient with acute lymphatic leukaemia presented with eosinophilia, a positive titre for

Toxocara canis and mitral valve insufficiency due to Loeffler’s endocarditis. Eosinophilia was very

high (33’000/mm3) and most likely due to the haematological disease. The authors interpreted the positive Toxocara canis titre as false positive or at least not causative for the eosinophilia (Files et al., 2009). •

In one case, the appearance of visceral larva migrans was caused by Baylisascaris spp. and not

by Toxocara spp. (Boschetti and Kasznica, 1995). •

In one patient, cardiac symptoms were most likely due to a coronary artery disease with the

detection of Toxocara spp. antibodies as a coincidental finding (Leibetseder, 1981). Twenty-two articles, including a case at our own hospital (unpublished), fulfilled the inclusion criteria. Since one article described 3 patients, 24 cases were selected for analysis (see figure 1). A description of these cases including clinical signs and symptoms, laboratory tests, ECG, sonography, treatment, and response to treatment is summarized in tables 1-3. The collective describes 10 females and 14 males between 15 months and 74 years of age. Ten were children of less than five years of age(Becroft, 1964; Brill et al., 1953; Dao and Virmani, 1986; De Cock et al., 1998; Dent et al., 1956; Friedman and Hervada, 1960; Rayes et al., 1999; Vargo et al., 1977)(Becroft, 1964; Brill et al., 1953; Dao and Virmani, 1986; De Cock et al., 1998; Dent et al., 1956; Friedman and Hervada, 1960; Rayes et al., 1999; Vargo et al., 1977)(Becroft, 1964; Brill et al., 1953; Dao and Virmani, 1986; De Cock et al., 1998; Dent et al., 1956; Friedman and Hervada, 1960; Rayes et al., 1999; Vargo et al., 1977)(Becroft, 1964; Brill et al., 1953; Dao and Virmani, 1986; De Cock et al., 1998; Dent et al., 1956; Friedman and Hervada, 1960; Rayes et al., 1999; Vargo et al., 1977), 13 were adults between the age of 17 and 65 years and one patient was older than 65 years (for references see Table 1). Myocarditis was the most frequent clinical presentation (14/24), followed by pericarditis (6/24) with (3/24) (Borlot et al., 2006; Eicher et al., 2009; Herry et al., 1997)(Borlot et al., 2006; Eicher et al., 2009; Herry et al., 1997)(Borlot et al., 2006; Eicher et al., 2009; Herry et al., 1997)(Borlot et al., 2006; Eicher et al., 2009; Herry et al., 1997)or without (3/24) tamponade, and Loeffler’s endocarditis (4/24). Two of the cases presenting with a myocarditis showed signs of an additional pericarditis. Three cases,

two with Loeffler’s endocarditis and one with pericarditis, showed formation of a thrombus (for references see Table 1). Heart specific examinations such as ECG, chest x-ray, echocardiography and laboratory tests confirmed the expected findings. ECG findings were normal or showed nonspecific abnormalities including peripheral and thoracic low voltage and nonspecific ST-T alterations. The chest x-ray showed cardiomegaly and signs of pulmonary congestion. The findings in echocardiography showed the typical signs either of myocarditis (oedema, wall thickening, hypokinesia and a reduced left ventricle ejection fraction), of pericarditis (pericardial effusion, tamponade) or of endomyocardfibrosis (fibrosis, restrictive cardiopathy) or a combination of the above. In three patients, thrombotic complications were described: two had an intraventricular thrombus, leading to pulmonary emboli in one and to emboli to the leg and bacterial superinfection with septicaemia in the other patient. A third patient presented with thrombotic occlusion of the aorta and the femoral arteries, necessitating aboveknee amputation of one leg due to gangrene. Blood tests such as CK-MB, troponin and BNP were not done on a regular basis. If available, they were usually elevated showing myocardial inflammation/necrosis or congestive heart failure (for references see Tables 1 and 2). Response to treatment Eleven patients received treatment with both, an anti-inflammatory and an anthelmintic drug. Only one of them died and the cause of death was most probably not due to the Toxocara spp. infection but due to fulminant hepatitis contracted through blood transfusions (Dent et al., 1956). Of the other ten patients receiving a combined treatment, none died (Abe et al., 2002; De Cock et al., 1998; Enko et al., 2009; Kim et al., 2012; Lemaire et al., 2013; Matsuki et al., 2007; Prunier et al., 2001; Thomas et al., 2000) + Kuenzli et al.). While some of the patients showed a dramatic improvement after initiation of therapy (Enko et al., 2009; Kim et al., 2012), in two patients a second course of treatment had to be applied (Prunier et al., 2001) + own unpublished case). Similarly, patients receiving only an anthelmintic drug without corticosteroids showed a good outcome (Eicher et al., 2009; Herry et al., 1997; Kawano et al., 2011; Rayes et al., 1999; Traboulsi et al., 2006). Of the three patients receiving only corticosteroids, one died (Becroft, 1964), one required a second course of treatment with

corticosteroids (Friedman and Hervada, 1960), and for one no long term follow up was available (Haralambidou et al., 2005). Of the six patients who received neither anthelmintic treatment nor corticosteroids (Borlot et al., 2006; Brill et al., 1953; Dao and Virmani, 1986; Vargo et al., 1977), one had complete resolution of symptoms after drainage of the pericardial effusion (Borlot et al., 2006), one showed improvement of symptoms (Vargo et al., 1977), three died (Brill et al., 1953; Vargo et al., 1977), and for one no information on the outcome was stated (Dao and Virmani, 1986). Discussion While VLM is usually a mild disease, serious complications can occur. The clinical spectrum of cardiac involvement in Toxocara spp. infections includes myocarditis, pericarditis and Loeffler’s endocarditis and combinations of these, with or without intraventricular thrombus. Based on the available data, myocarditis is the predominant clinical presentation. The severity of the disease ranges from asymptomatic or oligosymptomatic cardiac involvement, detected incidentally in autopsies and histological specimens of patients dying from or being operated for other diseases than toxocariasis (Vargo et al., 1977), to life threatening disease with acute cardiac failure or tamponade (Becroft, 1964; Borlot et al., 2006; Brill et al., 1953; Eicher et al., 2009; Enko et al., 2009; Herry et al., 1997; Vargo et al., 1977). Toxocariasis-associated myocarditis affects all age groups, but children of less than five years of age appear to be more frequently affected (Lee et al., 2014). There is no obvious reason why some of the patients described in this systematic review had severe or even fatal disease. Interestingly, none of the patients described here seem to have had a relevant immunosuppression or tested HIV positive. Common clinical signs and symptoms that were found in this patient collective were chest pain, dyspnoea, and hypotension, corresponding to the usual findings of heart failure and thus completely nonspecific. Since cardiac toxocariasis is a rare, but potentially life threatening disease, the question arises in which situation this disease has to be considered and treated. The presence of signs and symptoms of other organs infected by Toxocara spp., as well as unspecific signs of parasitic infections such as eosinophilia and fever might be a clue to the diagnosis. Abdominal symptoms (abdominal pain, diarrhoea/vomiting) and pulmonary symptoms (pneumonitis, pleural effusion, asthma) occurred in

about one third to one half of patients (Becroft, 1964; Borlot et al., 2006; Brill et al., 1953; Dent et al., 1956; Eicher et al., 2009; Friedman and Hervada, 1960; Haralambidou et al., 2005; Herry et al., 1997; Matsuki et al., 2007; Rayes et al., 1999). Furthermore, fever, generalised fatigue, joint aches, loss of appetite, lymphadenopathy, hepatosplenomegaly, and skin rashes due to allergic reactions were observed (Abe et al., 2002; Borlot et al., 2006; Brill et al., 1953; Dent et al., 1956; Eicher et al., 2009; Friedman and Hervada, 1960; Haralambidou et al., 2005; Lemaire et al., 2013; Rayes et al., 1999; Thomas et al., 2000; Traboulsi et al., 2006). These findings often preceded the cardiac failure. Eosinophilia was present in nearly all patients, with an average of 9612/mm3 (range 329/mm3 to 37’800/mm3). Since the presence of eosinophilia is considered a relevant criterion for the diagnosis of active toxocariasis (Beaver et al., 1952), it was one of the inclusion criteria for selecting case reports for this review. Thus, no conclusions about the incidence of eosinophilia incardiac toxocariasis can be made based on this data. The level of eosinophilia does not necessarily correlate with the severity of cardiac disease: while the patient described by Abe et al. had high eosinophilia of 26’000/mm3 but only mild cardiac dysfunction (Abe et al., 2002), the patient described by Enko et al. had a considerably lower eosinophilic count (1’053/mm3) but suffered from fulminant perimyocarditis with cardiogenic shock (Enko et al., 2009). In most cases, the presence of eosinophilia led to parasitological examinations including serological tests i.e. for Toxocara spp. However, the interpretation of the serological titre, even if positive, is often not conclusive on its own. The seroprevalence of Toxocara spp. in the general population varies in industrialized countries between 0.7% in New Zealand, 1.6% in Japan, 2.4% in Denmark, 7.5% in Australia, 24% in the USA, and 15% in Poland and is much higher in less industrialized countries such as in Nigeria (30%), Brazil (36%), Indonesia (63%), and La Réunion (93%) (Macpherson, 2013). While a single positive titre indicates that a person has had contact with Toxocara spp. in the past, it cannot distinguish between active infection and a serological scar (Rubinsky-Elefant et al., 2010). An increasing titre over time or a decrease following treatment are both strong indicators for an active infection. However, it has to be kept in mind that a comparison of serological results is only possible if the same test, ideally with parallel testing of all sera, is used. Usually, the titre has to be interpreted in

the context of clinical findings and the eosinophil count and cross reactions with other helminths have to be ruled out. Histological findings of the heart show interstitial oedema with diffuse eosinophilic inflammatory infiltrate and myocardial necrosis (Becroft, 1964; Enko et al., 2009), subendocardial fibrosis (De Cock et al., 1998; Thomas et al., 2000), and granuloma specific for VLM, with or without remnants of the larva (Brill et al., 1953; Dao and Virmani, 1986; Dent et al., 1956; Vargo et al., 1977). The myocarditis is a consequence of direct invasion of the larva leading to granulomatous lesions and/or of hypersensitivity reactions (Abe et al., 2002). A study in rats infected with Toxocara canis showed that eosinophils induce cardiac damage that correlates with the level of eosinophilia in the absence of direct larval infiltration of the heart. The effect is probably due to the release of cytotoxic products by activated eosinophils. It can even be observed when isolated hearts of healthy animals are in contact with activated eosinophils. The exposure to activated eosinophils is probably the first step of the process of myocardial injury following infection with Toxocara canis in rodents (Schaffer et al., 1992). Since the cardiac symptoms seem to be a combination of direct tissue damage caused by the migrating larvae and an immunological/hypersensitivity reaction, which can be aggravated after treatment with anthelmintics through the antigens released by the dying larvae, combinations of an anthelmintic drug (i.e. albendazole, thiabendazole or ivermectin (only in older reports)) and corticosteroids appear to be the logical choice and were applied in most patients. While either anthelmintics alone or in combination with corticosteroids seem to be an adequate treatment regimen, no clear recommendations regarding dosage or duration of treatment exist. No objective means exist to evaluate success of treatment since parasite eradication in VLM patients cannot be assessed (Ahn et al., 2014; Rubinsky-Elefant et al., 2010). Albendazole (500 mg given twice daily for 5 days) is the currently recommended treatment for VLM (Castanheira et al., 2011). Adjunct steroids are recommended for severe ocular involvement (Rubinsky-Elefant et al., 2010) and signs of systemic inflammation (Castanheira et al., 2011).

In the reviewed case reports, albendazole has been used in dosages of 200-1000 mg per day from seven days up to three months. In two patients receiving an initial treatment for only 1-2 weeks, a second course had to be applied due to recurrence of symptoms (Prunier et al., 2001) + own unpublished case). Since cardiac toxocariasis is a potentially life threatening disease we suggest using higher doses (15mg/kg or 800-1200 mg per day) and, based on the fact that none of the patients treated for more than 2-3 weeks had a relapse described, for a duration of at least 3-4 weeks. When giving albendazole for more than 3-4 weeks, the adverse events of albendazole – mainly hepatic toxicity and bone marrow suppression– have to be balanced against the potential benefits. The relevance of the additional use of corticosteroids seems less clear. Regimens ranging from steroids given from three days to up to several months have been used without clearly influencing the outcome. However, since the addition of corticosteroids can lead to a rapid improvement of symptoms (Abe et al., 2002; Enko et al., 2009), this is advisable, especially in cases showing severe signs of systemic inflammation. We propose prednisone at a starting dose of 1mg/kg body weight for one week. The consecutive tapering should be based on clinical signs and symptoms and the eosinophil count. Treatment should be guided by close clinical and laboratory monitoring, including the eosinophil count and liver enzymes. A second course of anthelmintics and steroids may be necessary. Treatment of heart failure is according to the usual guidelines and is not in the scope of this article. The formation of a thrombus might occur as a complication of Loeffler’s endocarditis and would demand anticoagulation. Limitations Since there is a high prevalence of active toxocariasis in some countries, it might not always be possible to distinguish myocarditis caused by Toxocara spp. from myocarditis caused by other aetiologies, or toxocariasis being a co-infection not responsible for the cardiac manifestations. Another limitation is that in some of the reported case studies no detailed information on the serologic testing methodologies including their sensitivity, specificity and possible cross reactions was given. Additionally, publication bias might have led to an overrepresentation of more severe presentations of cardiac toxocariasis, while cases presenting with mild symptoms may be underrepresented.

Conclusions In case of unspecific organ manifestations, (i.e. heart, lungs, liver), accompanied by fever and eosinophilia with or without allergic skin rashes, tissue infestation by parasites should be considered. The diagnosis of toxocariasis would then be based on serological titres ideally showing an evolution over time with an increase during the symptomatic phase or a decrease after treatment when tested in parallel. However, it has to be kept in mind that serological titres may remain positive for years after successful treatment (Cypess et al., 1977; Elefant et al., 2006). Therefore, to assess treatment success, a normalization of the eosinophilic count, in combination with a clinical improvement, is a more valid parameter than serological testing, even though it might be distorted by the steroid treatment. Nevertheless, even though a long duration of seropositivity does not have to signify treatment failure, re-infection, especially in high-endemic regions, should always be considered in cases with stagnant serological titres after adequate treatment. We propose a combination treatment with an anthelmintic drug and corticosteroids. The optimal duration of treatment has not been defined, but is generally considered to be longer than that of common toxocariasis and needs to be adapted individually in each case.

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Enko, K., Tada, T., Ohgo, K.O., Nagase, S., Nakamura, K., Ohta, K., Ichiba, S., Ujike, Y., Nawa, Y., Maruyama, H., Ohe, T., Kusano, K.F., 2009. Fulminant eosinophilic myocarditis associated with visceral larva migrans caused by Toxocara canis infection. Circulation Journal 73, 1344-1348. Farinha, N.-J., Bartolo, A., Trindade, L., Vaz, T., Monterroso, J., Areias, J.C., Teixeira Santos, N., 1997. Pericardite aguda na crianca: experiencia de 9 anos de um centro de referencia terciario. Acta Medica Portuguesa 10, 157-160. Files, M.D., Zenel, J.A., Armsby, L.B., Langley, S.M., 2009. A child with eosinophilia, Loeffler Endocarditis, and acute lymphoblastic leukemia. Pediatr Cardiol 30, 530-532. Friedman, S., Hervada, A.R., 1960. Severe myocarditis with recovery in a child with visceral larva migrans. The Journal of Pediatrics 56, 91-96. Glickman, L.T., Magnaval, J.-F., Domanski, L.M., Shofer, F.S., Lauria, S.S., Gottstein, B., Brochier, B., 1987. Visceral larva migrans in French adults: a new disease syndrome? American journal of epidemiology 125, 1019-1034. Haralambidou, S., Vlachaki, E., Ioannidou, E., Milioni, V., Haralambidis, S., Klonizakis, I., 2005. Pulmonary and myocardial manifestations due to Toxocara canis infection. European Journal of Internal Medicine 16, 601-602. Herry, I., Philippe, B., Hennequin, C., Danel, C., Lejeunne, C., Meyer, G., 1997. Acute life-threatening toxocaral tamponade. Chest 112, 1692-1693. Hidron, A., Vogenthaler, N., Santos-Preciado, J.I., Rodriguez-Morales, A.J., Franco-Paredes, C., Rassi, A.J., 2010. Cardiac involvement with parasitic infections. Clinical Microbiology Reviews 23, 324-349. Holland, C., Smith, H. (Eds.). Toxocara: the enigmatic parasite. CABI Publishing, Wallingford, UK (2006). Hotez, P.J., 1993. Visceral and ocular larva migrans. Seminars in Neurology 13, 175-179. Jacob, C.M., Pastorino, A.C., Peres, B.A., Mello, E.O., Okay, Y., Oselka, G.W., 1994. Clinical and laboratorial features of visceral toxocariasis in infancy. Revista do Instituto de Medicina Tropical de Sao Paulo 36, 19-26. Kawano, S., Kato, J., Kawano, N., Yoshimura, Y., Masuyama, H., Fukunaga, T., Sato, Y., Maruyama, H., Mihara, K., Ueda, A., Toyoda, K., Imamura, T., Kitamura, K., 2011. Clinical features and outcomes of eosinophilic myocarditis patients treated with prednisolone at a single institution over a 27-year period. Internal Medicine 50, 975-981. Kim, J.H., Chung, W.-B., Chang, K.-Y., Ko, S.-Y., Park, M.-H., Sa, Y.-K., Choi, Y.-S., Park, C.-S., Lee, M.-Y., 2012. Eosinophilic myocarditis associated with visceral larva migrans caused by Toxocara canis infection. J Cardiovasc Ultrasound 20, 150-153. Lee, R.M., Moore, L.B., Bottazzi, M.E., Hotez, P.J., 2014. Toxocariasis in North America: A Systematic Review. PLOS Neglected Tropical Diseases 8, e3116. Leibetseder, F., 1981. Jahrelange Eosinophilie bei positivem Antikörpernachweis auf Toxocara-canisLarven. Wiener Medizinische Wochenschrift 7, 185-188. Lemaire, A., Trouillier, S., Samou, F., Delevaux, I., Aumaître, O., 2013. Syndrome de larva migrans viscéral avec atteinte cardiaque: une observation et revue de la littérature. La Revue de médecine interne, pii: S0248-8663(0213)01072-01072. Macpherson, C.N., 2013. The epidemiology and public health importance of toxocariasis: A zoonosis of global importance. International Journal of Parasitology 43, 999-1008. Matsuki, Y., Fujii, T., Nakamura-Uchiyama, F., Hiromatsu, K., Nawa, Y., Hayashi, T., Ohtomi, S., 2007. Toxocariasis presenting with multiple effusions in the pericardial space, thoracic cavity, and Morrison's Pouch. Internal Medicine 46, 913. Noemi, I., Schuh, W., Herskovic, P., Rios, E., Cerva, L., Torres, M.T., Tassara, R., Urzua, M.E., dal Borgo, P., Gutiérrez, C., 1984. Larva Migrans Visceral en Ninos. Revista Chilena de Pediatria 55, 244-248. Pawlowski, Z., 2001. Toxocariasis in humans: clinical expresion and treatment dilemma. Journal of Helminthology 75, 299-305. Prunier, F., Deléphine, S., Victor, J., de Gentile, L., Moreau, C., Laporte, J., Dupuis, J.M., Geslin, P., 2001. Endocardite fibroblastique de Löffler. Archives des maladies du coeur et des vaisseaux 94, 226230.

Rayes, A., Teixeira, D., Nobre, V., Serufo, J.C., Goncalves, R., Valadares, L., Lambertucci, J.R., 1999. Visceral larva migrans syndrome complicated by liver abscess. Sandinavian Journal of Infectious Diseases 31, 324-325. Rubinsky-Elefant, G., Hirata, C.E., Yamamoto, J.H., Ferreira, M.U., 2010. Human toxocariasis: diagnosis, worldwide seroprevalences and clinical expression of the systemic and ocular forms. Annals of Tropical Medicine & Parasitology 104, 3-23. Rugiero, E., Cabrera, M.E., Ducach, G., Noemi, I., Viovy, A., 1995. Systemic toxocariasis in the adult patient. Report of eight cases. Revista Médica de Chile 123, 612-616. Schaffer, S.W., Dimayuga, E.R., Kayes, S.G., 1992. Development and characterization of a model of eosinophil-mediated cardiomyopathy in rats infected with Toxocara canis. The American journal of physiology 262, H1428-1434. Shrestha, S., Dongol Singh, S., Shrestha, N.C., Shrestha, R.P.B., 2012. Clinical and laboratory profile of children with eosinophilia at Dhulikhel Hospital. Kathmandu University Medical Journal 11, 58-62. Taylor, M.R., Keane, C.T., O'Connor, P., Girdwood, R.W., Smith, H., 1987. Clinical features of covert toxocariasis. Sandinavian Journal of Infectious Diseases 19, 693-696. Taylor, M.R., Keane, C.T., O'Connor, P., Mulvihill, E., Holland, C., 1988. The expanded spectrum of toxocaral disease. Lancet 1, 692-695. Thomas, K., NIxdorff, U., Manger, B., Geiler, T., Lorenz, H.-M., Faller, G., Moshage, W., 2000. Myokardiale Beteiligung des Eosinophilie-Syndroms bei einer Fadenwurminfektion. Medizinische Klinik 95, 163-167. Traboulsi, R., Boueiz, A., Kanj, S.S., 2006. Catastrophic aortic thrombosis due to Toxocara infection. Scandinavian Journal of Infectious Diseases 39, 283-285. Vargo, T.A., Singer, D.B., Gillette, P.C., Fernbach, D.J., 1977. Myocarditis due to visceral larva migrans. The Journal of Pediatrics 90, 322-323. Wilder, H.C., 1950. Nematode endophthalmitis. Transactions of the American Academy of Ophthalmology and Otolaryngology 55, 99-109.

Figure Captions Figure 1: Flow chart of methodology for articles chosen for the review

Literature search Database: PubMed, Embase

Duplicates removed (n=38)

Articles evaluated based on title and abstract (n=118)

Excluded (n=98) Did not meet or address inclusion criteria Articles taken to full review (n=20)

Excluded (n=7) Case series: symptoms not attributable to individual patient (n=4) Toxocara only co-factor but not causative (n=2)

Included articles (n=13)

Articles found in the reference lists of included articles & own unpublished case (n=8)

All articles included (n=21)

Causative pathogen Baylisascaris not Toxocara (n=1)

Tables Table 1: Description of the collective including age, sex and diagnostic criteria Reference

Age/sex

Eosinophil count

45/m

Serological Titre * positive

Kuenzli 2014 Brill 1953 (Brill et al., 1953)

2/m

not done

12’560/mm3

Dent 1956 (Dent et al., 1956)

19 months/m

not done

1st episode: 16’000-37’800/mm3

5000/mm3

2nd episode: 329/mm3

Friedmann 1960 (Friedman and Hervada, 1960) Becroft 1964 (Becroft, 1964)

18

Histology/Detection of Parasite

31 month/f

not done

3600/mm3

15 month/f

not done

Eosinophilia in bone marrow, not examined in peripheral blood

Granulomas in the lung, the heart, the liver, and the kidneys; larva in several tissue slides Longitudinal fragment of larval parasite; focal areas of interstitial myocarditis Detection of ova of T. canis in the stool of the pet dog Interstitial infiltration of myocardium with lymphocytes, plasma cells, eosinophils and histiocytes, and small foci of necrosis. Subcapsular lesions in the liver, in accordance with visceral larva migrans; one secondstage larva of T. canis

Cardiac Involvement Loeffler’s endocarditis with thrombus Myocarditis

Myocarditis

Myocarditis

Myocarditis with fulminant heart failure

Vargo 1977 (Case 1) (Vargo et al., 1977)

2/m

not done

Elevated (no exact value given)

VLM granulomas in the myocardium with a remnant of a Toxocara spp. larva

Vargo 1977 (Case 2) (Vargo et al., 1977)

2/f

not done

not reported

Vargo 1977 (Case 3) (Vargo et al., 1977)

20 month/f

not done

not reported

Dao 1986 (Case 1) (Dao and Virmani, 1986)

18 month/f

not done

not reported

liver biopsy with granuloma due to Toxocara spp. Cardiac hypertrophy and dilatation with myocardial granulomas due to Toxocara spp. Eosinophilic granuloma with remnants of nematode

Herry 1997 (Herry et al., 1997)

50/m

Titre elevated (0,5 (<0.3) optical density (ELISA)

2’200/mm3

Nonspecific subacute inflammation of pericard and pleura with sparse eosinophilic infiltration

Pericarditis with pericardial tamponade

12’915/mm3(45%)

Loeffler’s endocarditis

Loeffler’s endocarditis with intraventricular thrombus

De Cock 1998 (De Cock et al., 1998)

19

4/f

Increase over time 0,50,7 (day 10)2,2 (day 17) positive

Asymptomatic myocarditis with 10% of myocard infiltrated with eosinophils, plasma cells and lymphocytes Myocarditis with heart failure Myocarditis leading to death

Focal eosinophilic myocarditis

Rayes 1999 (Rayes et al., 1999)

2/m

Elevated titre (1:1218)

1’332 / mm3

Thomas 2000 (Thomas et al., 2000)

57/m

Titre elevated (ELISA) (no values given)

1’980 /mm3

Prunier 2001 (Prunier et al., 2001)

56/f

Abe 2002 (Abe et al., 2002)

26/m

Increase over time before treatment, decrease after treatment Positive (ELISA and Western Blot) Elevated titre (ELISA) Increase over time 0.22 (day 21)0.29 day 63)  0.25 (day 77)

20

Pericardial effusion

Singular myocyte necrosis, subendocardial fibrosis with eosinophilic granulocytes

1200-2300/ mm3

Loeffler’s fibroblastic endocarditis

1’387/mm3 (initially) 26’000/mm3 14 days later)

Myocarditis

Haralambidou 2005 (Haralambidou et al., 2005) Borlot 2006 (Borlot et al., 2006)

38/m

Traboulsi 2006 (Traboulsi et al., 2006)

29/m

Matsuki 2007 (Matsuki et al., 2007)

31/f

Eicher 2009 (Eicher et al., 2009)

31/m

31/m

Titre elevated (ELISA) Positive (ELISA and Western Blot) ELISA 4.3 (no 1.1), (confirmed by Western blot) Titre elevated (1,732 OD, neg. controls 0,019) (ELISA) 4 months: 1.27 OD 9 months: 0.96 OD Positive (ELISA and Western Blot) Decrease under

21

16’500/mm3

Myocarditis

17’800/mm3

Pericarditis with tamponade

15’000/mm3

Pericarditis with thrombotic occlusion of Aorta

695/ mm3

Pericarditis with effusion

1200/mm3

Pericarditis with tamponade

treatment Enko 2009 (Enko et al., 2009)

19/m

Positive (ELISA)

1053/ mm3

Kawano 2011 (Kawano et al., 2011) Kim 2012 (Kim et al., 2012) Lemaire 2013 (Lemaire et al., 2013)

57/f

Positive (ELISA) Positive

5’548/ mm3

41/f

8’430/mm3

Positive 20’000/mm3 (ELISA and Western Blot) * the used serological assay was not specified in the original publication

22

74/m

Extensive interstitial oedema; diffuse inflammatory interstitial infiltrate (partially degranulated eosinophils) and myocardial necrosis

Perimyocarditis

Myocarditis Myocyte necrosis and degeneration

Myocarditis Myopericarditis with effusion

Table 2: Signs, symptoms and laboratory examinations Reference Kuenzli 2014

Brill 1953 (Brill et al., 1953)

Dent 1956 (Dent et al., 1956)

Friedman 1960 (Friedman and Hervada, 1960)

Becroft 1964 (Becroft, 1964) Vargo 1977 (Case 1) (Vargo et al., 1977)

23

Non Cardiac Symptoms Joint ache, fatigue, loss of appetite

Cardiac Manifestations

Acute phase: low grade fever, abdominal pain, lethargy, listlessness, transient facial edema

Cyanosis, tachycardia (164/min), tachypnea (60/min)

ECG

Sonography

Other

Fibrosis of the endocard

not done

Prior: facial eczema, asthmatic attack First presentation: Fever, cough, abdominal distension, hepatomegaly, general malaise

Second presentation: Chills, fever, delirium, prostration, jaundice Fine papular rash, lymphadenopathy, cough, hepatomegaly Day 19 of hospitalization: pneumonitis and fever Cough, wheeze, fever, vomiting Asymptomatic Toxcarainfection

Chest X-ray

Peribronchial infiltration of left upper lung field

not done

Hb 72 g/l, BSR 14 mm/h, 2 stool species negative for ova and parasites

Diffuse pneumonitis in the lower half of the right lung field Normal chest-Xray

Cardiac failure

Sinus tachycardia

3 and 4 months later relapse of cardiac failure (reinfection?) Dyspnoea, cyanosis

not done

Cardiomegaly

Indirect bilirubin 20.6mg%

not done

Tachycardia, gallop rhythm, orthopnea, ronchi, generalized edema, hepatomegaly Acute respiratory distress, gallop rhythm

Vargo 1977 (Case 2) (Vargo et al., 1977)

Vargo 1977 (Case 3) (Vargo et al., 1977)

Dao 1986 (Case 1) (Dao and Virmani, 1986)

None

Herry 1997 (Herry et al., 1997)

17 days prior: appendicitis, pleural effusion, eosinophilia of 600/mm3

De Cook 1998 (De Cock et al., 1998)

Rayes 1999 (Rayes et al., 1999)

Fever, lymphadenopathy, hepatosplenomegaly, liver abscess Prior 3 months: Weight loss, abdominal distension, malaise

24

Cyanosis, shortness of breath , weakness (attributed to a tetralogy of Fallot) Severe dyspnea

Low voltage QRS complexes and T waves

Cardiomegaly, pulmonary edema

Low voltage QRS complexes and T waves

Poorly contracting, dilatated left ventricle (cineangicardiograph y)

Cardiomegaly, bilateral pleural effusion

Cough and pulmonary embolism due to thrombus in the right apex, hepatomegaly; 2/6 systolic murmur

Cardiomegaly

Bilateral expiratory ronchi

Cardiomegaly suggestive of pericardial effusion CT: pericardial and pleural effusions

800 ml pericardial effusion (20% eosinophils) Apical thrombus in the right ventricle, diastolic dysfunction of the right ventricle, tricuspid and mitral regurgitation, small restrictive right ventricle, pericardic effusion Pericardial effusion

Thomas 2000 (Thomas et al., 2000)

Weight loss, general fatigue

Prunier 2001 (Prunier et al., 2001)

2-3 months prior to admission: Visual hallucinations, paresthesia in lower and upper extremities, walking problems

Abe 2002 (Abe et al., 2002)

General fatigue

Haralambidou 2005 (Haralambidou et al., 2005)

7 months prior: periods of cough and dyspnea resolving with bronchodilatator

Cardial decompensation, chest pain, bilateral pulmonary edema, bilateral pleural effusions Dyspnea, edema with increase of body weight of 10 kg

R-loss in V1-V3

Dyspnea, palpitations, chest pain, paradoxical pulse Dyspnea, cough, chest pain

ST-Segment elevation in all leads except aVR, V1/2 ST-T wave abnormalities

Repolarisation alterations

25

Fever, abdominal pain, pruritic papular skin rash

Slight dilatation of LV, minimally reduced LVEF without regional hypokinesis, restrictive cardiopathy, slightly insufficient aortic valve No LV dilatation or hypertrophy, good systolic function, restrictive cardiopathy

Diffuse hypokinesis of left ventricular wall, increased LV wall thickness, pericardial effusion Normal

Chest pain, cardiac arrest, pericardial tamponade

Normal

Cortical lesions on brain MRI 2-3 months before cardiac problem , cerebro-spinal fluid positive for Toxocara antibodies (Western Blot) CPK elevation

CK-MB and troponin elevation

CT scan : noncavitating pulmonary lesions

4 months prior: malaise, sweating, vague abdominal symptoms Last month prior to admission: fever and diarrhea Borlot 2006 (Borlot et al., 2006)

Cardiomegaly, pleural effusions

Pericardial effusion

Traboulsi 2006 (Traboulsi et al., 2006)

Pain of lower extremities; generalized fatigue 5 months earlier

Matsuki 2007 (Matsuki et al., 2007)

Abdominal pain and watery diarrhea 3 days prior

not done

Minute syncope, arterial hypotension (78/42 mm Hg), slight tachycardia

Suspected dissection of aortic aneurysma in CT Intraoperatively blood clots extending from aorta to ileofemoral artery Cardiomegaly and bilateral pleural effusions

Moderate pericardial effusion, LVEF 76%

Chest CT: pericardial and pleural effusion Eicher 2009 (Eicher et al., 2009)

Skin: urticaria Rhinopharyngitis Abdominal pain: peritoneal effusion

Cardiac arrest

Enko 2009 (Enko et al., 2009)

None reported

Chest discomfort and pain, hypotension (BP 80/40) and tachycardia (130/min) Chest pain

Kawano 2011 (Kawano et al., 2011) Kim 2012 (Kim et al., 2012)

26

Chest discomfort and pain, hypotension (94/60 mmHg) and tachycardia (100/min)

Pericardial effusion, tamponade

ST-segment elevation in all leads except aVR ST elevation /depression Low voltage in peripheral and precordial leads

Cardiomegaly, pulmonary congestion, left pleural effusion

Cardiomegaly, pleural effusions

Severe hypokinesis of LV wall , thickening of left ventricle, LVEF 24%, pericardial effusion LVEF 66%, mild hypokinesis (septal mid ventricle – apex) Edematous left ventricular myocardium, global hypokinesis, mild left ventricular systolic dysfunction (LVEF 48%), small pericardial effusion

Elevated troponin CK-MB and troponin elevation

Lemaire 2013 (Lemaire et al., 2013)

27

Skin: urticaria four months previously Lungs: bilateral interstitial infiltration

Dyspnea, orthopnea, chest pain, hepatomegaly, neck vein distension, lower leg edema

Normal

Pericardial effusion (14mm) LVEF 61%

Elevated troponin (0.13ug/l [<0.03ug/l]) and BNP (1195ng/l [<738ng/l]) Cardiac MRI: circumscribed enhancement in accordance with myocardial fibrosis

Table 3: Treatment and Follow up Reference

Antiparasitic Treatment

Corticostroids

Other

Outcome

Kuenzli 2014

Albendazole 800mg/day for 2 weeks

Prednisone 90 mg/d for 5 days

Antibiotics Anticoagulation

3 months later persisting high serologic titre, left ventricular thrombus with peripheral emboli, staphylococcal septicemia.Finally healing

Brill 1953 (Brill et al., 1953) Dent 1956 (Dent et al., 1956)

None

None

Died within 54 hours

Diethylcarbamazine (dose and duration unknown)

Cortisone 150mg/d for 5 weeks

Antibiotics Antihistaminics Terramycin

Friedmann 1960 (Friedman and Hervada, 1960)

None

Cortisone 100 mg/d (1stevent) Cortisone 75g/d (3rd event)

Digitalis (2nd event)

Hydrocortisone

Erythromycine and penicilline

Becroft 1964 (Becroft, 1964) Vargo 1977 (Case 1) (Vargo et al., 1977) Vargo 1977 (Case 2) (Vargo et al., 1977) Vargo 1977 (Case 3) (Vargo et al., 1977)

28

None

None

None

None

None

None

Treatment for congestive heart failure Treatment for congestive heart failure

Initially improvement, finally death due to hepatic coma (possibly due to overwhelming homologous serum hepatitis contracted from a blood transfusion) 2nd episode 3 months later (respiratory distress, tachycardia, oedema) 3rd episode of pneumonitis 1 month later Cessation of symptoms after prolonged corticosteroid treatment Death due to acute heart failure

Time of Follow up 1 year

Death

2 ½ years

Death

Died due to other disease

Death

Clinical improvement

1 month

Died due to heart failure

Death

Dao 1986 (Case 1) (Dao and Virmani, 1986) Herry 1997 (Herry et al., 1997)

None

None

Ivermectin 200 µg/kg/day day 0 and 15

Not reported

Evacuation of pericardial effusion

De Cook 1998 (De Cock et al., 1998)

Albendazole 50 mg/kg/day for 28 days

Prednisolone 2 mg/kg, reduced over 4 weeks

Rayes 1999 (Rayes et al., 1999) Thomas 2000 (Thomas et al., 2000)

Thiabendazole 7d

None

Albendazole 600mg/d for 14 days

Prednisolone (no dose or duration given)

Surgical removal of the thrombus Anticoagulation (Acenocoumarol 1.5mg/d for 3 months) Ceftriaxone and clindamycin ACE blockers, diuretics

Prunier 2001 (Prunier et al., 2001)

First course: Albendazole 1000 mg/d for 7 days

Abe 2002 (Abe et al., 2002)

Second course: for 3 months Albendazole 1000mg/d for 4 weeks

Haralambidou 2005 (Haralambidou et al., 2005) Borlot 2006 (Borlot et al., 2006)

29

Corticosteroids

Diuretics, anticoagulation

Prednisolone 35 mg/d, tapering over 4 weeks

None

Corticosteroids (no details reported)

Nitrates, heparin, beta-blocker

None

None

Drainage of pericardial effusion, Aspirin

Resolving of symptoms, decrease of Toxocara-antibody-titre to 0.8 OD and decrease of eosinophil count to 300/mm3 Complete resolving of symptoms including heart murmur, reduction of eosinophil count

Resolution of symptoms and clinical findings Prolonged dyspnea, improvement over time Persistent restrictive cardiopathy in sonography Healing

Decrease of eosionphilic count and antibody titre after intial increase under treatment with complete resolution of symptoms Normalization of lab findings, resolution of symptoms Healing

> 1 month

unknown >3 months

3 months

3 months

17 d

Traboulsi 2006 (Traboulsi et al., 2006)

Albendazole (dose not known) for 3 months

Matsuki 2007 (Matsuki et al., 2007)

Albendazole 600 mg/d for 7 weeks (after Methylprednisolone and clinical improvement) Albendazole

Methylprednisolone 1000 mg/day for 3 d

Enko 2009 (Enko et al., 2009)

Albendazole 600 mg/d for 4 weeks (started 4 months after discharge from hospital)

Kawano 2011 (Kawano et al., 2011) Kim 2012 (Kim et al., 2012)

Albendazol for 8 weeks

Methylprednisolone 500 mg/d i.v. for 3 days Prednisolone 50 mg/day p. os, tapered over a period of 8 weeks None

Albendazole 2 x 400 mg for 2 weeks

Prednisolone 1 mg/kg for 3 d (prior to Albendazole)

Lemaire 2009 (Lemaire et al., 2013)

Albendazole 200 mg/d for 3 weeks

Prednisolone 100 mg/d, tapering over 1 month

Eicher 2009 (Eicher et al., 2009)

Aspirin, colchicine Drainage of effusion Intra-aortic ballon Normalization of eosinophil count pump, Complete resolution of symptoms percutaneous cardiopulmonary support None Normalisation ECG and echocardiography

Abbreviations: LV = left ventricle; LVEF = left ventricular ejection fraction; RV = right ventricle

30

Left leg gangrene warranting aboveknee amputation. Finally asymptomatic with normal eosinophil count Rapid decrease of effusions within 2 weeks after starting steroids, normalization of Toxocara-titres and eosinophilic levels Healing

Improvement within 1 week after starting corticosteroids; normalization LV wall thickness and recovery of myocardial contractility Normalization of eosinophil count and troponin within 15 days, normalization of LVEF and reduction of tamponade Serology remained elevated at 3 months

1 year

9 months

6 months

621 d

12 months