Longitudinal study based on a safety registry for malaria patients treated with artenimol-piperaquine in six European countries.

BACKGROUND: European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)-piperaquine (APQ) Eurartesim® during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap. METHODS: Participants were recruited through Health Care Provider's safety registry in 15 centres across 6 European countries in the period 2013-2016. Adverse events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett's (QTcB) or Fridericia's (QTcF) methods, at baseline and after treatment. QTcB and/or QTcF prolongation were defined by a value > 450 ms for males and children and > 470 ms for females. RESULTS: Among 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8 years old (13.2) and 25.9 kg/m2 (4.7). Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection. Women and Non-African participants had significantly (p < 0.05) more AEs. Among AEs, 21 were due to cardiotoxicity (7.1%), mostly QT prolongation, while 6 were due to neurotoxicity (2.0%), mostly dizziness. Using QTcF correction, QT prolongation was observed in 17/143 participants (11.9%), only 2 of them reporting QTcF > 500 ms (milliseconds) but no clinical symptoms. Using QTcB correction increases of > 60 ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65 years of age but only a few subjects were in this group. No new safety signal was reported. The overall efficacy rate was 255/257 (99.2%). CONCLUSIONS: APQ appears as an effective and well-tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries. Trial registration This study has been registered in EU Post-Authorization Studies Register as EUPAS6942.

Travel-associated chikungunya acquired in Myanmar in 2019.

Eighteen cases of chikungunya virus infection in travellers returning from Myanmar were reported to the GeoSentinel Surveillance Network, its subnetwork EuroTravNet and TropNet in 2019, reflecting an ongoing local outbreak. This report reinforces the importance of travellers as sentinels of emerging arboviral outbreaks and highlights the importance of vigilance for imported cases, due to the potential for dissemination of the virus into areas with competent local vectors and conducive environmental conditions.

Clinical management of imported malaria in Italy: results from a national cross-sectional survey in 2015.

In Italy, malaria continues to be one of the most common imported parasitoses; therefore, continuous surveillance of epidemiological data and clinical management is needed. In 2016, the National Institute for Infectious Diseases 'Lazzaro Spallanzani' in Rome promoted a retrospective questionnaire-based survey to assess the clinical management of imported malaria cases in Italy in 2015. The questionnaire was sent to 104 Tropical and/or Infectious Diseases Units in the country, and 37 of them filled out and returned the questionnaires. A total of 399 malaria cases were reported in 2015, mostly caused by Plasmodium falciparum and imported from Africa. Malaria chemoprophylaxis was correctly used by a minority of patients. Most patients presented with uncomplicated malaria and were treated orally. In severe cases, intravenous artesunate or quinine alone or in combination were administered, although one third of these severe cases received oral treatment. This retrospective survey reveals a lack of homogeneity in management of malaria-imported cases in Italy. Improvement of malaria chemoprophylaxis, standardization of clinical management of malaria cases and harmonization of oral and intravenous drug availability are needed throughout the country.

Neglected tropical diseases in Europe: rare diseases and orphan drugs?

Neglected tropical diseases are becoming more and more frequent in Europe due to the increasing immigration from endemic areas. Nonetheless specific treatments are scarcely available in many European countries, since they are neither officially licensed nor marketed. Only a few referral health centres can afford to access drugs for NTDs due to complex bureaucracy and high cost, importing or providing them via the WHO. Health professionals and institutions in this domain should solicit other stakeholders (such as NGOs, the civil society, scientific societies) to sensitize health authorities to improve access to treatment for such debilitating diseases.

Severe malaria in Europe: an 8-year multi-centre observational study.

BACKGROUND: Malaria remains one of the most serious infections for travellers to tropical countries. Due to the lack of harmonized guidelines a large variety of treatment regimens is used in Europe to treat severe malaria. METHODS: The European Network for Tropical Medicine and Travel Health (TropNet) conducted an 8-year, multicentre, observational study to analyse epidemiology, treatment practices and outcomes of severe malaria in its member sites across Europe. Physicians at participating TropNet centres were asked to report pseudonymized retrospective data from all patients treated at their centre for microscopically confirmed severe Plasmodium falciparum malaria according to the 2006 WHO criteria. RESULTS: From 2006 to 2014 a total of 185 patients with severe malaria treated in 12 European countries were included. Three patients died, resulting in a 28-day survival rate of 98.4%. The majority of infections were acquired in West Africa (109/185, 59%). The proportion of patients treated with intravenous artesunate increased from 27% in 2006 to 60% in 2013. Altogether, 56 different combinations of intravenous and oral drugs were used across 28 study centres. The risk of acute renal failure (36 vs 17% p = 0.04) or cerebral malaria (54 vs 20%, p = 0.001) was significantly higher in patients ≥60 years than in younger patients. Respiratory distress with the need for mechanical ventilation was significantly associated with the risk of death in the study population (13 vs 0%, p = 0.001). Post-artemisinin delayed haemolysis was reported in 19/70 (27%) patients treated with intravenous artesunate. CONCLUSION: The majority of patients with severe malaria in this study were tourists or migrants acquiring the infection in West Africa. Intravenous artesunate is increasingly used for treatment of severe malaria in many European treatment centres and can be given safely to European patients with severe malaria. Patients treated with intravenous artesunate should be followed up to detect and manage late haemolytic events.

A retrospective study of viral central nervous system infections: relationship amongst aetiology, clinical course and outcome.

PURPOSE: To describe the clinical pattern of viral central nervous system (CNS) infections and compare meningitis and encephalitis. METHODS: This is a retrospective study reporting the clinical characteristics and outcome of 138 cases of viral meningitis and meningoencephalitis in a real life experience at a referral centre in Turin, Northern Italy. RESULTS: Enteroviruses were predominant in younger patients who were mainly presenting with signs of meningitis, had shorter hospital admission and absence of complications, whereas herpesviruses had more often signs of encephalitis, were more frequent in elderly patients, had longer hospital admission and frequent complications and sequelae. CONCLUSIONS: Two main clinical entities with different epidemiology, clinical aspects and prognosis may be identified within the group of viral CNS inefctions.

Sentinel surveillance of imported dengue via travellers to Europe 2012 to 2014: TropNet data from the DengueTools Research Initiative.

We describe the epidemiological pattern and genetic characteristics of 242 acute dengue infections imported to Europe by returning travellers from 2012 to 2014. The overall geographical pattern of imported dengue (South-east Asia > Americas > western Pacific region > Africa) remained stable compared with 1999 to 2010. We isolated the majority of dengue virus genotypes and epidemic lineages causing outbreaks and epidemics in Asia, America and Africa during the study period. Travellers acted as sentinels for four unusual dengue outbreaks (Madeira, 2012-13; Luanda, 2013; Dar es Salaam, 2014; Tokyo, 2014). We were able to characterise dengue viruses imported from regions where currently no virological surveillance data are available. Up to 36% of travellers infected with dengue while travelling returned during the acute phase of the infection (up to 7 days after symptom onset) or became symptomatic after returning to Europe, and 58% of the patients with acute dengue infection were viraemic when seeking medical care. Epidemiological and virological data from dengue-infected international travellers can add an important layer to global surveillance efforts. A considerable number of dengue-infected travellers are viraemic after arrival back home, which poses a risk for dengue introduction and autochthonous transmission in European regions where suitable mosquito vectors are prevalent.

Unmet Needs for a Rapid Diagnosis of Chikungunya Virus Infection.

Rapid Diagnosis of Chikungunya Virus Infection.

Intravenous Artesunate Reduces Parasite Clearance Time, Duration of Intensive Care, and Hospital Treatment in Patients With Severe Malaria in Europe: The TropNet Severe Malaria Study.

Intravenous artesunate improves survival in severe malaria, but clinical trial data from nonendemic countries are scarce. The TropNet severe malaria database was analyzed to compare outcomes of artesunate vs quinine treatment. Artesunate reduced parasite clearance time and duration of intensive care unit and hospital treatment in European patients with imported severe malaria.

Malaria prophylaxis and guidelines.

BACKGROUND: Malaria prophylaxis recommendations issued by different health authorities in Europe are inhomogeneous, and so is the opinion of experts, but a general trend towards reducing its use is evident, and prescribers apparently adhere more easily to more restrictive recommendations. METHODS AND RESULTS: A new Italian guideline has been produced, looking both at scientific evidence (data on malaria risk and drugs' side effects) and at the opinion of experts (surveys and previously issued recommendations). CONCLUSIONS: Collecting data on imported malaria, stating a clear methodology and introduce a discussion at international level should be the next goals in order to homogenise recommendations for malaria prophylaxis in Europe.

A case of histological diagnosis of Toxoplasma gondii myositis in a person living with HIV.

We report the case of a 58-year-old male with a recent diagnosis of HIV infection admitted for progressive muscular weakness and psychomotor impairment. Cerebrospinal examination documented a mild hyperproteinorrachia, with normal cells count and reduced glycorrhachia. Brain gadolinium-enhanced MRI showed bilateral T2 and FLAIR hyperintensities in the nucleo-capsular region and irregular contrast-enhancement of the globi pallidi and the right putamen. The histologic analysis of a quadriceps biopsy showed several foci of inflammatory infiltrates with concomitant muscular fiber atrophy and degeneration. Scattered intracytoplasmic inclusions were observed in muscle fibers, representing the main pathological feature. A positive PCR for Toxoplasma gondii and a Toxoplasma gondii specific monoclonal antibody immunohistochemical staining confirmed the diagnosis.

Therapy of uncomplicated falciparum malaria in Europe: MALTHER - a prospective observational multicentre study.

BACKGROUND: Malaria continues to be amongst the most frequent infectious diseases imported to Europe. Whilst European treatment guidelines are based on data from studies carried out in endemic areas, there is a paucity of original prospective treatment data. The objective was to summarize data on treatments to harmonize and optimize treatment for uncomplicated malaria in Europe. METHODS: A prospective observational multicentre study was conducted, assessing tolerance and efficacy of treatment regimens for imported uncomplicated falciparum malaria in adults amongst European centres of tropical and travel medicine. RESULTS: Between December 2003 and 2009, 504 patients were included in 16 centres from five European countries. Eighteen treatment regimens were reported, the top three being atovaquone-proguanil, mefloquine, and artemether-lumefantrine. Treatments significantly differed with respect to the occurrence of treatment changes (p = 0.005) and adverse events (p = 0.001), parasite and fever clearance times (p < 0.001), and hospitalization rates (p = 0.0066) and durations (p = 0.001). Four recrudescences and two progressions to severe disease were observed. Compared to other regimens, quinine alone was associated with more frequent switches to second line treatment, more adverse events and longer inpatient stays. Parasite and fever clearance times were shortest with artemether-mefloquine combination treatment. Vomiting was the most frequent cause of treatment change, occurring in 5.5% of all patients but 9% of the atovaquone-proguanil group. CONCLUSIONS: This study highlights the heterogeneity of standards of care within Europe. A consensus discussion at European level is desirable to foster a standardized management of imported falciparum malaria.

Trichinella britovi outbreak in Piedmont, North-West Italy, 2019-2020: Clinical and epidemiological insights in the one health perspective.

BACKGROUND: Trichinellosis, a foodborne zoonosis due to nematodes of the genus Trichinella, occurs in the form of outbreaks following meat consumption. North Italy has been rarely involved. We report here the most significant wildlife derived trichinellosis outbreak ever registered in the Piedmont region. METHOD: We retrospectively included 96 outpatients referred to our institution (December 20th, 2019-January 15th, 2020) 2020 after consuming raw sausages prepared from a single wild boar hunted in the Susa Valley, 59 km away from Torino, in November 2019. RESULTS: We confirmed 35 cases and found additional 10 probable/suspected cases. Our cohort found that 47% of patients were symptomatic, with a median time from symptoms to presentation at clinic and serology testing of 14 days. Peripheral blood eosinophilia >500/µl and CK alterations were common. Further qualitative and quantitative analysis at the International Trichinella Reference Center c/o ISS, Rome identified T. britovi as the causative agent. CONCLUSIONS: No autochthonous human case has ever been detected in Torino province, and a single wild boar has tested positive for Trichinella since active surveillance was implemented in 2013. This outbreak should raise attention on the preventive role of veterinary surveillance and the need to optimize sampling procedures and targeted health education.

Malaria chemoprophylaxis recommendations for immigrants to Europe, visiting relatives and friends--a Delphi method study.

BACKGROUND: Numbers of travellers visiting friends and relatives (VFRs) from Europe to malaria endemic countries are increasing and include long-term and second generation immigrants, who represent the major burden of malaria cases imported back into Europe. Most recommendations for malaria chemoprophylaxis lack a solid evidence base, and often fail to address the cultural, social and economic needs of VFRs. METHODS: European travel medicine experts, who are members of TropNetEurop, completed a sequential series of questionnaires according to the Delphi method. This technique aims at evaluating and developing a consensus through repeated iterations of questionnaires. The questionnaires in this study included questions about professional experience with VFRs, controversial issues in malaria prophylaxis, and 16 scenarios exploring indications for prescribing and choice of chemoprophylaxis. RESULTS: The experience of participants was rather diverse as was their selection of chemoprophylaxis regimen. A significant consensus was observed in only seven of 16 scenarios. The analysis revealed a wide variation in prescribing choices with preferences grouped by region of practice and increased prescribing seen in Northern Europe compared to Central Europe. CONCLUSIONS: Improving the evidence base on efficacy, adherence to chemoprophylaxis and risk of malaria and encouraging discussion among experts, using techniques such as the Delphi method, may reduce the variability in prescription in European travel clinics.

The incidence of malaria in travellers to South-East Asia: is local malaria transmission a useful risk indicator?

BACKGROUND: The presence of ongoing local malaria transmission, identified though local surveillance and reported to regional WHO offices, by S-E Asian countries, forms the basis of national and international chemoprophylaxis recommendations in western countries. The study was designed to examine whether the strategy of using malaria transmission in a local population was an accurate estimate of the malaria threat faced by travellers and a correlate of malaria in returning travellers. METHODS: Malaria endemicity was described from distribution and intensity in the local populations of ten S-E Asian destination countries over the period 2003-2008 from regionally reported cases to WHO offices. Travel acquired malaria was collated from malaria surveillance reports from the USA and 12 European countries over the same period. The numbers of travellers visiting the destination countries was based on immigration and tourism statistics collected on entry of tourists to the destination countries. RESULTS: In the destination countries, mean malaria rates in endemic countries ranged between 0.01 in Korea to 4:1000 population per year in Lao PDR, with higher regional rates in a number of countries. Malaria cases imported into the 13 countries declined by 47% from 140 cases in 2003 to 66 in 2008. A total of 608 cases (27.3% Plasmodium falciparum (Pf)) were reported over the six years, the largest number acquired in Indonesia, Thailand and Korea. Four countries had an incidence > 1 case per 100,000 traveller visits; Burma (Myanmar), Indonesia, Cambodia and Laos (range 1 to 11.8-case per 100,000 visits). The remaining six countries rates were < 1 case per 100,000 visits. The number of visitors arriving from source countries increased by 60% from 8.5 Million to 13.6 million over the 6 years. CONCLUSION: The intensity of malaria transmission particularly sub-national activity did not correlate with the risk of travellers acquiring malaria in the large numbers of arriving visitors. It is proposed to use a threshold incidence of > 1 case per 100,000 visits to consider targeted malaria prophylaxis recommendations to minimize use of chemoprophylaxis for low risk exposure during visits to S-E Asia. Policy needs to be adjusted regularly to reflect the changing risk.

Outpatient treatment of imported uncomplicated Plasmodium falciparum malaria: results from a survey among TropNet and GeoSentinel experts for tropical medicine.

BACKGROUND: Plasmodium falciparum malaria (P.f. malaria) is frequently imported to non-endemic countries. Recommendations on outpatient treatment differ largely due to differences in country-level guidelines and even between tropical medicine referral centres within the same country. METHODS: This survey among experts from TropNet or GeoSentinel referral centres for tropical medicine outside malaria endemic areas investigated common practices in P.f. malaria management, selection criteria for outpatient management and diagnostic procedures as a first step for developing a future common and evidence-based approach. RESULTS: A total of 44 referral centres participated. Most of the centres are located in Europe (n = 37). Overall, 27 centres (61%) treat uncomplicated P.f. malaria patients as outpatients, of which eight centres (18%) reported treating ≥75% of patients on an outpatient basis. Seventeen centres (39%) reported treating patients only as inpatients. No single criterion stands out for the decision regarding outpatient treatment, but three groups of factors were identified: (i) clinical criteria including laboratory parameters, clinical condition and tolerance of oral medication; (ii) factors such as patient compliance, reachability by phone and support at home and (iii) patient origin and place of residence as a proxy for possible underlying semi-immunity. The threshold parasitaemia for outpatient treatment varied from 0.1 to 5% with a median of 2%. A median of 0.5% of outpatients were admitted during follow-up. During the last 10 years, 33 complications were reported by nine of the 27 centres and three deaths by one centre. CONCLUSION: This study gives insight into the heterogeneous management of P.f. malaria patients outside endemic regions. Although there is no consensus among experts, the majority of centres includes outpatient treatment in their clinical routine. However, the lack of evidence-based criteria and established safety for this approach shows the need for prospective studies to define and evaluate criteria and practices for safe outpatient management.

Schistosomiasis, strongyloidiasis and Chagas disease: the leading imported neglected tropical diseases in Italy.

BACKGROUND: In recent years, an increasing number of individuals affected by neglected tropical diseases (NTDs) have been observed in Italy, due to migration, international travels and climate changes. Reliable data on the current NTD epidemiology in Italy and the health system preparedness on this issue are not available. METHODS: We report the results of a survey on selected NTDs (schistosomiasis, strongyloidiasis, echinococcosis, Chagas disease, leishmaniasis, cysticercosis, filariasis and scabies) in nine Italian sentinel centres, in order to investigate their occurrence throughout the country and identify which ones are a priority for public health interventions, development of protocols for case management, and training activities. To explore the preparedness of the centres, we investigate the availability of specific diagnostic tools and drugs, needed for the management of the most common NTDs. We also reviewed and summarized the available national policies, recommendations and guidelines on NTDs in Italy. RESULTS: Overall, 4123 NTDs cases were diagnosed in nine Italian centres within a 7-year period (2011-2017). Schistosomiasis and strongyloidiasis were the most common NTDs, accounting for about one-third each of all the diagnosed cases, followed by Chagas disease. The number of cases showed a significant trend to increase over time, mainly due to foreign-born subjects. Serology for Schistosoma spp. and Strongyloides stercoralis was available in seven and five centres, respectively. Agar plate stool culture for S. stercoralis was available in three sites. Ivermectin and praziquantel were always available in six centres. Six national policies, recommendations and guidelines documents were available, but for the most part, they are not fully implemented yet. CONCLUSIONS: This survey showed how some NTDs, such as schistosomiasis and strongyloidiasis, are becoming more common in Italy, due to multiple components. A list of seven key actions was proposed, in order to improve diagnosis, management and control of NTDs in Italy.

Added value of loop-mediated isothermal amplification technology (LAMP) in real life for the diagnosis of malaria in travellers.

Malaria diagnosis in non-endemic countries is questioned by lack of experience and low levels of parasite densities. Loop-mediated isothermal amplification (LAMP) is aimed at simplifying these challenges. In a prospective evaluation over a 2-year period, LAMP significantly simplified malaria identification in 478 febrile travellers and can be considered the primary diagnostic test in this setting.