Ana Requena-Méndez

The Laboratory Diagnosis and Follow Up of Strongyloidiasis: A Systematic Review

Background Strongyloidiasis is frequently under diagnosed since many infections remain asymptomatic and conventional diagnostic tests based on parasitological examination are not sufficiently sensitive. Serology is useful but is still only available in reference laboratories. The need for improved diagnostic tests in terms of sensitivity and specificity is clear, particularly in immunocompromised patients or candidates to immunosuppressive treatments. This review aims to evaluate both conventional and novel techniques for the diagnosis of strongyloidiasis as well as available cure markers for this parasitic infection. Methodology/Principal Findings The search strategy was based on the data-base sources MEDLINE, Cochrane Library Register for systematic review, EmBase, Global Health and LILACS and was limited in the search string to articles published from 1960 to August 2012 and to English, Spanish, French, Portuguese and German languages. Case reports, case series and animal studies were excluded. 2003 potentially relevant citations were selected for retrieval, of which 1649 were selected for review of the abstract. 143 were eligible for final inclusion. Conclusions Sensitivity of microscopic-based techniques is not good enough, particularly in chronic infections. Furthermore, techniques such as Baermann or agar plate culture are cumbersome and time-consuming and several specimens should be collected on different days to improve the detection rate. Serology is a useful tool but it might overestimate the prevalence of disease due to cross-reactivity with other nematode infections and its difficulty distinguishing recent from past (and cured) infections. To evaluate treatment efficacy is still a major concern because direct parasitological methods might overestimate it and the serology has not yet been well evaluated; even if there is a decline in antibody titres after treatment, it is slow and it needs to be done at 6 to 12 months after treatment which can cause a substantial loss to follow-up in a clinical trial.

Severe strongyloidiasis: a systematic review of case reports

BackgroundStrongyloidiasis is commonly a clinically unapparent, chronic infection, but immuno suppressed subjects can develop fatal disease. We carried out a review of literature on hyperinfection syndrome (HS) and disseminated strongyloidiasis (DS), in order to describe the most challenging aspects of severe strongyloidiasis.MethodsWe conducted a structured search using PubMed to collect case reports and short case series on HS/DS published from 1991 to 2011. We restricted search to papers in English, Spanish, Italian and French. Case reports were classified as HS/DS according to given definitions.ResultsRecords screened were 821, and 311 were excluded through titles and abstract evaluation. Of 510 full-text articles assessed for eligibility, 213 were included in qualitative analysis. As some of them were short case series, eventually the number of cases analyzed was 244.Steroids represented the main trigger predisposing to HS and DS (67% cases): they were mostly administered to treat underlying conditions (e.g. lymphomas, rheumatic diseases). However, sometimes steroids were empirically prescribed to treat signs and symptoms caused by unsuspected/unrecognized strongyloidiasis. Diagnosis was obtained by microscopy examination in 100% cases, while serology was done in a few cases (6.5%). Only in 3/29 cases of solid organ/bone marrow transplantation there is mention of pre-transplant serological screening. Therapeutic regimens were different in terms of drugs selection and combination, administration route and duration. Similar fatality rate was observed between patients with DS (68.5%) and HS (60%).ConclusionsProper screening (which must include serology) is mandatory in high - risk patients, for instance candidates to immunosuppressive medications, currently or previously living in endemic countries. In some cases, presumptive treatment might be justified. Ivermectin is the gold standard for treatment, although the optimal dosage is not clearly defined in case of HS/DS.

Diagnostic Accuracy of Five Serologic Tests for Strongyloides stercoralis Infection

Background The diagnosis of Strongyloides stercoralis (S. stercoralis) infection is hampered by the suboptimal sensitivity of fecal-based tests. Serological methods are believed to be more sensitive, although assessing their accuracy is difficult because of the lack of sensitivity of a fecal-based reference (“gold”) standard. Methods The sensitivity and specificity of 5 serologic tests for S. stercoralis (in-house IFAT, NIE-ELISA and NIE-LIPS and the commercially available Bordier-ELISA and IVD-ELISA) were assessed on 399 cryopreserved serum samples. Accuracy was measured using fecal results as the primary reference standard, but also using a composite reference standard (based on a combination of tests). Results According to the latter standard, the most sensitive test was IFAT, with 94.6% sensitivity (91.2–96.9), followed by IVD-ELISA (92.3%, 87.7–96.9). The most specific test was NIE-LIPS, with specificity 99.6% (98.9–100), followed by IVD-ELISA (97.4%, 95.5–99.3). NIE-LIPS did not cross-react with any of the specimens from subjects with other parasitic infections. NIE-LIPS and the two commercial ELISAs approach 100% specificity at a cut off level that maintains ≥70% sensitivity. Conclusions NIE-LIPS is the most accurate serologic test for the diagnosis of S. stercoralis infection. IFAT and each of the ELISA tests are sufficiently accurate, above a given cut off, for diagnosis, prevalence studies and inclusion in clinical trials.

Strongyloides stercoralis: a plea for action.

Strongyloidiasis remains an underestimated public health problem, just as it was at the dawn of last century.

Prevalence of Chagas disease in Latin-American migrants living in Europe: a systematic review and meta-analysis.

Background Few studies have assessed the burden of Chagas disease in non-endemic countries and most of them are based on prevalence estimates from Latin American (LA) countries that likely differ from the prevalence in migrants living in Europe. The aim of this study was to systematically review the existing data informing current understanding of the prevalence of Chagas disease in LA migrants living in European countries. Methods We conducted a systematic review and meta-analysis of studies reporting prevalence of Chagas disease in European countries belonging to the European Union (EU) before 2004 in accordance with the MOOSE guidelines and based on the database sources MEDLINE and Global Health. No restrictions were placed on study date, study design or language of publication. The pooled prevalence was estimated using random effect models based on DerSimonian & Laird method. Results We identified 18 studies conducted in five European countries. The random effect pooled prevalence was 4.2% (95%CI:2.2-6.7%); and the heterogeneity of Chagas disease prevalence among studies was high (I2 = 97%,p<0.001). Migrants from Bolivia had the highest prevalence of Chagas disease (18.1%, 95%CI:13.9–22.7%). Conclusions Prevalence of Chagas in LA migrants living in Europe is high, particularly in migrants from Bolivia and Paraguay. Data are highly heterogeneous dependent upon country of origin and within studies of migrants from the same country of origin. Country-specific prevalence differs from the estimates available from LA countries. Our meta-analysis provides prevalence estimates of Chagas disease that should be used to estimate the burden of disease in European countries.

Accuracy of Five Serologic Tests for the Follow up of Strongyloides stercoralis Infection

Background Traditional faecal-based methods have poor sensitivity for the detection of S. stercoralis, therefore are inadequate for post-treatment evaluation of infected patients who should be carefully monitored to exclude the persistence of the infection. In a previous study, we demonstrated high accuracy of five serology tests for the screening and diagnosis of strongyloidiasis. Aim of this study is to evaluate the performance of the same five tests for the follow up of patients infected with S. stercoralis. Methods Retrospective study on anonymized, cryo-preserved samples available at the Centre for Tropical Diseases (Negrar, Verona, Italy). Samples were collected before and from 3 to 12 months after treatment. The samples were tested with two commercially-available ELISA tests (IVD, Bordier), two techniques based on a recombinant antigen (NIE-ELISA and NIE-LIPS) and one in-house IFAT. The results of each test were evaluated both in relation to the results of fecal examination and to those of a composite reference standard (classifying as positive a sample with positive stools and/or at least three positive serology tests). The associations between the independent variables age and time and the dependent variable value of serological test (for all five tests), were analyzed by linear mixed-effects regression model. Results A high proportion of samples demonstrated for each test a seroreversion or a relevant decline (optical density/relative light units halved or decrease of at least two titers for IFAT) at follow up, results confirmed by the linear mixed effects model that showed a trend to seroreversion over time for all tests. In particular, IVD-ELISA (almost 90% samples demonstrated relevant decline) and IFAT (almost 87%) had the best performance. Considering only samples with a complete negativization, NIE-ELISA showed the best performance (72.5% seroreversion). Conclusions Serology is useful for the follow up of patients infected with S. stercoralis and determining test of cure.

Health Policies to Control Chagas Disease Transmission in European Countries

Chagas disease (CD) is a highly prevalent parasitic disease in immigrants from Mexico, as well as all of Central and South America. The total number of infected people is estimated between eight and ten million [1], [2], of whom 30%–40% either have, or will, develop cardiopathy, gastrointestinal disease, or both [1]. Cardiac involvement is the main cause of death from this infection through arrhythmias and cardiomyopathy. Nifurtimox and benznidazole are the only available medicines with proven efficacy against Trypanosoma cruzi infection in acute, congenital infection and early chronic infection. Until recently the treatment of chronic disease, particularly of adult patients with indeterminate form, was controversial; but during the past decade there has been a trend to offer treatment to adult patients and those with early cardiomyopathy [3]. To understand the magnitude of the problem, some economic studies have calculated the global cost of the disease worldwide at around 7,200,000,000 American dollars per year [4], which is mainly due to cardiovascular disease and early mortality. This cost is similar to, or even higher than, other prominent conditions such as rotavirus disease or cervical cancer [4]. In endemic countries, the main transmission route to humans is vectorial transmission through the faeces of infected triatomine bugs [1]. Oral transmission also occurs in endemic countries when beverages or food are contaminated with triatomine faeces [5]. Transmission through blood transfusion, organ transplantation from an infected donor, or from mother to child are less common routes, although they are of increasing importance, particularly in nonendemic areas where vectorial and oral transmission do not occur [1]. Another sporadic route of transmission is through the syringe sharing among drug users [6]. During the past decade, the infection has become a public health problem in some nonendemic countries, mainly due to migration and the chronic carriage of T. cruzi infection among a proportion of immigrants from endemic Latin American countries [7]. Since the first report of a case of CD in Europe was published in 1981 [8], sporadic cases have been detected in different European countries [9]. Since 2000, the number of reported cases has alarmingly increased, particularly in Spain and, to a lesser extent, in Italy and Switzerland [9]–[15]. In Europe, the currently estimated number of people with CD is between 68,000 and 122,000, but by 2009 only 4,290 had been diagnosed (index of underdiagnosis 93.9%–96.4%) [16]. The risk of transmission of T. cruzi infection in nonendemic countries through blood transfusion and organ transplantation has been described in multiple studies in the USA and more recently in Europe [17]–[21]. Moreover, several confirmed cases of T. cruzi transmission have already been detected in Europe [9], [22]. Accordingly, some studies have shown that it is cost-effective to screen for T. cruzi infection at blood banks, but depending on the prevalence of the disease, a mass screening of subjects—testing all—or a more selected strategy with screening questions to determine the risk level—screening and testing—should be applied [23]. Regarding congenital transmission, several studies have reported a rate of seroprevalence in Europe from 1.53% to 9.7% in pregnant women with the Bolivian population showing the highest seroprevalence rate [10], [24], [25], and with a transmission rate to newborn of around 7.3% [10]. Moreover, the strategy of screening pregnant women to control and treat newly diagnosed infected newborns has also shown to be cost-effective [26]. In response, several nongovernmental and later governmental initiatives have developed strategies to tackle this public health problem in the last years. The main aim of these initiatives has been to control the main transmission routes in nonendemic countries. Accordingly, some European countries have implemented national or regional measures to control transmission [27], [28], but many countries still have no legislation about it. In 2009, the World Health Organization (WHO) convened a WHO informal consultation (jointly organized by WHO headquarters and the WHO Regional Office for Europe) that performed a comprehensive review outlining this specific issue in Europe [29]. In collaboration with WHO, a research group working on migrant health, COHEMI, (COordinating resources to assess and improve HEalth status of MIgrants from Latin America) has undertaken this study aimed at reviewing the health policies implemented in European Union countries with the highest disease prevalence, plus Switzerland, to control the transmission of CD through blood transfusion, organ transplantation, and the congenital route.

StrongNet: An International Network to Improve Diagnostics and Access to Treatment for Strongyloidiasis Control

Strongyloidiasis is a disease caused by an infection with a soil-transmitted helminth that affects, according to largely varying estimates, between 30 million and 370 million people worldwide [1,2]. Not officially listed as a neglected tropical disease (NTD), strongyloidiasis stands out as particularly overlooked [3]. Indeed, there is a paucity of research and public health efforts pertaining to strongyloidiasis. Hence, clinical, diagnostic, epidemiologic, treatment, and control aspects are not adequately addressed to allow for an effective management of the disease, both in clinical medicine and in public health programs [4]. The manifold signs and symptoms caused by Strongyloides stercoralis infection, coupled with the helminth’s unique potential to cause lifelong, persistent infection, make strongyloidiasis relevant beyond tropical and subtropical geographic regions, where, however, most of the disease burden is concentrated. Indeed, strongyloidiasis is acquired through contact with contaminated soil, and the infection is, thus, primarily transmitted in areas with poor sanitation, inadequate access to clean water, and lack of hygiene. While the actual morbidity of chronically infected, immunocompetent individuals is subtle and difficult to appreciate [5], the particular importance of this parasitic worm is linked to its potential for maintaining lifelong autoinfections and causing a life-threatening hyperinfection syndrome in immunocompromised individuals [6]. Lack of point-of-care (POC) diagnostics and poor availability of, and access to, ivermectin (the current treatment of choice) are the two most significant bottlenecks that hinder effective management of the disease both in clinical and in public health settings. Examples of the management and importance of strongyloidiasis in two clinical contexts (in a tropical setting and a high-income country) and from a public health perspective are given in Boxes 1–3. Box 1. Individual Living in an Endemic Area with Diarrhea, Abdominal Pain, Pruritus, and Significant Dermatological Manifestations [10] A 43-year-old male farmer, living in the rural eastern part of Preah Vihear province, northern Cambodia, was diagnosed with a heavy Strongyloides stercoralis infection (924 and 478 larvae present in two Baermann examinations). Additionally, larvae and adult S. stercoralis were detected in Koga agar plate culture examinations of the stools. The patient was co-infected with hookworm and presented with abdominal pain, diarrhea, nausea, vomiting, fever, and a pronounced and persistent skin rash, which had been present with extensive itching for more than two years. The rash was observed on the back, chest, abdomen, and extremities and, due to frequent and intense scratching, showed signs of focal infection. Three weeks after treatment with a single oral dose of ivermectin (200 μg/kg) and a single oral dose of mebendazole, the patient’s rash had almost disappeared, and he was free of episodes of intensive itching.

Imported strongyloidiasis: epidemiology, presentations, and treatment.

Strongyloidiasis is extremely more frequent in immigrants than in travellers. Clinical presentations do not differ significantly between the two groups, and the most frequent picture is a chronic infection characterized by intermittent, mild, non-specific symptoms. Acute presentation is rare but it has been reported in travellers. Screening of asymptomatic subjects is not generally recommended, while a presumptive treatment with ivermectin might be justified for all travellers and immigrant patients presenting unexplained eosinophilia and/or compatible symptoms, even in case of negative test results. In fact, delayed diagnosis and treatment has life-threatening consequences in patients with conditions predisposing to development of hyperinfection and dissemination.

Evaluating Chagas disease progression and cure through blood-derived biomarkers: a systematic review

This article reviews the usefulness of various types of blood-derived biomarkers that are currently being studied to predict the progression of Chagas disease in patients with the indeterminate form, to assess the efficacy of antiparasitic drugs and to identify early cardiac and gastrointestinal damage. The authors used a search strategy based on MEDLINE, Cochrane Library Register for systematic review, EmBase, Global Health and LILACS databases. Out of 1716 screened articles, only 166 articles were eligible for final inclusion. The authors classified the biomarkers according to their biochemical structure and primary biological activity in four groups: i) markers of inflammation and cellular injury, ii) metabolic biomakers, iii) prothrombotic biomarkers and iv) markers derived from specific antigens of the parasite. Several potential biomarkers might have clinical potential for the detection of early cardiopathy. Such capacity is imperative in order to detect high-risk patients who require intensive monitoring and earlier therapy. Prospective studies with longer follow-ups are needed for the appraisal of biomarkers assessing clinical or microbiological cure after therapy. At the same time, studies evaluating more than one biomarker are useful to compare the efficacy among them given the lack of a recognized gold standard.