Andrea Angheben

The Role of Rapid Diagnostic Tests in Managing Malaria

Zeno Bisoffi and colleagues discuss a new clinical trial in Zanzibar comparing symptom-based clinical diagnosis of malaria versus clinical diagnosis plus rapid diagnostic tests.

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.

Rapid malaria diagnostic tests vs. clinical management of malaria in rural Burkina Faso: safety and effect on clinical decisions. A randomized trial

Objectives  To assess if the clinical outcome of patients treated after performing a Rapid Diagnostic Test for malaria (RDT) is at least equivalent to that of controls (treated presumptively without test) and to determine the impact of the introduction of a malaria RDT on clinical decisions.

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.

Randomized Clinical Trial on Ivermectin versus Thiabendazole for the Treatment of Strongyloidiasis

Background Strongyloidiasis may cause a life-threatening disease in immunosuppressed patients. This can only be prevented by effective cure of chronic infections. Direct parasitologic exams are not sensitive enough to prove cure if negative. We used an indirect immune fluorescent antibody test (IFAT) along with direct methods for patient inclusion and efficacy assessment. Methodology/Principal Findings Prospective, randomized, open label, phase III trial conducted at the Centre for Tropical Diseases (Verona, Italy) to compare efficacy and safety of ivermectin (single dose, 200 µg/kg) and thiabendazole (two daily doses of 25 mg/Kg for two days) to cure strongyloidiasis. The first patient was recruited on 6th December, 2004. Follow-up visit of the last patient was on 11th January, 2007. Consenting patients responding to inclusion criteria were randomly assigned to one of the treatment arms. Primary outcome was: negative direct and indirect (IFAT) tests at follow-up (4 to 6 months after treatment) or subjects with negative direct test and drop of two or more IFAT titers. Considering 198 patients who concluded follow-up, efficacy was 56.6% for ivermectin and 52.2% for thiabendazole (p = 0.53). If the analysis is restricted to 92 patients with IFAT titer 80 or more before treatment (virtually 100% specific), efficacy would be 68.1% for ivermectin and 68.9% for thiabendazole (p = 0.93). Considering direct parasitological diagnosis only, efficacy would be 85.7% for ivermectin and 94.6% for thiabendazole (p = 0.21). In ivermectin arm, mild to moderate side effects were observed in 24/115 patients (20.9%), versus 79/108 (73.1%) in thiabendazole arm (p = 0.00). Conclusion No significant difference in efficacy was observed, while side effects were far more frequent in thiabendazole arm. Ivermectin is the drug of choice, but efficacy of single dose is suboptimal. Different dose schedules should be assessed by future, larger studies. Trial Registration Portal of Clinical Research with Medicines in Italy 2004–004693–87

Accuracy of a rapid diagnostic test on the diagnosis of malaria infection and of malaria - attributable fever during low and high transmission season in Burkina Faso

BackgroundMalaria management policies currently recommend that the treatment should only be administered after laboratory confirmation. Where microscopy is not available, rapid diagnostic tests (RDTs) are the usual alternative. Conclusive evidence is still lacking on the safety of a test-based strategy for children. Moreover, no formal attempt has been made to estimate RDTs accuracy on malaria-attributable fever. This study aims at estimating the accuracy of a RDT for the diagnosis of both malaria infection and malaria - attributable fever, in a region of Burkina Faso with a typically seasonal malaria transmission pattern.MethodsCross-sectional study. Subjects: all patients aged > 6 months consulting during the study periods. Gold standard for the diagnosis of malaria infection was microscopy. Gold standard for malaria-attributable fever was the number of fevers attributable to malaria, estimated by comparing parasite densities of febrile versus non-febrile subjects. Exclusion criteria: severe clinical condition needing urgent care.ResultsIn the dry season, 186/852 patients with fever (22%) and 213/1,382 patients without fever (15%) had a Plasmodium falciparum infection. In the rainy season, this proportion was 841/1,317 (64%) and 623/1,669 (37%), respectively. The attributable fraction of fever to malaria was 11% and 69%, respectively. The RDT was positive in 113/400 (28.3%) fever cases in the dry season, and in 443/650 (68.2%) in the rainy season. In the dry season, the RDT sensitivity and specificity for malaria infection were 86% and 90% respectively. In the rainy season they were 94% and 78% respectively. In the dry season, the RDT sensitivity and specificity for malaria-attributable fever were 94% and 75%, the positive predictive value (PPV) was 9% and the negative predictive value (NPV) was 99.8%. In the rainy season the test sensitivity for malaria-attributable fever was 97% and specificity was 55%. The PPV ranged from 38% for adults to 82% for infants, while the NPV ranged from 84% for infants to over 99% for adults.ConclusionsIn the dry season the RDT has a low positive predictive value, but a very high negative predictive value for malaria-attributable fever. In the rainy season the negative test safely excludes malaria in adults but not in children.

Imported Malaria in Adults and Children: Epidemiological and Clinical Characteristics of 380 Consecutive Cases Observed in Verona, Italy

BACKGROUND Since the year 2000, in Italy, there has been a constant decrease in the number of cases of imported malaria in immigrants. Nevertheless, immigrants still account for about 70% of reported cases. To our knowledge, no data are yet available on imported malaria in children. This paper describes the main characteristics of malaria cases observed in recent years in the three main hospitals in Verona (roughly representing 10% of all cases reported in Italy in the period), with a special focus on the poorly known problem of imported malaria in children. METHOD All malaria cases occurring from 2000 to 2004 were retrospectively examined. Semi-immune and nonimmune patients were analyzed for clinical, laboratory, and parasitological findings. A separate analysis was carried out for children who traveled to endemic areas to visit relatives and friends (VRF) and children born in endemic countries who came to Italy for immigration purposes. RESULTS A total of 380 cases of imported malaria occurred in Verona in the 5-year period, 43 being children. Semi-immune patients had a significantly lower parasitemia (p = 0.0032) and parasite clearance time and significantly shorter fever duration than nonimmune (p = 0.025 and p = 0.0026). VRF children presented significantly higher parasitemia and significantly lower platelet count (p = 0.016 and p = 0.042) than recent immigrants. Parasitemia clearance time and fever duration were longer in VRF children than in recent immigrants (p = 0.014 and p = 0.0085). We observed 23 cases of severe malaria, including 4 cases in immigrants. CONCLUSIONS Our data confirm a significant difference both in clinical and in parasitological findings between semi-immune and nonimmune patients. We identified two populations of immigrant children: semi-immune (recent immigrants) and nonimmune (VRF). The latter is a high-risk group for severe malaria. Educational actions should be specially designed for immigrants traveling to VRF, focusing on the risk of severe malaria for both adults and children.

Evaluation of an indirect immunofluorescence assay for strongyloidiasis as a tool for diagnosis and follow-up.

ABSTRACT The diagnostic accuracy of an indirect immunofluorescence antibody test (IFAT) for Strongyloides stercoralis at different serum antibody titers was evaluated. To assess diagnostic sensitivity, sera from 156 patients with known strongyloidiasis were collected. Negative control sera were obtained from a composite group of 427 subjects (blood donors and hospitalized patients). With an area under the receiver-operating characteristic plot of 0.98, the IFAT showed a high level of diagnostic accuracy for strongyloidiasis. An antibody titer of ≥1:20, with 97% sensitivity and 98% specificity, was identified as the diagnostic threshold with the best overall performance. Cross-reactions were evaluated with 41 additional samples from patients with other known helminth infections, and the IFAT detected low-titer positivity in only one subject with filariasis. A positive IFAT result at an antibody dilution of ≥1:80 was virtually 100% specific, with 71% sensitivity. To test the usefulness of the IFAT as a monitoring tool, the changes in specific-antibody titers after treatment in a group of 155 patients were evaluated. Seroreversion or a decrease in antibody titer of twofold or more was observed in 60% of the patients. Response to treatment was directly correlated to the initial antibody titer, and a baseline titer of ≥1:80 was identified as the best predictor of response. In conclusion, a positive IFAT result at an antibody dilution of ≥1:20 is the optimal cutoff for screening. A titer of ≥1:80, with virtually no false-positive result, is a reliable cutoff for a serological assessment of treatment efficacy and for inclusion in clinical trials.

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.