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Performance of an algorithm based on WHO recommendations for the diagnosis of smear-negative pulmonary tuberculosis in patients without HIV infection
No full textObjective To evaluate the performance of an algorithm based on WHO recommendations for diagnosis of smear-negative pulmonary tuberculosis in HIV-negative patients. Methods We recruited HIV-negative patients with clinical suspicion of tuberculosis who had had three negative sputum smears in Lima, Peru. All included subjects underwent a complete anamnesis, physical examination and chest X-ray, and had a sputum specimen cultured in Ogawa, Middlebrook 7H9 media and MGIT(R). We applied an algorithm based on WHO recommendations to classify patients as having tuberculosis or not. The diagnostic performance of the algorithm was evaluated comparing its results against the reference standard of a positive culture for M. tuberculosis in either of the media used. Results A total of 264 of the 285 patients included (92.6%) completed evaluation and follow up. Of these, 70 (26.5%) had a positive culture for M. tuberculosis. Clinical response to a broad spectrum course of antibiotics was good in 32 of these 70 patients (45.7; 95%CI 34.0-57.4%). Overall, the algorithm attained a sensitivity of 22.9% (95% CI 13.1-32.7%) and a specificity of 95.4 % (95% CI 92.4-98.3%) compared to culture results. The positive likelihood ratio was 4.93 and the negative likelihood ratio was 0.81. Conclusions The sensitivity and negative likelihood ratio of the algorithm is poor. It should be re-evaluated, and possibly adapted to local circumstances before further use. The clinical response to an antibiotic trial is the most important component to reassess. We also suggest considering performing chest X-ray earlier in the diagnostic work-up
Food insecurity, school absenteeism and educational attainment of adolescents in Jimma Zone Southwest Ethiopia: a longitudinal study
No full textTowards a standardised surveillance for Trichinella in the European Union
No full textEach year, more than 167 million pigs in the European Union (EU) are tested for Trichinella spp. under the current meat hygiene regulations. This imposes large economic costs on countries, yet the vast majority of these pigs test negative and the public health risk in many countries is therefore considered very low. This work reviewed the current Trichinella status across the EU as well as the national level of monitoring and reporting. It also reviewed which animal species were affected by Trichinella and in which species it should be surveyed. This information was used to design a cost-effective surveillance programme that enables a standardised monitoring approach within the EU. The proposed surveillance programme relies on identifying sub-populations of animals with a distinct risk. Low-risk pigs are finisher pigs that originate from so-called controlled housing. All other pigs are considered high-risk pigs. Controlled housing is identified by the application of a specific list of management and husbandry practices. We suggest that member states (MS) be categorised into three classes based on the confidence that Trichinella can be considered absent, in the specified sub-population of pigs above a specified design prevalence which we set to 1 per million pigs. A simple and transparent method is proposed to estimate this confidence, based on the sensitivity of the surveillance system, taking into account the sensitivity of testing and the design prevalence. The probability of detecting a positive case, if present, must be high (>95 or >99%) to ensure that there is a low or negligible risk of transmission to humans through the food chain. In MS where the probability of a positive pig is demonstrated to be negligible, testing of fattening pigs from a sub-population consisting of pigs from controlled housing can be considered unnecessary. Furthermore, reduced testing of finishers from the sub-population consisting of pigs from non-controlled housing might even be considered, if conducted in conjunction with a proportionate sampling scheme and a risk-based wildlife surveillance programme where applicable. The proposed surveillance programme specifies the required number of samples to be taken and found negative, in a MS. A MS with no data or positive findings will initially be allocated to class 1, in which all pigs should be tested. When a MS is able to demonstrate a 95% or 99% confidence that Trichinella is absent, the MS will be allocated to class 2 or 3, in which the testing requirement is lower than in class 1
Efficacy and safety of a 4-drug fixed-dose combination regimen compared with separate drugs for treatment of pulmonary tuberculosis: the Study C randomized controlled trial
No full textCONTEXT: Fixed-dose combinations (FDCs) of drugs for treatment of tuberculosis have been advocated to prevent the emergence of drug resistance. OBJECTIVE: To assess the efficacy and safety of a 4-drug FDC for the treatment of tuberculosis. DESIGN, SETTING, AND PATIENTS: The Study C trial, a parallel-group, open-label, noninferiority, randomized controlled trial conducted in 11 sites in Africa, Asia, and Latin America between 2003 and 2008. Patients were 1585 adults with newly diagnosed smear-positive pulmonary tuberculosis. INTERVENTIONS: Patients were randomized to receive daily treatment with 4 drugs (rifampicin, isoniazid, pyrazinamide, ethambutol) given as an FDC (n = 798 patients) or separately (n = 787) in the 8-week intensive phase of treatment. MAIN OUTCOME MEASURE: Favorable treatment outcome, defined as negative culture result at 18 months post randomization and not having already been classified as unfavorable. Noninferiority was dependent on consistent results from a per-protocol and modified intention-to-treat analysis, using 2 different models for the latter, classifying all changes of treatment or refusal to continue treatment (eg, bacteriological failure/relapse, adverse event, default, drug resistance) as unfavorable (model 1) and classifying changes of treatment for reasons other than therapeutic outcomes according to their 18-month bacteriological outcome if available (post hoc model 2). The prespecified noninferiority margin was 4%. RESULTS: In the per-protocol analysis, 555 of 591 patients (93.9%) had a favorable outcome in the FDC group vs 548 of 579 (94.6%) in the separate-drugs group (risk difference, -0.7% [90% confidence interval {CI}, -3.0% to 1.5%]). In the model 1 analysis, 570 of 684 patients (83.3%) had a favorable outcome in the FDC group vs 563 of 664 (84.8%) in the separate-drugs group (risk difference, -1.5% [90% CI, -4.7% to 1.8%]). In the post hoc model 2 analysis, 591 of 658 patients (89.8%) in the FDC group and 589 of 647 (91.0%) in the separate-drugs group had a favorable outcome (risk difference, -1.2% [90% CI, -3.9% to 1.5%]). Adverse events related to trial drugs were similarly distributed among treatment groups. CONCLUSIONS: Compared with a regimen of separately administered drugs, a 4-drug FDC regimen for treatment of tuberculosis satisfied prespecified noninferiority criteria in 2 of 3 analyses. Although the results do not demonstrate full noninferiority of the FDCs compared with single drugs given separately using the strict definition applied in this trial, use of FDCs is preferred because of potential advantages associated with the administration of FDCs compared with separate-drug formulations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00216333
A stochastic model accommodating the FAMACHA((c)) system for estimating worm burdens and associated risk factors in sheep naturally infected with Haemonchus contortus
No full textA previously developed multiple regression algorithm was used as the basis of a stochastic model to simulate worm burdens in sheep naturally infected with Haemonchus contortus over five consecutive Haemonchus seasons (November to January/February) on a farm in the summer rainfall region in South Africa, although only one season is discussed. The algorithm associates haemoglobin levels with worm counts in individual animals. Variables were represented by distributions based on FAMACHA((c)) scores and body weights of sheep, and Monte Carlo sampling was used to simulate worm burdens. Under conditions of high disease risk, defined as the sampling event during the worm season with the lowest relative mean haemoglobin level for a class of sheep, the model provided a distribution function for mean class H. contortus burdens and the probability of these occurring. A mean H. contortus burden for ewes (n=130 per sample) of approximately 1000 (range 51-28,768) and 2933 (range 78-44,175) for rams (n=120 per sample) was predicted under these conditions. At the beginning of the worm season when the risk of disease was lowest (i.e. when both classes had their highest estimated mean haemoglobin levels), a mean worm burden of 525 (range 39-4910) for ewes and 651 (range 37-17,260) for rams was predicted. Model indications were that despite being selectively drenched according to FAMACHA((c)) evaluation, 72% of the ewes would maintain their mean worm burden below an arbitrarily selected threshold of 1000 even when risk of disease was at its highest. In contrast, far fewer rams (27%) remained below this threshold, especially towards the end of the worm season. The model was most sensitive to changes in haemoglobin value, and thus by extrapolation, the haematocrit, which is used as the gold standard for validating the FAMACHA((c)) system. The mean class haemoglobin level at which there was a 50% probability of worm burdens being </=1000 worms was 7.05g/dl in ewes and 7.92g/dl in rams
Human Immunodeficiency Virus Type 1 (cross-) resistance to non-nucleoside reverse transcriptase inhibitors currently under development as microbicides
No full textMicrobicides based on non-nucleoside reverse transcriptase inhibitors (NNRTIs) are currently being developed to protect woman from HIV acquisition through sexual contact. However, the large-scale introduction of these products raises two major concerns. First, when these microbicides are used by undiagnosed HIV+ woman, they could potentially select for viral resistance which may compromise subsequent therapeutic options. Second, NNRTI-based microbicides which are inactive against NNRTI-resistant strains, might promote the selective transmission of these viruses. In order to address these concerns, drug resistance was selected in vitro by serial passage of three viral isolates from subtypes B, C, and CRF02_AG in activated peripheral blood mononuclear cells (PBMC) under increasing concentrations of three NNRTIs (i.e., TMC120, UC781, and MIV-160) which are currently being developed as candidate microbicides. TMC120 and MIV-160 displayed a high genetic barrier to resistance development whereas resistance to UC781 emerged rapidly, similar to efavirenz and nevirapine. Phenotypically, the selected viruses appeared highly cross-resistant to current first-line therapeutic NNRTIs (i.e., delavirdine, nevirapine, and efavirenz) although they retained some susceptibility to the more recently developed NNRTIs lersivirine and etravirine. The ability of UC781, TMC120 and MIV-160 to inhibit the in vitro selected NNRTI-resistant viruses was also limited, although residual activity could be observed for the candidate microbicide NNRTI MIV-170. Interestingly, only four p2/p7/p1/p6/PR/RT/INT-recombinant NNRTI-resistant viruses (i.e., TMC120-r VI829, EFV-r VI829, MIV-160-r VI829, and EFV-r MP568) showed impairment in replicative fitness. Overall, these in vitro analyses demonstrate that, due to potential cross-resistance, the large scale introduction of mono-RTI-based microbicides should be considered with caution
Isolation of Trypanosoma brucei gambiense from cured and relapsed sleeping sickness patients and adaptation to laboratory mice
No full textBACKGROUND: Sleeping sickness due to Trypanosoma brucei (T.b.) gambiense is still a major public health problem in some central African countries. Historically, relapse rates around 5% have been observed for treatment with melarsoprol, widely used to treat second stage patients. Later, relapse rates of up to 50% have been recorded in some isolated foci in Angola, Sudan, Uganda and Democratic Republic of the Congo (DRC). Previous investigations are not conclusive on whether decreased sensitivity to melarsoprol is responsible for these high relapse rates. Therefore we aimed to establish a parasite collection isolated from cured as well as from relapsed patients for downstream comparative drug sensitivity profiling. A major constraint for this type of investigation is that T.b. gambiense is particularly difficult to isolate and adapt to classical laboratory rodents. METHODOLOGY/PRINCIPAL FINDINGS: From 360 patients treated in Dipumba hospital, Mbuji-Mayi, D.R. Congo, blood and cerebrospinal fluid (CSF) was collected before treatment. From patients relapsing during the 24 months follow-up, the same specimens were collected. Specimens with confirmed parasite presence were frozen in liquid nitrogen in a mixture of Triladyl, egg yolk and phosphate buffered glucose solution. Isolation was achieved by inoculation of the cryopreserved specimens in Grammomys surdaster, Mastomys natalensis and SCID mice. Thus, 85 strains were isolated from blood and CSF of 55 patients. Isolation success was highest in Grammomys surdaster. Forty strains were adapted to mice. From 12 patients, matched strains were isolated before treatment and after relapse. All strains belong to T.b. gambiense type I. CONCLUSIONS AND SIGNIFICANCE: We established a unique collection of T.b. gambiense from cured and relapsed patients, isolated in the same disease focus and within a limited period. This collection is available for genotypic and phenotypic characterisation to investigate the mechanism behind abnormally high treatment failure rates in Mbuji-Mayi, D.R. Congo
Evaluation of the Genotype(R) MTBDRplus assay as a tool for drug resistance surveys
No full textSETTING: A national tuberculosis (TB) drug resistance survey in Tanzania. OBJECTIVE: To compare the performance of the Genotype(R) MTBDRplus line-probe assay (LPA) on smear-positive sputum specimens with conventional culture and isoniazid (INH) plus rifampicin (RMP) drug susceptibility testing (DST). DESIGN: Mycobacterium tuberculosis isolates tested at the Tanzanian Central TB Reference Laboratory (CTRL) were submitted for quality assurance of phenotypic DST to its supranational reference laboratory (SRL), together with ethanol-preserved sputum specimens for LPA DST. RESULTS: Only 321 samples could be tested using LPA; of these, three were identified as being non-tuberculous mycobacteria using CTRL DST. Both tests had 269 sets with interpretable results. CTRL DST yielded almost the same number of interpretable results as LPA, with 90% concordance (kappa = 0.612, P < 0.001). Five (1.9%) multidrug-resistant (MDR) strains, 46 (17.1%) resistant to INH only and 0 RMP only, were found by CTRL DST. For the LPA, these results were respectively 5 (1.9%), 26 (9.7%) and 2 (0.7%). With SRL DST as the gold standard, LPA was more accurate than CTRL DST for RMP, but missed almost half the INH-resistant samples. CONCLUSION: LPA applied directly on ethanol-preserved sputum specimens was similar to phenotypic DST in terms of yield of interpretable results. Although probably more accurate for RMP and MDR-TB, it appears to seriously underestimate INH resistance. Considering speed, easy and safe specimen transportation and low infrastructure requirements, LPA DST from sputum can be recommended for surveys in resource-poor settings
False positive circumsporozoite protein ELISA: a challenge for the estimation of the entomological inoculation rate of malaria and for vector incrimination
No full textBACKGROUND: The entomological inoculation rate (EIR) is an important indicator in estimating malaria transmission and the impact of vector control. To assess the EIR, the enzyme-linked immunosorbent assay (ELISA) to detect the circumsporozoite protein (CSP) is increasingly used. However, several studies have reported false positive results in this ELISA. The false positive results could lead to an overestimation of the EIR. The aim of present study was to estimate the level of false positivity among different anopheline species in Cambodia and Vietnam and to check for the presence of other parasites that might interact with the anti-CSP monoclonal antibodies. METHODS: Mosquitoes collected in Cambodia and Vietnam were identified and tested for the presence of sporozoites in head and thorax by using CSP-ELISA. ELISA positive samples were confirmed by a Plasmodium specific PCR. False positive mosquitoes were checked by PCR for the presence of parasites belonging to the Haemosporidia, Trypanosomatidae, Piroplasmida, and Haemogregarines. The heat-stability and the presence of the cross-reacting antigen in the abdomen of the mosquitoes were also checked. RESULTS: Specimens (N=16,160) of seven anopheline species were tested by CSP-ELISA for Plasmodium falciparum and Plasmodium vivax (Pv210 and Pv247). Two new vector species were identified for the region: Anopheles pampanai (P. vivax) and Anopheles barbirostris (Plasmodium malariae). In 88% (155/176) of the mosquitoes found positive with the P. falciparum CSP-ELISA, the presence of Plasmodium sporozoites could not be confirmed by PCR. This percentage was much lower (28% or 5/18) for P. vivax CSP-ELISAs. False positive CSP-ELISA results were associated with zoophilic mosquito species. None of the targeted parasites could be detected in these CSP-ELISA false positive mosquitoes. The ELISA reacting antigen of P. falciparum was heat-stable in CSP-ELISA true positive specimens, but not in the false positives. The heat-unstable cross-reacting antigen is mainly present in head and thorax and almost absent in the abdomens (4 out of 147) of the false positive specimens. CONCLUSION: The CSP-ELISA can considerably overestimate the EIR, particularly for P. falciparum and for zoophilic species. The heat-unstable cross-reacting antigen in false positives remains unknown. Therefore it is highly recommended to confirm all positive CSP-ELISA results, either by re-analysing the heated ELISA lysate (100degreesC, 10 min), or by performing Plasmodium specific PCR followed if possible by sequencing of the amplicons for Plasmodium species determination