Nucleic acid and antigen detection tests for leptospirosis.

BACKGROUND: Early diagnosis of leptospirosis may contribute to the effectiveness of antimicrobial therapy and early outbreak recognition. Nucleic acid and antigen detection tests have the potential for early diagnosis of leptospirosis. With this systematic review, we assessed the sensitivity and specificity of nucleic acid and antigen detection tests. OBJECTIVES: To determine the diagnostic test accuracy of nucleic acid and antigen detection tests for the diagnosis of human symptomatic leptospirosis. SEARCH METHODS: We searched electronic databases including MEDLINE, Embase, the Cochrane Library, and regional databases from inception to 6 July 2018. We did not apply restrictions to language or time of publication. SELECTION CRITERIA: We included diagnostic cross-sectional studies and case-control studies of tests that made use of nucleic acid and antigen detection methods in people suspected of systemic leptospirosis. As reference standards, we considered the microscopic agglutination test alone (which detects antibodies against leptospirosis) or in a composite reference standard with culturing or other serological tests. Studies were excluded when the controls were healthy individuals or when there were insufficient data to calculate sensitivity and specificity. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data from each study. We used the revised Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2) to assess risk of bias. We calculated study-specific values for sensitivity and specificity with 95% confidence intervals (CI) and pooled the results in a meta-analysis when appropriate. We used the bivariate model for index tests with one positivity threshold, and we used the hierarchical summary receiver operating characteristic model for index tests with multiple positivity thresholds. As possible sources of heterogeneity, we explored: timing of index test, disease prevalence, blood sample type, primers or target genes, and the real-time polymerase chain reaction (PCR) visualisation method. These were added as covariates to the meta-regression models. MAIN RESULTS: We included 41 studies evaluating nine index tests (conventional PCR (in short: PCR), real-time PCR, nested PCR, PCR performed twice, loop-mediated isothermal amplification, enzyme-linked immunosorbent assay (ELISA), dot-ELISA, immunochromatography-based lateral flow assay, and dipstick assay) with 5981 participants (1834 with and 4147 without leptospirosis). Methodological quality criteria were often not reported, and the risk of bias of the reference standard was generally considered high. The applicability of findings was limited by the frequent use of frozen samples. We conducted meta-analyses for the PCR and the real-time PCR on blood products.The pooled sensitivity of the PCR was 70% (95% CI 37% to 90%) and the pooled specificity was 95% (95% CI 75% to 99%). When studies with a high risk of bias in the reference standard domain were excluded, the pooled sensitivity was 87% (95% CI 44% to 98%) and the pooled specificity was 97% (95% CI 60% to 100%). For the real-time PCR, we estimated a summary receiver operating characteristic curve. To illustrate, a point on the curve with 85% specificity had a sensitivity of 49% (95% CI 30% to 68%). Likewise, at 90% specificity, sensitivity was 40% (95% CI 24% to 59%) and at 95% specificity, sensitivity was 29% (95% CI 15% to 49%). The median specificity of real-time PCR on blood products was 92%. We did not formally compare the diagnostic test accuracy of PCR and real-time PCR, as direct comparison studies were lacking. Three of 15 studies analysing PCR on blood products reported the timing of sample collection in the studies included in the meta-analyses (range 1 to 7 days postonset of symptoms), and nine out of 16 studies analysing real-time PCR on blood products (range 1 to 19 days postonset of symptoms). In PCR studies, specificity was lower in settings with high leptospirosis prevalence. Other investigations of heterogeneity did not identify statistically significant associations. Two studies suggested that PCR and real-time PCR may be more sensitive on blood samples collected early in the disease stage. Results of other index tests were described narratively. AUTHORS' CONCLUSIONS: The validity of review findings are limited and should be interpreted with caution. There is a substantial between-study variability in the accuracy of PCR and real-time PCR, as well as a substantial variability in the prevalence of leptospirosis. Consequently, the position of PCR and real-time PCR in the clinical pathway depends on regional considerations such as disease prevalence, factors that are likely to influence accuracy, and downstream consequences of test results. There is insufficient evidence to conclude which of the nucleic acid and antigen detection tests is the most accurate. There is preliminary evidence that PCR and real-time PCR are more sensitive on blood samples collected early in the disease stage, but this needs to be confirmed in future studies.

The interaction between sickle cell disease and HIV infection: a systematic review.

Human immunodeficiency virus (HIV) and sickle cell disease (SCD) are regarded as endemic in overlapping geographic areas; however, for most countries only scarce data on the interaction between HIV and SCD and disease burden exist. HIV prevalence in SCD patients varies between 0% and 11.5% in published studies. SCD has been suggested to reduce disease progression of HIV into AIDS. Various interactions of antiretroviral therapy with SCD exist. Both SCD and HIV act as common risk factors for stroke, avascular necrosis, severe splenic dysfunction, pulmonary arterial hypertension, and sepsis, which may result in synergistic increase in risk of developing these diseases. No treatment guidelines regarding SCD with HIV coinfection were identified. Available evidence is mainly based on small clinical studies, thus making strong recommendations difficult. An increased effort to elucidate the precise interactions is warranted to better understand both diseases and effect more adequate treatment approaches, especially in view of their geographical coprevalence.

Efficacy and safety of artemisinin combination therapy (ACT) for non-falciparum malaria: a systematic review.

BACKGROUND: Artemisinin combination therapy (ACT) is recommended as first-line treatment for uncomplicated Plasmodium falciparum malaria, whereas chloroquine is still commonly used for the treatment of non-falciparum species (Plasmodium vivax, Plasmodium ovale and Plasmodium malariae). A more simplified, more uniform treatment approach across all malaria species is worthwhile to be considered both in endemic areas and for malaria as an imported condition alike. METHODS: A PROSPERO-registered systematic review to determine the efficacy and safety of ACT for the treatment of non-falciparum malaria was conducted, following PRISMA guidelines. Without language restrictions, Medline/PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, Biosis Previews and the African Index Medicus were searched for studies published up to November 2014. RESULTS: The literature search identified 986 reports; 40 publications were found eligible for inclusion, all of them on non-falciparum malaria in endemic areas. Most evidence was available for P. vivax (n = 35). Five clinical trials in total were identified evaluating ACT for P. ovale, P. malariae and Plasmodium knowlesi. Most ACT presentations have high efficacy against P. vivax parasites; artemisinin-based combinations have shorter parasite and fever clearance times compared to chloroquine. ACT is as effective as chloroquine in preventing recurrent parasitaemia before day 28. Artemisinin-based combinations with long half-lives show significantly fewer recurrent parasitaemia up to day 63. The limited evidence available supports both the use of chloroquine and an ACT for P. ovale and P. malariae. ACT seems to be preferable for optimal treatment of P. knowlesi. CONCLUSION: ACT is at least equivalent to chloroquine in effectively treating non-falciparum malaria. These findings may facilitate development of simplified protocols for treating all forms of malaria with ACT, including returning travellers. Obtaining comprehensive efficacy and safety data on ACT use for non-falciparum species particularly for P. ovale, P. malariae and P. knowlesi should be a research priority. TRIAL REGISTRATION: CRD42014009103.

Leptospirosis in Sub-Saharan Africa: a systematic review.

BACKGROUND: Leptospirosis is an emerging zoonotic infection worldwide, possibly due to climate change and demographic shifts. It is regarded as endemic in Sub-Saharan Africa; however, for most countries scarce epidemiological data, if any, exist. The primary objectives were to describe the prevalence of leptospirosis in countries in Sub-Saharan Africa, and to develop options for prevention and control in the future. METHODS: A systematic review was conducted to determine the prevalence of leptospirosis in Sub-Saharan Africa; the PRISMA guidelines were followed. Medline/PubMed, Embase, The Cochrane Library, Web of Science, BIOSIS Previews, the African Index Medicus, AJOL, and Google Scholar were searched. RESULTS: Information about the prevalence and incidence of leptospirosis in humans is available, but remains scarce for many countries. Data are unavailable or outdated for many countries, particularly those in Central Africa. Most data are available from animals, probably due to the economic losses caused by leptospirosis in livestock. In humans, leptospirosis is an important cause of febrile illness in Sub-Saharan Africa. It concerns numerous serogroups, harboured by many different animal carriers. DISCUSSION: A wide variety of data was identified. Prevalence rates vary throughout the continent and more research, especially in humans, is needed to reliably gauge the extent of the problem. Preventive measures need to be reconsidered to control outbreaks in the future.

Serum lipids and lipoproteins in malaria--a systematic review and meta-analysis.

BACKGROUND: Serum lipid profile changes have been observed during malaria infection. The underlying biological mechanisms remain unclear. The aim of this paper is to provide an overview on those serum lipid profile changes, and to discuss possible underlying biological mechanisms and the role of lipids in malaria pathogenesis. METHODS: A systematic review and meta-analysis to determine lipid profile changes during malaria was conducted, following PRISMA guidelines. Without language restrictions, Medline/PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, Biosis Previews and the African Index Medicus were searched for studies published up to 11 July, 2013, that measured serum lipid parameters in malaria patients. Also, major trial registries were searched. Mean differences in lipid profile parameters were combined in fixed and random effects meta-analysis, with a separate analysis for different groups of controls (healthy, other febrile illnesses or very low parasitaemia). These parameters were also compared between severe malaria and uncomplicated malaria. Funnel plots were used to test for publication bias. RESULTS: Of 2,518 studies reviewed, 42 met the criteria for inclusion in the qualitative analysis, and of these, 15 reported the necessary data for inclusion in the meta-analysis for cholesterol; nine for high-density lipoprotein (HDL), eight for low-density lipoprotein (LDL), and nine for triglycerides, respectively. Total cholesterol, HDL and LDL concentrations were lower in malaria and other febrile diseases compared to healthy controls. The decline was more pronounced and statistically significant during malaria compared to other febrile diseases. These results were consistent across included studies. Triglycerides were raised compared to healthy controls, but not statistically significant when compared to symptomatic controls. CONCLUSIONS: This meta-analysis suggests that the observed lipid profile changes are characteristic for malaria. Although a definite link with the pathogenesis of malaria cannot yet be demonstrated, plausible hypotheses of biological mechanisms involving host lipid alterations and the pathogenesis of malaria exist. An increased research effort to elucidate the precise pathways is warranted, since this could lead to better understanding of malaria pathophysiology and consequently to novel treatment approaches.

Is there an increased risk of post-operative surgical site infection after orthopaedic surgery in HIV patients? A systematic review and meta-analysis.

BACKGROUND: There is dilemma as to whether patients infected with the Human Immunodeficiency Virus (HIV) requiring implant orthopaedic surgery are at an increased risk for post-operative surgical site infection (SSI). We conducted a systematic review to determine the effect of HIV on the risk of post-operative SSI and sought to determine if this risk is altered by antibiotic use beyond 24 hours. METHODS: We searched electronic databases, manually searched citations from relevant articles, and reviewed conference proceedings. The risk of postoperative SSI was pooled using Mantel-Haenszel method. RESULTS: We identified 18 cohort studies with 16 mainly small studies, addressing the subject. The pooled risk ratio of infection in the HIV patients when compared to non-HIV patients was 1.8 (95% Confidence Interval [CI] 1.3-2.4), in studies in Africa this was 2.3 (95% CI 1.5-3.5). In a sensitivity analysis the risk ratio was reduced to 1.4 (95% CI 0.5-3.8). The risk ratio of infection in patients receiving prolonged antibiotics compared to patients receiving antibiotics for up to 24 hours was 0.7 (95% CI 0.1-4.2). CONCLUSIONS: The results may indicate an increased risk in HIV infected patients but these results are not robust and inconclusive after conducting the sensitivity analysis removing poor quality studies. There is need for larger good quality studies to provide conclusive evidence. To better develop surgical protocols, further studies should determine the effect of reduced CD4 counts, viral load suppression and prolonged antibiotics on the risk for infection.