A longitudinal and cross-sectional study ofEpstein-Barr virus DNA load: a possible predictor of AIDS-related lymphoma in HIV-infected patients.

INTRODUCTION: HIV-infected patients are more than 100-fold greater at risk for developing malignant AIDS-related lymphoma (ARL) compared to the general population. Most ARLs are EBV related. The main purpose of this study was to investigate whether a high peak EBV DNA load in HIV-infected patients is predictive of ARL, including classical Hodgkin lymphoma. METHODS: From an ongoing prospective HIV positive cohort study, we conducted a case-control study between 2004 and 2016 among patients from whom at least one EBV DNA load in serum or plasma was available. We compared peak EBV DNA load between patients with (49 cases) and without ARL (156 controls). RESULTS: The geometric mean of the peak EBV DNA load measured before diagnosis of malignant lymphoma was 52,565 IU/mL in EBER-positive lymphoma patients vs. 127 IU/mL in controls (p < .001). Patients with EBV DNA loads >100,000 IU/mL have an increased risk for diagnosis of malignant lymphoma compared to patients with EBV DNA loads ≤100,000 IU/mL (adjusted OR 12.53; 95%CI: 4.08; 38.42). In the longitudinal study, including 13 patients with at least three left-over plasma samples available for retesting, measurements of EBV-DNA during the preceding 12 months proved to be of poor value for predicting subsequent lymphoma diagnosis. CONCLUSIONS: A EBV DNA load >100,000 IU/mL can be useful in clinical setting to accelerate time to diagnosis and treatment. EBV-DNA loads in samples taken during the preceding year of ARL diagnosis showed to be of poor predictive value.

Diagnostic performance of influenza viruses and RSV rapid antigen detection tests in children in tertiary care.

BACKGROUND: Rapid antigen detection tests (RADTs) are increasingly used to detect influenza viruses and respiratory syncytial virus (RSV). However, their sensitivity and specificity are a matter of debate, challenging their clinical usefulness. OBJECTIVES: Comparing diagnostic performances of BinaxNow Influenza AB(®) (BNI) and BinaxNow RSV(®) (BNR), to those of real-time reverse transcriptase PCR (RT-PCR), virus isolation and direct immunofluorescence (D-IF) in paediatric patients. STUDY DESIGN: Between November 2005 and September 2013, 521 nasal washings from symptomatic children (age <5 years) attending our tertiary care centre were tested, with a combination of the respective assays using RT-PCR as gold standard. RESULTS: Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of BNI were 69% (confidence interval [CI] [51-83]), 96% [94-97], 55% [39-70] and 98% [96-99] respectively. Of eleven false-negative samples, RT-PCR Ct-values were higher than all RT-PCR positive test results (27 vs 22, p=0.012). Of twenty false-positive samples, none were culture positive and two tested positive in D-IF. Sensitivity, specificity, PPV and NPV for BNR were 79% [73-85], 98% [96-99], 97% [93-99] and 88% [84-91]. Of the 42 false-negative samples the median Ct-value was higher than that of all RT-PCR positive samples (31 vs 23, p<0.0001). Five false-positive samples were detected. Three of these tested positive for RSV in virus isolation and D-IF. CONCLUSIONS: RADTs have a high specificity with BNR being superior to BNI. However, their relative low sensitivity limits their usefulness for clinical decision making in a tertiary care paediatric hospital.

Profiling of humoral immune responses to influenza viruses by using protein microarray.

The emergence of pandemic A(H1N1) 2009 influenza showed the importance of rapid assessment of the degree of immunity in the population, the rate of asymptomatic infection, the spread of infection in households, effects of control measures, and ability of candidate vaccines to produce a response in different age groups. A limitation lies in the available assay repertoire: reference standard methods for measuring antibodies to influenza virus are haemagglutination inhibition (HI) assays and virus neutralization tests. Both assays are difficult to standardize and may be too specific to assess possible partial humoral immunity from previous exposures. Here, we describe the use of antigen-microarrays to measure antibodies to HA1 antigens from seven recent and historical seasonal H1, H2 and H3 influenza viruses, the A(H1N1) 2009 pandemic influenza virus, and three avian influenza viruses. We assessed antibody profiles in 18 adult patients infected with A(H1N1) 2009 influenza virus during the recent pandemic, and 21 children sampled before and after the pandemic, against background reactivity observed in 122 persons sampled in 2008, a season dominated by seasonal A(H1N1) influenza virus. We show that subtype-specific and variant-specific antibody responses can be measured, confirming serological responses measured by HI. Comparison of profiles from persons with similar HI response showed that the magnitude and broadness of response to individual influenza subtype antigens differs greatly between individuals. Clinical and vaccination studies, but also exposure studies, should take these findings into consideration, as they may indicate some level of humoral immunity not measured by HI assays.

HIV testing and antiretroviral treatment strategies for prevention of HIV infection: impact on antiretroviral drug resistance.

'Test and treat' is a strategy in which widespread screening for human immunodeficiency virus (HIV) is followed by immediate antiretroviral therapy for those testing positive, thereby potentially reducing infectiousness in larger cohorts of infected patients. However, there is a concern that test and treat could lead to increased the levels of transmissible drug-resistant HIV, especially if viral load and/or drug resistance is not routinely monitored. Reviews of the existing literature show that up to now, even in the absence of laboratory tests, drug resistance has not created major problems in sub-Saharan Africa. Here, we discuss the current evidence for the effectiveness of a preventive test and treat approach and the challenges and implications for daily clinical practice and public health.

HIV-1 drug-resistance patterns among patients on failing treatment in a large number of European countries.

BACKGROUND: Information about patterns of HIV-1 drug resistance among treatment-exposed patients is crucial for the development of novel effective drugs. Currently no system exists that monitors patterns of resistance in patients failing therapy. METHODS: The study included 1,988 HIV-1 sequences from patients experiencing therapy failure collected between 2000 and 2004 in 15 European countries. Genotypic resistance was interpreted using the ANRS algorithm. Phenotypic resistance was predicted using the Virco geno- to phenotype system. RESULTS: 80.7% of the sequences included at least one drug-resistance mutation. Mutations were found for NRTIs (73.5%), NNRTIs (48.5%), and protease inhibitors (35.8%). Ninety percent of sequences with genotypic resistance harbored M184V, M41L, K103N, D67N, and/or T215Y. Among NRTIs, resistance was most frequently predicted for lamivudine. About half of all sequences had reduced susceptibility for NNRTIs. Resistance to most boosted protease inhibitors was found in < 25%. No sequence had resistance to all currently available drugs. CONCLUSION: Levels of resistance among patients with therapy failure were high. The patterns of resistance reflect resistance to drugs available for a longer time. Fully suppressive regimens can be designed even for the most mutated HIV because boosted protease inhibitors have remained active against most circulating viruses and new drug classes have become available.

Effectiveness of highly active antiretroviral therapy administered by general practitioners in rural South Africa.

The purpose of this study was to assess the one-year efficacy of highly active antiretroviral therapy (HAART) administered by general practitioners in a primary care community clinic in rural South Africa. We performed an observational cohort study of 675 treatment-naive human immunodeficiency virus (HIV)-infected patients (including 66 children) who began HAART at least 12 months prior to the data analyses. Throughout treatment, the CD4+ T-cell count (percentage of CD4+ T-cells in children) and plasma HIV-RNA level were determined and the patient's weight was recorded. The primary outcome was mortality. Secondary outcomes were viral suppression, immunological response, and weight gain. One year after the start of HAART, 100 of the 675 (15%) patients were lost to follow-up and 119 patients (18%), including six children, died. Mortality was highest during the first few months of treatment. Based on an on-treatment analysis at one year after the start of therapy, 83% of adults and 71% of children had a viral load <400 copies/ml; the viral load was <50 copies/ml in 70% of adults and 61% of children. At one year, the mean CD4+ T-cell count in adults had increased by 236/mm(3), and the mean body mass index (BMI) had increased by 3.5 kg/m(2). In children, the mean CD4% had increased by 17.6. A low Karnofsky score and a low baseline CD4+ T-cell count were independently associated with death. In addition to these factors, a low baseline BMI and gender were predictive of a poor immunological outcome. Our study shows that adequately monitored HIV/acquired immunodeficiency syndrome (AIDS) care administered by general practitioners and their staff is feasible and leads to good results in a rural, primary care center in sub-Saharan Africa. In order to achieve even better results, early mortality should be reduced and efforts should be made to start HAART earlier.

Enterobacter colonisation in newborn infants: predictors, follow-up and implications for infection control.

Outbreaks with Enterobacter spp. have been described frequently in neonatal intensive care units (NICUs). This study investigated the factors that determine whether a neonate becomes colonised with Enterobacter spp., how long colonisation continues and whether the termination of isolation measures leads to spread of the organism. Neonates transferred from the NICUs of tertiary care hospitals were screened for the presence of Enterobacter spp. and any potential predictors for colonisation recorded. Those infected were monitored during their hospital stay and colonised neonates were screened every month for six months. Isolation infection control precautions were lifted and all neonates were screened for the presence of Enterobacter spp. six and 12 months later. Fifteen colonised neonates and 33 non-colonised controls were identified for study. Multivariate analysis showed that antibiotic therapy for more than three days and an Apgar score of <8 after 1 min were independently associated with Enterobacter spp. colonisation. Molecular typing using single-enzyme amplified-fragment length polymorphism (seAFLP) analysis revealed 22 different seAFLP genotypes. Three infants remained colonised with the same Enterobacter genotype after discharge; however, most neonates lost their strain or became colonised with another genotype. Lifting infection control measures for neonates colonised with Enterobacter spp. in a neonatal ward did not lead to increased incidence of colonisation and none of the infants became infected. Isolating neonates with susceptible Enterobacter spp. was not found to be necessary.

Start of a selective serotonin reuptake inhibitor (SSRI) and increase of antiparkinsonian drug treatment in patients on levodopa.

AIMS: We determined whether the start of selective serotonin reuptake inhibitors (SSRI) in levodopa users was followed by a faster increase of antiparkinsonian drug treatment. METHODS: Selected were all levodopa users of 55 years and older from the PHARMO prescription database. The rate of increase of antiparkinsonian drug treatment was compared using Cox's proportional hazard model for starters of SSRI (n = 15) with starters of tricyclic antidepressants (TCA) (n = 31) and with patients not using antidepressants (n = 304), and was adjusted for age, gender, and duration of levodopa use. RESULTS: The hazard ratio for the SSRI group compared with the TCA group was 4.2 (95% confidence interval 1.4, 12.6) and compared with the second control group was 2.7 (1.2, 5.2). CONCLUSIONS: The start of SSRI therapy in levodopa users is followed by a faster increase of antiparkinsonian drug treatment.

Antipsychotics and Parkinson's disease: association with disease and drug choice during the first 5 years of antiparkinsonian drug treatment.

OBJECTIVE: Psychosis is a common complication of the drug treatment of Parkinson's disease (PD). Treatment of this complication is difficult as most antipsychotic drugs worsen motor symptoms of PD. Only the atypical antipsychotic clozapine improves psychosis without worsening of parkinsonism. The aim of the present study was to assess the rate of initiation of antipsychotic treatment in patients with PD compared with controls. The quality of pharmacotherapy was determined by assessing which antipsychotic drugs were initiated. METHODS: Data came from the PHARMO database, which includes drug-dispensing information for all residents of six Dutch cities. Selected were all persons aged 55 years and older who used levodopa for at least 180 days and who started antiparkinsonian drugs at least 180 days after entry into PHARMO. These patients were matched to at most three controls for age, gender, pharmacy and time of use. The association between rate of initiation of antipsychotic drug treatment and PD was determined using the Cox proportional hazards model. RESULTS: The study included 271 patients with PD and 748 controls. During follow-up, 38 patients and 25 controls started taking an antipsychotic drug; relative risk was 3.9 (95% confidence interval 2.3, 6.4). Six patients with PD received an atypical agent (16%). Clozapine was given to five patients with PD. No control used clozapine. Haloperidol was most frequently prescribed to the patients (29%) and the controls (36%). CONCLUSION: Patients with PD began taking antipsychotic drugs almost four times more frequently than controls. The quality of pharmacotherapy can be improved by prescribing atypical antipsychotic drugs to patients with PD.

Influence of benzodiazepines on antiparkinsonian drug treatment in levodopa users.

OBJECTIVES: Animal studies showed that benzodiazepines decrease the concentration of dopamine in the striatum. Benzodiazepines may therefore affect the treatment of Parkinson's disease. This study determined whether start of a benzodiazepine in patients on levodopa was followed by a faster increase of antiparkinsonian drug treatment. METHODS: Data came from the PHARMO database, which includes information on drug dispensing for all residents of six Dutch cities. Selected were all patients aged 55 years and older who used levodopa for at least 360 days. The rate of increase of antiparkinsonian drug treatment was compared between starters of a benzodiazepine and controls who did not start a benzodiazepine with the use of Cox's proportional hazard model. RESULTS: Identified were 45 benzodiazepine starters (27 women, mean age 76.4 years) and 169 controls (83 women, 74.3 years). Antiparkinsonian drug treatment increased faster in the benzodiazepine group; relative risk was 1.44 (95% confidence interval 0.80-2.59). CONCLUSION: This study has not found any statistically significant increase in antiparkinsonian drug treatment when a benzodiazepine was started in a small population of chronic levodopa users.

Evaluation of antiparkinsonian drugs in pharmacy records as a marker for Parkinson's disease.

AIM: The aim of this study was to determine whether use of antiparkinsonian drugs in pharmacy records can be used as a marker for patients with Parkinson's disease (PD). METHOD: Data were obtained from the Rotterdam Study, a community-based prospective cohort study among people aged 55 years or older who were all screened for PD. For 5510 persons, of whom 74 had PD, pharmacy records were available. Stepwise logistic regression analysis was used to evaluate whether age, sex and use of the antiparkinsonian drugs amantadine, anticholinergics, dopamine agonists, levodopa and selegiline, were predictive variables for PD. For each individual a probability for having PD was calculated. Sensitivity, specificity and positive predictive value (PPV) were calculated at different cut-off values based on calculated probabilities. RESULTS: More than 90% of the users of levodopa, bromocriptine, selegiline, and users of at least two different antiparkinsonian drugs had PD. Age, use of amantadine, anticholinergics, bromocriptine, levodopa, and selegiline were predictive variables for PD. After application of different cut-off values, sensitivity was at most 66.2%, and specificity was at least 99.8%. A PPV of higher than 90% was obtained at higher probabilities. CONCLUSION: Based on the high PPV of our predictive model, antiparkinsonian drugs can be used as a reliable marker for PD in pharmacy records. Because sensitivity is low, pharmacy records cannot be used to estimate prevalence of PD.

Estimation of incidence and prevalence of Parkinson's disease in the elderly using pharmacy records.

PURPOSE: We determined the prevalence and incidence of Parkinson's disease among persons aged 55 years and older in pharmacy records. METHODS: Data came from the PHARMO database which includes information on drug dispensing for all residents of six Dutch cities. We selected all persons aged 55 years and older who had used antiparkinsonian drugs, and calculated a chance for having Parkinson's disease with use of a previously validated logistic regression model. We used a cut-off of 0.5 (sensitivity 62%, positive predictive value 92%). Prevalence was estimated on the first Wednesday of October 1997, incidence on the first Wednesday of October 1993 until 1997. A patient was incident, if the first prescription for an anti-parkinsonian drug was dispensed at least 180 days after entry into PHARMO. Prevalence and incidence were standardized to the Netherlands population of 1 January 1998. The prevalence was adjusted for the sensitivity and positive predictive value of the model. RESULTS: The unadjusted prevalence (per 100,000) for those aged 55-64 years was 111, 65-74 years 598, 75-84 years 1551 and for persons aged 85 years and older 1847. The adjusted and standardized prevalence was 970 per 100,000 (95% confidence interval 869 to 1071). The incidence (per 100,000 person years) for persons aged 55-64 years was 12, 65-74 years 108, 75-84 years 257 and for persons aged 85 years and older 247. The standardized incidence was 109 per 100,000 person years (96 to 121). CONCLUSIONS: Prevalence and incidence were in range with the literature. Pharmacy records therefore seem to be a useful tool for continuous monitoring of incidence and prevalence of Parkinson's disease.