Poul-Erik Kofoed

Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data

Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the ‘therapeutic’ day 7 lumefantrine concentration threshold needs to be defined better, particularly for important patient and parasite sub-populations. The WorldWide Antimalarial Resistance Network (WWARN) conducted a large pooled analysis of individual pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on study design, methodology and missing data. Of 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21 studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations (HR 1.59 (95 % CI 1.36 to 1.85) per halving of day 7 concentrations) and high baseline parasitemia (HR 1.87 (95 % CI 1.22 to 2.87) per 10-fold increase). Adjusted for mg/kg dose, day 7 concentrations were lowest in very young children (<3 years), among whom underweight-for-age children had 23 % (95 % CI −1 to 41 %) lower concentrations than adequately nourished children of the same age and 53 % (95 % CI 37 to 65 %) lower concentrations than adults. Day 7 lumefantrine concentrations were 44 % (95 % CI 38 to 49 %) lower following unsupervised treatment. The highest risk of recrudescence was observed in areas of emerging artemisinin resistance and very low transmission intensity. For all other populations studied, day 7 concentrations ≥200 ng/ml were associated with >98 % cure rates (if parasitemia <135,000/μL). Current artemether-lumefantrine dosing recommendations achieve day 7 lumefantrine concentrations ≥200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.

Patient surveys—A key to organizational change?

OBJECTIVE The objective was to investigate whether semi-customized patient satisfaction surveys are seen as useful by hospital management, and to explore their possible effects on quality improvement over time at a low organizational level. METHODS Data were collected from three sources: (1) patient surveys administered in eight public hospitals with a total of 2200 beds in a Danish county; (2) questionnaires completed by the hospital and clinical department managers; and (3) data from the countys Management Information System. RESULTS Patient satisfaction surveys were widely accepted as a tool for change. Bad results seemed to be an incentive for improvement unless hindered by fluctuation in patient turnover. Acceptance of the patient surveys as a way to generate change diminished over time. CONCLUSION Patient surveys may be an incentive for change if: (1) they have sufficient validity; (2) feedback is detailed on an organizational level and the units have significantly lower scores than comparable units; and (3) there are obvious actions to address the problems. PRACTICAL IMPLICATIONS Both qualitative and quantitative results should be analyzed for small organizational units within hospitals. Perceived usefulness of the surveys may be increased by involving medical professionals in the design and evaluation of the survey system.

Comparison of nasopharyngeal aspirate and nasal swab specimens for detection of respiratory syncytial virus in different settings in a developing country

OBJECTIVE To compare detection of respiratory syncytial virus (RSV) for diagnostic purposes using nasopharyngeal aspirate (NPA) and nasal swabs (NS) in different clinical settings in a community study in Guinea‐Bissau.

User satisfaction is influenced by the interval between a health care service and the assessment of the service

In order to improve the quality of patient care, questionnaires are often used to identify users experiences and evaluations, but only a few studies have examined whether measuring user satisfaction at different time points influences the assessment of health care. Several studies have shown equivalency between paper and electronic patient reported outcomes; however, none of these studies have considered the fact that electronic questionnaires are usually completed at the hospital, while paper questionnaires are typically completed at home weeks after the visit. In order to ensure that the comparison of results collected by the two different methods are not biased, the aim of this study was to determine if the interval between an outpatient visit and the assessment of the quality of care influences user satisfaction and to compare response rates between questionnaires completed at different times. In a follow-up study, parents from a paediatric outpatient clinic in Denmark were quasi-randomised to 1 of 3 groups: group 1 completed an electronic questionnaire on a touch screen computer in the outpatient clinic and a paper questionnaire 3-6 weeks after the visit; group 2 completed a paper questionnaire in the outpatient clinic and a paper questionnaire 3-6 weeks after the visit; and group 3 completed a paper questionnaire 3-6 weeks after the visit. A total of 1148 parents completed at least 1 questionnaire. User satisfaction was significantly lower when the assessment was made after a visit to the outpatient clinic compared to an assessment made at the clinic. The response rates of questionnaires completed at the clinic were significantly higher than the response rates of questionnaires completed after the visit. Both the timing of surveys and response rates need to be taken into consideration when planning user surveys. Outcomes from surveys conducted at different times are not readily comparable.

Can life coaching improve health outcomes? – A systematic review of intervention studies

BackgroundIn recent years, coaching has received special attention as a method to improve healthy lifestyle behaviours. The fact that coaching has found its way into healthcare and may provide new ways of engaging the patients and making them accountable for their health, justifies the need for an overview of the evidence regarding coaching interventions used in patient care, the effect of the interventions, and the quality of the studies published. However, in order to provide a clear definition of the coaching interventions selected for this review, we have found it necessary to distinguish between health coaching and life coaching. In this review, we will only focus on the latter method and on that basis assess the health related outcomes of life coaching.MethodsIntervention studies using quantitative or qualitative methods to evaluate the outcome of the life coach interventions were identified through systematic literature searches in PubMed, Embase, Psycinfo, and CINAHL. The quality of the methodology was independently assessed by three of the authors using a criteria list.ResultsA total of 4359 citations were identified in the electronic search and five studies were included; two of them were randomized controlled trials and met all quality criteria. The two studies investigating objective health outcomes (HbA1c) showed mixed but promising results, especially concerning the patient group that usually does not benefit from intensified interventions.ConclusionBecause of the very limited number of solid studies, this review can only present tendencies for patient outcomes and a preliminary description of an effective life coaching intervention.The coaching method used in these studies aims to improve self-efficacy and self-empowerment. This may explain why the studies including disadvantaged patients showed the most convincing results. The findings also indicate that some patients benefit from being met with an alternative approach and a different type of communication than they are used to from health care personnel.In order to get a closer look at what is in the ‘black box’, we suggest that the description and categorisation of the coaching methods are described more comprehensively, and that research into this area is supplemented by a more qualitative approach.

Bacillus Calmette-Guérin immunisation at birth and morbidity among Danish children: A prospective, randomised, clinical trial

BACKGROUND Studies from low-income countries report positive non-specific effects of early Bacillus Calmette-Guérin (BCG) immunisation on childhood health and survival. Neonatal immunisation with BCG may prime the immune system and offer partial protection against other infectious and possibly allergic diseases. The potential clinical value of these non-specific effects has not yet been examined in a large randomised trial in high-income countries. METHODS The Danish Calmette Study is a multicentre randomised clinical trial conducted between October 2012 and November 2015. Within the first 7 days of life, infants were randomly assigned to intra-dermal vaccination with BCG or no intervention. At 3 and 13 months of age structured telephone interviews and clinical examinations of the children were conducted. In a subgroup of children blood samples were drawn and stool samples collected at age 4 days, 3 and 13 months. Thymus index was assessed by ultrasound in a subgroup at randomisation and at 3 months. The primary study outcome is hospitalisation within the first 15 months of life as assessed in Danish health registers. Secondary outcomes include infectious disease hospitalisations, wheezing, eczema, use of prescribed medication, growth, development, thymus index, T- and B-cell subpopulations assessed by flow cytometry, in vitro cytokine responses and specific antibody responses to other vaccines. Adverse reactions were registered. DISCUSSION With participation of 4184 families and more than 93% adherence to clinical follow-up at 3 and 13 months, this randomised clinical trial has the potential to create evidence regarding non-specific effects of BCG vaccination in a high-income setting.

BCG vaccination at birth and early childhood hospitalisation: a randomised clinical multicentre trial

Background The BCG vaccine is administered to protect against tuberculosis, but studies suggest there may also be non-specific beneficial effects upon the infant immune system, reducing early non-targeted infections and atopic diseases. The present randomised trial tested the hypothesis that BCG vaccination at birth would reduce early childhood hospitalisation in Denmark, a high-income setting. Methods Pregnant women planning to give birth at three Danish hospitals were invited to participate. After parental consent, newborn children were allocated to BCG or no intervention within 7 days of age. Randomisation was stratified by prematurity. The primary study outcome was number of all-cause hospitalisations analysed as repeated events. Hospitalisations were identified using The Danish National Patient Register. Data were analysed by Cox proportional hazards models in intention-to-treat and per-protocol analyses. Results 4184 pregnant women were randomised and their 4262 children allocated to BCG or no intervention. There was no difference in risk of hospitalisation up to 15 months of age; 2129 children randomised to BCG experienced 1047 hospitalisations with a mean of 0.49 hospitalisation per child compared with 1003 hospitalisations among 2133 control children (mean 0.47), resulting in a HR comparing BCG versus no BCG of 1.05 (95% CI 0.93 to 1.18) (intention-to-treat analysis). The effect of BCG was the same in children born at term (1.05 (0.92 to 1.18)) and prematurely (1.07 (0.63 to 1.81), p=0.94). The effect was also similar in the two sexes and across study sites. The results were essentially identical in the per-protocol analysis and after adjustment for baseline characteristics. Conclusions BCG vaccination at birth did not reduce the risk of hospitalisation for somatic acquired disease until 15 months of age in this Danish study population. Trial registration number NCT01694108, results.

Duration of secretory IgM and IgA antibodies to respiratory syncytial virus in a community study in Guinea-Bissau.

Respiratory syncytial virus (RSV) is probably the single major cause of lower respiratory infection (LRI) among infants worldwide. Its relative importance may be underestimated, as the diagnosis is based on antigen detection and antigen may only be detectable in the early phase of infection. We have therefore assessed the duration of secretory IgM and IgA antibody responses and whether assays for these antibodies can be used to improve the diagnosing of RSV-associated infections. During two RSV epidemics in Guinea-Bissau, 32 RSV antigen-positive children with LRI were followed with sequential nasopharyngeal suction on days 7, 14, 30, 60 and 120 in the first epidemic and every fortnight for 6 mo after the second epidemic to measure the duration of secretory IgM and IgA responses. Nearly all of the children had an IgM response during the first month after infection. The response ratio was highest on days 7 and 14, being 84% and 71%, respectively. After 30 d the IgM response decreased rapidly. Among 27 age- and sex-matched controls, only 1 child was positive for IgM. During the second epidemic, when the children were followed more intensively, half of the children were IgM-positive after the acute phase of infection. A secondary response may be more likely in children with low IgM responses in the acute phase (RR = 2.08 (95% confidence interval (CI) 0.92-4.70)). The IgA response was highest on days 28 and 42 after antigen detection, 72% having a detectable IgA response within the first 1.5 mo. Among 27 controls, only 2 were IgA-positive (7%). In the second epidemic with more intensive follow-up, 62% (8/13) of the IgA-positive children had a response that lasted 10 wk. Of the children with no persistent IgA response, half (5/10) had a subsequent IgA-positive response after the first 42 d. All of these children had a simultaneous IgM-positive response. When 29 of the children were tested after an epidemic when they were 1-3-y-old, >80% again had high IgM (24/29, 82%) and IgA (28/29, 94%) levels. Among samples collected over a 1-y period from infants with LRI in a community morbidity surveillance conducted at the local health centre and via paediatric outpatient consultation, 17% (110/659) were antigen-positive, 26% (171/659) IgM-positive and 38% (248/659) either antigen- or IgM-positive. IgM responses are short-lived among infants and may therefore be used as an indication of recent RSV infection among children with LRI. Using both antigen and IgM detection may significantly improve our detection of RSV infections.

Secretory IgM and IgA antibodies to respiratory syncytial virus in nasopharyngeal aspirates: a diagnostic supplement to antigen detection

BACKGROUND RSV-shedding during an RSV-infection declines dramatically after the first week of infection. It could be of interest to be able to diagnose RSV-infection for a longer period of time by detection of specific RSV-IgM and RSV-IgA in nasopharyngeal aspirates (NPA) in order to minimize unnecessary antibiotics. OBJECTIVES To evaluate an ELISA to detect specific RSV-IgM and RSV-IgA in NPA as a supplement to RSV-antigen detection. STUDY DESIGN A total of 104 NPA from 101 children (median age 9 months) with acute respiratory disease (group 1) admitted to hospital and consecutive NPA (collected on day 0, 7, 14, 30 and 60) from 11 children (median age 3 months) with a proven RSV infection (group 2) were collected. All NPA from group 1 were analysed for RSV-antigen, RSV-IgM and RSV-IgA. NPA from group 2 were analysed for RSV-IgM and RSV-IgA. RESULTS Thirty-five NPA in group 1 were positive for RSV-antigen and 64 were positive for RSV-antigen test alone found 44% and the RSV-IgM test alone found 80%. In group 2 8/11 (73%) has an excellent RSV-IgM response day 7, the rest responded later. Only 5/11 (46%) had a less pronounced RSV-IgA response on day 7, three cases responded later and three did not respond at all. RSV-IgM disappeared in 8/11 (73%) and RSV-IgA in 7/8 (88%) between day 30-60. CONCLUSIONS Specific RSV-IgM is a valuable supplement to RSV-antigen detection for the diagnosis of acute and recent RSV infection.

Assessment of health care by children and adolescents depends on when they respond to the questionnaire

OBJECTIVE The aim of this study was to examine the assessments and priorities by children and adolescents of health care in a paediatric outpatient clinic, to examine the influence of the time factor on the assessments and priorities by children and adolescents of health care, and to determine their preferred method of evaluation. DESIGN A quasi-randomized follow-up study in which children and adolescents either completed a questionnaire at an outpatient clinic and again 3-6 weeks after the visit, or only 3-6 weeks after the visit. SETTING A Danish paediatric outpatient clinic. PARTICIPANTS Children and adolescents from the outpatient clinic. MAIN OUTCOME MEASURES Comparison between assessments given at the clinic and assessments given 3-6 weeks after the visit. RESULTS Three hundred forty-six children and adolescents completed at least one questionnaire. Children and adolescents were generally satisfied with the consultation at the paediatric outpatient clinic, but the visit was assessed less positive 3-6 weeks post-visit compared with assessments given immediately after the visit. Assessments and priorities of more general matters were not influenced by the time factor. Electronic surveys via touch screen computers were preferred to paper questionnaires by children and adolescents. CONCLUSIONS When comparing user satisfaction from different studies and when planning a survey of user satisfaction, the interval between the rendering of the health-care service and the assessment should be taken into consideration.