Rosalind L. Smyth

IFITM3 restricts the morbidity and mortality associated with influenza

The 2009 H1N1 influenza pandemic showed the speed with which a novel respiratory virus can spread and the ability of a generally mild infection to induce severe morbidity and mortality in a subset of the population. Recent in vitro studies show that the interferon-inducible transmembrane (IFITM) protein family members potently restrict the replication of multiple pathogenic viruses. Both the magnitude and breadth of the IFITM proteins’ in vitro effects suggest that they are critical for intrinsic resistance to such viruses, including influenza viruses. Using a knockout mouse model, we now test this hypothesis directly and find that IFITM3 is essential for defending the host against influenza A virus in vivo. Mice lacking Ifitm3 display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, mirroring the destruction inflicted by the highly pathogenic 1918 ‘Spanish’ influenza. Similar increased viral replication is seen in vitro, with protection rescued by the re-introduction of Ifitm3. To test the role of IFITM3 in human influenza virus infection, we assessed the IFITM3 alleles of individuals hospitalized with seasonal or pandemic influenza H1N1/09 viruses. We find that a statistically significant number of hospitalized subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C) that alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. Together these data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans.

Dual Infection of Infants by Human Metapneumovirus and Human Respiratory Syncytial Virus Is Strongly Associated with Severe Bronchiolitis

Abstract The association between severe bronchiolitis and dual infection by human metapneumovirus (hMPV) and human respiratory syncytial virus (hRSV) was investigated in !2-year-old infants with bronchiolitis who were admitted to the hospital during the 2001–2002 winter season. hMPV in nasopharyngeal aspirate and/or cells and fluid collected by nonbronchoscopic bronchoalveolar lavage was detected by reverse transcriptase-polymerase chain reaction (RT-PCR). hRSV was detected in nasopharyngeal aspirate and/or cells and fluid collected by nonbronchoscopic bronchoalveolar lavage by enzyme immunoassay, tissue culture, and RT-PCR. Dual infection with hMPV and hRSV confers a 10-fold increase in relative risk (RR) of admission to a pediatric intensive-care unit for mechanical ventilation (RR, 10.99 [95% confidence interval, 5.0–24.12]; P < .001, by Fisher exact test). Dual infection by hMPV and hRSV is associated with severe bronchiolitis.

Research with children: Paediatric practice needs better evidence—gained in collaboration with parents and children

All those concerned with the clinical care of children have a responsibility to improve that care, and one way of achieving this is by research. The importance of research into normal childhood development and into the methods of promoting good health, together with studies of the aetiology, natural history, diagnosis, and treatment of childhood diseases is well recognised. So too are the perils of relying on information from studies conducted in adults and generalising these to children. However, undertaking clinical research in children presents unique challenges.1 The most obvious of these are the ethical ones: the need to protect children from harm while respecting their autonomy and to obtain properly informed consent from parents, and, when possible, the children themselves. There are also methodological challenges. Outcome measures, developed and validated in adults, are unlikely to be appropriate or feasible for children and babies. The proportions of children affected by chronic diseases are smaller and the diseases often more heterogeneous than in adults, and diagnostic …

Using the Delphi technique to determine which outcomes to measure in clinical trials: recommendations for the future based on a systematic review of existing studies.

Ian Sinha and colleagues advise that when using the Delphi process to develop core outcome sets for clinical trials, patients and clinicians be involved, researchers and facilitators avoid imposing their views on participants, and attrition of participants be minimized.

Strictures of ascending colon in cystic fibrosis and high-strength pancreatic enzymes

We have observed five children with cystic fibrosis, who presented over 2 months, with meconium ileus equivalent that failed to respond to medical management. At surgery, four had a stricture in the ascending colon, and all had histopathological changes of post-ischaemic ulceration repair, with mucosal and submucosal fibrosis. The only common change in the management of these children was a switch from conventional enteric-coated pancreatic enzymes to high-strength products 12-15 months before presentation.

Infrared ear thermometry compared with rectal thermometry in children: a systematic review

BACKGROUND Infrared ear thermometry is frequently used in children, because this is a quick method of taking temperature and the ear is easily accessible. Our aim was to evaluate agreement between temperature measured at the rectum and ear in children. METHODS We did a systematic review of studies comparing temperature measured at the rectum (the reference site) using mercury, electronic, or indwelling probe thermometers, with temperature measured at the ear (the test site) using infrared ear thermometers. Heterogeneity between studies was investigated by exploring subgroups according to the mode of the infrared ear thermometer. FINDINGS 44 studies containing 58 comparisons (5935 children) were eligible for inclusion in this review. Outcome data were available in reports from 12 comparisons (2312 [39%] children), and data on individual patients were obtained for a further 19 comparisons (2129 [36%] children). 31 comparisons (4441 [75%] children) were therefore included in the meta-analysis. The pooled mean temperature difference (rectal minus ear) was 0.29 degrees C (95% limits of agreement -0.74 to 1.32). We pooled data by ear device mode and the mean temperature differences were rectal mode 0.15 degrees C (-0.95 to 1.25), actual 0.70 degrees C (-0.20 to 1.60), core 0.25 degrees C (-0.78 to 1.27), oral 0.34 degrees C (-0.86 to 1.54), tympanic 0.62 degrees C (-0.40 to 1.64) and mode not stated 0.32 degrees C (-0.57 to 1.21). There was significant residual heterogeneity in both mean differences and sample SDs within the groups of ear device mode. INTERPRETATION Although the mean differences between rectal and ear temperature measurements were small, the wide limits of agreement mean that ear temperature is not a good approximation of rectal temperature, even when the ear thermometer is used in rectal mode. Our finding suggests that infrared ear thermometry does not show sufficient agreement with an established method of temperature measurement to be used in situations where body temperature needs to be measured with precision.

Temperature measured at the axilla compared with rectum in children and young people: systematic review

Abstract Objective: To evaluate the agreement between temperature measured at the axilla and rectum in children and young people Design: A systematic review of studies comparing temperature measured at the axilla (test site) with temperature measured at the rectum (reference site) using the same type of measuring device at both sites in each patient. Devices were mercury or electronic thermometers or indwelling thermocouple probes. Studies reviewed: 40 studies including 5528 children and young people from birth to 18 years. Data extraction: Difference in temperature readings at the axilla and rectum. Results: 20 studies (n=3201 (58%) participants) had sufficient data to be included in a meta-analysis. There was significant residual heterogeneity in both mean differences and sample standard deviations within the groups using different devices and within age groups. The pooled (random effects) mean temperature difference (rectal minus axillary temperature) for mercury thermometers was 0.25°C (95% limits of agreement −0.15°C to 0.65°C) and for electronic thermometers was 0.85°C (−0.19°C to 1.90°C). The pooled (random effects) mean temperature difference (rectal minus axillary temperature) for neonates was 0.17°C (−0.15°C to 0.50°C) and for older children and young people was 0.92°C (−0.15°C to 1.98°C). Conclusions: The difference between temperature readings at the axilla and rectum using either mercury or electronic thermometers showed wide variation across studies. This has implications for clinical situations where temperature needs to be measured with precision.

A systematic review of studies that aim to determine which outcomes to measure in clinical trials in children.

Background In clinical trials the selection of appropriate outcomes is crucial to the assessment of whether one intervention is better than another. Selection of inappropriate outcomes can compromise the utility of a trial. However, the process of selecting the most suitable outcomes to include can be complex. Our aim was to systematically review studies that address the process of selecting outcomes or outcome domains to measure in clinical trials in children. Methods and Findings We searched Cochrane databases (no date restrictions) in December 2006; and MEDLINE (1950 to 2006), CINAHL (1982 to 2006), and SCOPUS (1966 to 2006) in January 2007 for studies of the selection of outcomes for use in clinical trials in children. We also asked a group of experts in paediatric clinical research to refer us to any other relevant studies. From these articles we extracted data on the clinical condition of interest, description of the method used to select outcomes, the people involved in the selection process, the outcomes selected, and limitations of the method as defined by the authors. The literature search identified 8,889 potentially relevant abstracts. Of these, 70 were retrieved, and 25 were included in the review. These studies described the work of 13 collaborations representing various paediatric specialties including critical care, gastroenterology, haematology, psychiatry, neurology, respiratory paediatrics, rheumatology, neonatal medicine, and dentistry. Two groups utilised the Delphi technique, one used the nominal group technique, and one used both methods to reach a consensus about which outcomes should be measured in clinical trials. Other groups used semistructured discussion, and one group used a questionnaire-based survey. The collaborations involved clinical experts, research experts, and industry representatives. Three groups involved parents of children affected by the particular condition. Conclusions Very few studies address the appropriate choice of outcomes for clinical research with children, and in most paediatric specialties no research has been undertaken. Among the studies we did assess, very few involved parents or children in selecting outcomes that should be measured, and none directly involved children. Research should be undertaken to identify the best way to involve parents and children in assessing which outcomes should be measured in clinical trials.

Effect of respiratory virus infections including rhinovirus on clinical status in cystic fibrosis.

One hundred and eight patients with cystic fibrosis were investigated over one year to determine whether an association existed between rhinovirus or other respiratory virus infection and clinical status. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), Shwachman score, Chrispin-Norman chest radiograph score, and percentage weight for height were recorded at the beginning and end of the study; days of intravenous antibiotics were noted. Nasopharyngeal aspirates were taken for viral studies during respiratory exacerbations. Serum was collected at enrollment and 2-6 weeks after each respiratory exacerbation. One hundred and fifty seven exacerbations occurred in 76 patients. Respiratory virus infection was detected in 44 exacerbations and rhinovirus was present in 16% (25/157) of exacerbations. Patients with one or more respiratory virus infections were compared with those who had none. When all respiratory virus infections were considered, patients had a significantly greater deterioration in Shwachman score and received significantly more days of intravenous antibiotics. When rhinovirus was considered separately, patients received significantly more days of intravenous antibiotics, but showed no deterioration in clinical status. However, patients infected with another respiratory virus had a significant decline in FEV1, with trends towards significance for decline in FVC and Shwachman score.

Fibrosing colonopathy in cystic fibrosis: results of a case-control study.

Fibrosing colonopathy was first described in cystic fibrosis (CF) children in 1994. We have done a nested case-control study to identify possible associations with this condition. A case ascertainment within the UK CF population to identify any cases that occurred between January, 1984, and April, 1994, found 14 cases, all under 14 years and confirmed by independent histopathological review. All had presented since April, 1993; 12 were boys and six had received some or all of their care in Liverpool. Each case was matched, by date of birth, with four controls from the UK CF Registry. Information was obtained about cases and controls from their case records and by a structured interview with the families. In the 12 months before surgery, there was an association between the occurrence of fibrosing colonopathy and use of high-strength pancreatic enzyme preparations. This association was dose related. Odds ratio per extra 1000 high-strength capsules was 1.45 (95% CI 1.14-1.84). For use of protease, the odds ratio per million extra units per kg was 1.55 (1.19-2.03). For usage of individual high-strength products at any time during the 12 months before surgery some differences were observed; for Creon 25000 the odds ratio was 0.38 (0.10-1.42), for Nutrizym 22 43.4 (2.51-751), and for Pancrease HL 8.4 (1.95-36.1). These last two confidence intervals are extremely wide and compatible with these two products having the same odds ratios. Laxative use was independently predictive (odds ratio 2.42 [1.20-4.94]). We conclude that there is a dose-related association between high-strength pancreatic enzyme preparations and fibrosing colonopathy.