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Background The mechanisms regulating antibody expression within the human lung during airway infection are largely unknown. In this study, our objectives were to determine if infection with respiratory syncytial virus (RSV) upregulates expression of the B cell differentiation factors A proliferation inducing ligand (APRIL) and B cell activating factor of the TNF family (BAFF), if this is a common feature of viral airway infection, and how this is regulated in human airway epithelial cells. Methods We measured BAFF and APRIL protein expression in bronchoalveolar lavage (BAL) fluid from infants with severe RSV disease, and healthy control children, and in nasopharyngeal aspirates from preschool children with other single respiratory viral infections. We also measured mRNA expression in bronchial brushings from RSV-infected infants, and in RSV-infected paediatric primary airway epithelial cell cultures (pAEC). Beas-2B cell cultures were used to examine mechanisms regulating BAFF expression. Results BAFF protein and mRNA were elevated (in marked contrast with APRIL) in BAL and bronchial brushings, respectively, from RSV-infected infants. BAFF protein was also found in upper airway secretions from children with human metapneumovirus, H1N1, bocavirus, rhinovirus, RSV and Mycoplasma pneumoniae infection. BAFF mRNA and protein were expressed following in vitro RSV infection of both pAEC and Beas-2B cultures, with mRNA expression peaking 12-h postinfection. BAFF induction was blocked by addition of a neutralising anti-interferon-β antibody or palivizumab. Conclusions BAFF, produced through an interferon-β-dependant process, is a consistent feature of airway infection, and suggests a role for the airway epithelia in supporting protective antibody and B cell responses in the lung.

Background Assent is used to take children's wishes into account when they are invited into clinical trials, but the concept has attracted considerable criticism. We investigated children's accounts of decision‐making with the aim of informing practice in supporting children when invited to join a clinical trial. Methods We audio‐recorded qualitative, semi‐structured interviews with 22 children aged 8–16 years about being invited to take part in a clinical trial. Most children were interviewed with their parents. Analysis of the transcribed interviews examined the content of participants' accounts thematically, whilst also drawing on principles of discourse analysis, which examines how individuals use talk to achieve certain effects or social practices. Results It was not possible to separate children's knowledge of the clinical trial, or their decision‐making processes from that of their parents, with parents taking a substantial mediating role in producing their children's decisions. Decision‐making gradually unfolded across time and events and was interwoven within the family context, rather than happening in one moment or in the clinical setting. Whilst children valued their parents' role, a case study of child–parent disagreement indicated how children can struggle to be heard. Conclusions Decisions happen within a process of family dynamics, in contrast to ideas of assent that isolate it from this context. Parents have a substantial role in children's decisions, and thus how families come to provide consent. Reflecting this we argue that assent practices need to focus on supporting parents to support their children in learning and deliberating about trials. However, this needs to be accompanied by practitioners being alert to the possibility of divergence in child and parent views and enabling children's perspectives to be heard.

Summary. Haemophilia care is effective but therapy is expensive. Despite concentrates being available in some areas for more than 30 years, many scientific questions concerning the management of haemophilia, such as what doses and duration of factor are required for different bleeding episodes or for surgical procedures, remain inadequately answered. Modern rigorous methods of assessment of the evidence both assist in determining what facts are available, how reliable the evidence is, and also help to define what studies need to be done. Cochrane methodology can be applied to haemophilia, and an assessment of prophylaxis provides an example. International collaborative studies would be valuable and require enthusiastic participants.

The concept of 'evidence-based medicine' has now been in widespread use in clinical practice for over a decade. There are different types of clinical study, which may provide evidence on which to base clinical decisions, but some are much less robust than others. In making decisions about treatment, one of the highest levels of evidence in primary research is the randomized controlled trial. This study design has been used in clinical research for over 50 years. Systematic reviews of randomized controlled trial are scientific studies that review, critically appraise and, where appropriate, aggregate results from a number of different randomized controlled trials. They are increasingly being used throughout health care to provide guidance about treatment. Under the auspices of The Cochrane Collaboration, systematic reviews of randomized controlled trials are being conducted across the whole of health care. One of the most active areas for this work is within the field of asthma and clinicians are now able to access a large number of different systematic reviews on The Cochrane Library. If used appropriately, they can aid the clinician in making decisions about individual patients and provide a sound evidence base from which clinical guidelines can be developed.

Cystic fibrosis (CF) is one of the commonest lethal inherited conditions among Caucasians. It affects multiple organ systems and exhibits a range of clinical problems of varying severity. Life expectancy has improved in recent years as treatment regimes have become more intensive, but current treatments are expensive, often time consuming and may affect quality of life. This review summarises the treatments currently used in the management of patients with CF, and the evidence for these.

Body mass index (BMI) centile is recommended for assessing body fatness in children. We compared the reliability of two methods of deriving BMI centile. A total of 42 dietitians calculated the BMI centiles of six children, half using the Cole Calculator (a slide rule) and half calculating by hand and plotting on the BMI centile chart. The centile chart method was more reliable than the Cole Calculator, probably due to its greater familiarity.

It is known that adverse drug reactions (ADRs) cause admission to hospital in adults and children. A recent adult study showed that ADRs are an important and frequent cause of hospital admission. The objective of this study is to develop methodology to ascertain the current burden of ADRs through a prospective analysis of all unplanned admissions to a paediatric hospital.Prospective observational study over a 2-week period.There were 19 admissions to the main hospital wards related to an ADR, giving an estimated incidence of 4%, with the ADR directly leading to the admission in 71% of cases. There were no deaths attributable to ADR. 33% of the reactions were possibly avoidable. The drugs most commonly implicated in causing admissions were anti-neoplastic agents. The most common reactions were neutropenia, vomiting and diarrhoea. The health burden of ADRs in the paediatric population is likely to be significant. This pilot study will be used to inform a much larger prospective study providing more detailed evidence of the burden of ill-health from ADRs in children. This larger study will add to a body of research aiming to identify drug-related problems within children to aid paediatric pharmacovigilance.This study provides knowledge regarding the methodology to be used for a larger study investigating ADRs in children. The study will allow authors who wish to replicate the study in their own populations (internationally) to avoid some of the pitfalls in planning a large epidemiological study of paediatric ADRs. The study also provides an estimate of the incidence and problem of admissions caused by ADRs in a UK paediatric population.

OBJECTIVES: To investigate recruitment processes across a range of clinical trials and from the perspective of parents, young people and practitioners to identify strategies to improve recruitment and its conduct across the spectrum of trials of medicines for children. DESIGN: Qualitative interview and observational study. SETTING: Eleven paediatric clinical trial centres recruiting to four trials. PARTICIPANTS: Members of 60 families approached to consider entry to one of the participating trials and 31 practitioners. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Data were verbatim transcripts of (1) audio-recorded trial recruitment discussions between practitioners and families (n = 41) and (2) semi-structured interviews with parents (n = 62), young people (n = 22) and practitioners (19 doctors and 12 research nurses). Analyses were interpretive, following the general principles of the constant comparative method. RESULTS: Practitioners were concerned to avoid overburdening parents and some indicated that they found approaching families about trials to be aversive. By contrast, even in the most difficult situations, parents did not mind being asked about trials and they did not describe the approach as burdensome. Some parents viewed the trial approach as a positive or exciting opportunity. Parents and young people took little active part in the trial discussions and asked few questions. Despite this, they were satisfied with how they had been approached, and spoke of how they had felt involved, valued, cared for and comfortable to interject during the discussion. However, we identified several parents who had important misunderstandings about the trial. There were few differences between parents who consented and those who declined a trial. Regardless of whether they consented or declined, parents' trial decisions were influenced by their perceptions of the trial in relation to their child's safety and well-being, potential benefits to the child and family, potential benefits to others and the practicality of participation. Of these, parents' paramount consideration was safety. Parents', young people's and practitioners' views of what was important when considering a trial were broadly convergent, although families gave greater importance than practitioners to the trial's practical requirements. All parties valued the face-to-face trial discussion highly and wanted shorter and less complex written information. Parents did not feel pressured by the trial team to participate, but some described how their personal values made them reluctant to decline, and several parents who did decline described a passing sense of discomfort. CONCLUSIONS: The concerns of some practitioners that families would be overburdened were unfounded, as parents did not object to being asked about research. Practitioners may benefit from support that helps them feel personally more at ease in approaching families about trials. Parents and young people often described the trial discussions in strongly positive terms and emphasised the importance of the social and emotional aspects of these encounters. Informed consent training could be enhanced if it similarly emphasised these aspects of recruitment; the misunderstandings we identified indicate how this training could also help practitioners to improve the clarity of their trial discussions with families. Guidelines on informed consent documents should take account of findings that all groups thought that these documents should be shorter and more straightforward. FUNDING: This research was commissioned by the National Institute for Health Research Health Technology Assessment programme.

Introduction and objectives Respiratory Syncytial Virus (RSV) is a major cause of lower respiratory tract infection during infancy. Neutrophils are the predominant cell type within the RSV-infected airway, 80% of inflammatory cells from BAL of intubated infants being neutrophils. Despite extensive research unpicking innate viral responses to RSV little is known about the specific role the neutrophil plays. The aim of this work was to investigate the response of neutrophils to RSV using an in vitro model utilising neutrophils from adult volunteers. To investigate whether relative immaturity of infant neutrophils leads to impaired responses we are now comparing adult neutrophils with neonatal neutrophils, isolated from cord blood. Methods Highly purified neutrophils from whole blood of healthy adult donors were incubated with RSV. Samples were taken at 2, 4, and 20 h for QT-PCR of RSV N gene, western blot analysis and cytospin slides for confocal imaging of RSV F protein. Experiments were then replicated using neutrophils purified from cord blood, collected from the placenta following elective caesarean section, of healthy term neonates. Supernatants were stored for measurement of the cytokine response of the neutrophil to RSV. Results Uptake of RSV by adult neutrophils was shown by both western blot and quantitative RT-PCR. Maximal uptake was at 4 h with a reduction by 20 h. Confocal microscopy was undertaken, using a primary monoclonal antibody to RSV fusion protein. This showed that RSV was internalised inside the cytoplasm in a distribution suggestive of endosomal uptake (see figure) . Preliminary data suggests that neonatal neutrophils are also capable of this viral uptake but work is ongoing to determine differences between the two models. Conclusions We have shown that neutrophils may be involved in viral clearance as part of the immune response to viral invasion. They appear to take up virus with kinetics suggestive of endocytosis. Work is ongoing to establish the mechanism of entry using a panel of inhibitors. Initial results would suggest that neonatal neutrophils may respond similarly but work continues to establish whether this is the case and if there is any functional impairment that may explain infants’ propensity to severe disease.

Since July 1988, a total of 92 transbronchial biopsies (TBB) have been performed in 18 patients (aged 3-16 years). Twelve patients (67%) were heart-lung transplant (HLT) recipients undergoing surveillance for pulmonary graft rejection and infection. The remainder included immunocompromised patients at risk of opportunistic infections (n = 4), patients with fibrosing alveolitis (n = 1) and a collagen vascular disorder with suspected lung involvement (n = 1). TBB was performed through either a fiberoptic (n = 50) or a rigid (n = 41) bronchoscope, all under general anesthesia. On one occasion a cardiac bioptome was used through an endotracheal stent. The sensitivity of TBB for diagnosing acute and chronic rejection in HLT patients was 88% and 60%, respectively (specificity, 91% and 100%). Definitive diagnoses were made in 4 (67%) of the non-HLT group. Bronchoalveolar lavage (BAL) was performed during each procedure for microbiological and cytological examination. Thirty-four pathogenic organisms including Pseudomonas aeruginosa (16/34), Staphylococcus aureus (8/34), and Candida albicans (5/34) were isolated from BAL culture. Complications included pneumothorax (8%), transient pyrexia (7%), and dyspnea (2%).

The risk factors, clinical associations, and response to treatment of cytomegalovirus (CMV) pneumonia and infection were studied in 65 recipients of heart-lung transplantation. There were 29 episodes of CMV pneumonia in 22 patients. In 80% (20/25) of episodes of CMV pneumonia treated with intravenous ganciclovir, the histologic changes resolved and the patient survived. Among seronegative recipients, a seropositive donor was a significant risk factor for CMV pneumonia and infection in the first 90 days after heart-lung transplantation (P = .004 and .002, respectively). Among seropositive recipients, there was no additional risk associated with a sero-positive donor. Rates of CMV pneumonia and infection were significantly increased when treatment with augmented immunosuppression had been given in the preceding 30 days (P less than .001). A significant association was found between CMV pneumonia or infection and pulmonary bacterial infections occurring 30 days before or after such an episode (P less than .001).

From among 112 patients with cystic fibrosis who were assessed for heart-lung transplantation, 83 were accepted. Twenty-six died while awaiting heart-lung transplantation and 32 had the operation. The management and the outcome of these 32 patients is reported. Survival, infection, and rejection rates among these patients were compared with those of 61 patients without cystic fibrosis who underwent heart-lung transplantation between 1984 and 1990. The cumulative survival rate was 72.29% +/- 94.91% at 1 year and 55.59% +/- 7.50% at 3 years. The mortality rate was slightly higher in the group with cystic fibrosis during the first year after the operation but it was lower at 3 years. The difference, however, could have been due to chance alone (p = 0.308). The same was true for the prevalence of rejection (up to 6 months: chi 2 = 1.8141, p = 0.17), and infection (up to 6 months: chi 2 = 2.20, p = 0.14), between the two groups. It is concluded that cystic fibrosis does not constitute an additional risk in terms of survival and morbidity after heart-lung transplantation.

Sixty transbronchial biopsies have been performed in eight children after heart-lung transplantation. The selection of fiber-optic bronchoscope or a small (4 mm; 30 cm) rigid bronchoscope was made according to the size of endotracheal tube required at surgery. If the endotracheal tube was size 7.5 or greater, a fiber-optic bronchoscope was used, whereas if the endotracheal tube size was below 7, a rigid bronchoscope was used. For the diagnosis of lung rejection, the histology of biopsies revealed a sensitivity of 91% and specificity of 69% (similar to the result in adults). The histology also distinguished lung infection from rejection. Complications included three pneumothoraces and two clinically significant episodes of hemorrhage, one of which led to a cardiorespiratory arrest, which may have been caused by hypoxia. As a result, arterial oxygen saturation is now monitored during the procedure using a pulse oximeter.

The cyclosporin dose versus blood concentration relationship for 11 heart-lung transplant recipients with cystic fibrosis was studied retrospectively. Eleven patients, closely matched for age and gender, who received heart-lung transplantation for other diseases were selected as controls. Cystic fibrosis patients received 16.7 (SD 7.2) mg/kg/day of oral cyclosporin compared with 8.2 (SD 1.9) mg/kg/day given to the control patients (p less than 0.01). Nine of the cystic fibrosis patients received higher mean daily doses of cyclosporin. Mean blood cyclosporin concentrations were, however, not significantly different (p = 0.58), and there were no apparent differences in clinical outcome in terms of rejection, infection, and nephrotoxicity in the two groups. The apparent oral clearance of cyclosporin was significantly higher (p less than 0.01) in cystic fibrosis patients. Cyclosporin dosage individualization with the aid of cyclosporin blood concentration measurements is critically important in this subpopulation of heart-lung transplant recipients.

Cross-correlation of cyclosporine concentrations with results of biochemical tests of renal and liver function, measured during the first three months post-operatively, was carried out retrospectively in 24 heart and eight heart-lung transplant recipients to assess the temporal relationship between cyclosporine treatment and the development of possible toxic side-effects. We found a statistically significant negative correlation (95% confidence interval of the mean correlation coefficient did not overlap zero) between the five-day mean concentration of cyclosporine in whole blood (but not plasma) as measured with nonselective (NSRIA) and selective radioimmunoassays (SRIA) and the mean reciprocal creatinine concentration measured in the subsequent five days. In 15 of 32 (47%) patients the negative correlation coefficient exceeded 0.7 (high susceptibility), whereas in 11 of 32 (34%) it was between 0.5 and 0.7 (medium susceptibility), and in only six of 32 (19%) was it less than 0.3 (low susceptibility). We found no consistent correlations between cyclosporine measurements and results of other renal-function tests or liver-function tests. This suggests that therapeutic doses of the drug are not hepatotoxic in most patients. There was, however, a significantly correlated decrease in the NSRIA/SRIA ratio and in serum bilirubin concentration with time post-operatively, reflecting improvement in hepatic function and clearance of the cyclosporine metabolites that are detected by NSRIA. Assays of cyclosporine in whole blood, but not in plasma, are of value in anticipating changes in renal function after heart and heart-lung transplantation.

We report the intensive care management of 23 children (age 3-15 years) following orthotopic heart (HT) and combined heart and lung transplantation (HLT) performed at our 2 institutes between February 1985 and August 1989. Cyclosporin A, azathioprine and steroids were given as routine immunosuppression, whilst anti-thymocyte globulin (ATG) was used for the first 3 post-operative days. Mean ventilation time was 24.6 h (range 4-74 h). Cardiovascular support comprised isoprenaline infusions in all patients (mean period 65.7 h) whilst dopamine and other inotropic agents were used less frequently. Sequential atrioventricular pacing was required more often in the HT patients (n = 9) than in the HLT patients (n = 4). Fluid input was restricted to maintain a plasma osmolality of 290-300 mosm/kg. There were 2 perioperative deaths both due to acute right heart failure. Other post-operative complications included: bleeding (n = 3); acute graft rejection (n = 4); infection (n = 3); systemic hypertension (n = 6); neurological abnormalities (n = 2); renal dysfunction (n = 6) and hyperglycaemia (n = 6).

We report our experience of herpes simplex virus infection in a series of 51 recipients of heart lung transplantation (HLT). Nine patients, all of whom were seropositive for the virus preoperatively, developed HSV infection. Seven episodes of culture-proved mucocutaneous HSV infection without evidence of pulmonary involvement occurred in four patients. Six episodes of HSV pneumonia were seen in a further five patients, one of whom died. Diagnosis of HSV pneumonia was by histological appearances on transbronchial biopsy, together with culture of lung tissue or bronchoalveolar lavage. Concomitant cytomegalovirus infection occurred in four patients. All patients who developed HSV pneumonia did so within the first two postoperative months; in four patients following augmented immunosuppression. We now suggest that HLT recipients who are HSV antibody-positive should receive prophylactic acyclovir for the first two months after surgery and at times of augmented immunosuppression.

Since April 1984, 70 patients have received heart-lung transplants at our institution. Actuarial survival is 76% at 1 year and 68% at 2 years. All but 4 surviving patients have an unrestricted life style. Rejection was confirmed by lung transbronchial biopsy (TBB) on 277 occasions in 66 patients. Forty-two percent of episodes occurred within 1 month of surgery. Eight patients have developed evidence of chronic rejection with progressive irreversible fall in FEV1, of whom 4 have died or undergone single lung retransplantation. Seven patients had primary cytomegalovirus (CMV) of whom 4 patients died. Eight patients developed pneumocystis pneumonia of whom 1 died. Seven episodes of herpes simplex pneumonitis occurred of which one episode was fatal. Heart-lung transplantation is a valuable treatment for terminal cardiopulmonary disease and offers increasing hope of long-term survival.

There is a growing recognition about the critical role water plays in sustaining people and society. This workshop established dialog between disciplinary scientists and program managers from diverse backgrounds in order to share perspectives and broaden community understanding of ongoing fundamental and applied research on water as a complex environmental problem. Three major scientific themes emerged: (1) coupling of cycles and process, with emphasis on the role of interfaces; (2) coupling of human and natural systems across spatial and temporal scales; and (3) prediction in the face of uncertainty. In addition, the need for observation systems, sensors, and infrastructure; and the need for data management and synthesis were addressed. Current barriers to progress were noted as educational and institutional barriers and the integration of science and policy.

Respiratory syncytial virus (RSV) bronchiolitis is an important cause of severe respiratory disease in infants. This study aimed to characterise changes in pulmonary pro- and anti-inflammatory responses in infants with RSV bronchiolitis over the course of the illness. On the day of intubation (Day 1) and the day of extubation (Day X), nonbronchoscopic bronchoalveolar lavage was performed on term and preterm infants ventilated for RSV bronchiolitis and on control infants on Day 1. Tumour necrosis factor (TNF)-alpha, soluble TNF receptor (sTNFR) and interleukin (IL)-6 messenger ribonucleic acid (mRNA) and protein were measured. Twenty-four infants, born at term and 23 infants born preterm with RSV bronchiolitis and 10 controls were recruited. TNF-alpha and IL-6 mRNA and protein in infants with bronchiolitis were greater than the control group on Day 1. In preterm infants, who were ventilated for longer than term infants, TNF-alpha and IL-6 proteins decreased between Day 1 and Day X. Concentrations of sTNFRs differed between groups on Day 1, but levels did not change between Day 1 and Day X. Large amounts of tumour necrosis factor-alpha and interleukin-6 in the respiratory syncytial virus-infected lung suggest important roles for these cytokines in the pathogenesis of respiratory syncytial virus bronchiolitis. The decrease in tumour necrosis factor-alpha and interleukin-6 protein in preterm infants may reflect the prolonged clinical course seen in these infants.

Aim: To examine over time, the cellular response within the lungs of infants ventilated with respiratory syncytial virus (RSV) bronchiolitis and to compare this response in infants born at term with those born preterm. Methods: Non-bronchoscopic bronchoalveolar lavage (BAL) samples were taken from 47 infants (24 born at term and 23 born preterm) who were ventilated for RSV positive bronchiolitis and 10 control infants. BAL cellularity and differential cell counts were calculated using standard techniques. Results: Total cellularity in BAL over the first four days of ventilation in infants with RSV bronchiolitis was greater in term infants (median 2.2 (IQR 4.27) x 106 cells/ml) compared with preterm infants (0.58 (1.28) x 106 cells/ml). The magnitude of the cellular response in preterm infants with bronchiolitis was similar to that in the control group measured on day 1 (0.62 (0.77) x 106 cells/ml). BAL cellularity decreased progressively from the time of intubation in term infants, but remained relatively constant in preterm infants up to seven days after intubation. Conclusions: There are differences in the magnitude and type of pulmonary cellular response in term and preterm infants ventilated with RSV bronchiolitis. The cellular response in term infants with bronchiolitis differs from that in a control group of infants. These differences may reflect variations in cellular recruitment in the lung and/or variations in airway calibre.

Obliterative bronchiolitis (OB) continues to be a major cause of morbidity and mortality following heart-lung transplantation. We compared the incidence of death from obliterative bronchiolitis in 19 children and 72 adults following heart-lung transplantation at our institutes. The incidence of death from OB at 2 years was 38% for children compared with 17% for adults, this difference was significant (Cox-Mantel Z value = 2.243, P < 0.05). The frequency of acute lung rejection and persistent lung rejection, previously described as risk factors for OB in adults, were significantly more common in children, P = 0.004 and P = 0.001, respectively. Average forced expiratory volume in 1 s was lower in children than in adults for each 3-month period after transplantation (P < 0.001). In conclusion, identified risk factors for the development of OB were more common, and the risk of death from OB was greater in children than in adults following heart-lung transplantation.

Pharmacoepidemiology is the study of the use and the effect of drugs in large numbers of people. The work relies largely on standard epidemiological principles, which, applied in a new context, bring particular constraints and opportunities. In January 1994, a cluster of children with cystic fibrosis (CF) who developed strictures in the colon was reported. It was suggested that these may have been associated with high strength pancreatic enzyme preparations which had been introduced into use in these patients approximately one year previously. This hypothesis has been evaluated by a case-control study which confirms the association with high-strength pancreatic enzyme usage. The study is described and is used to illustrate statistical issues to provide a framework for future research in statistical methodology in pharmacoepidemiological case-control studies.

To determine 1) what proportion of abstracts of randomized controlled trials (RCTs) presented at international conferences on cystic fibrosis (CF) are published as full reports, 2) time to publication, and 3) factors that might delay or prevent publication.At the end of 1995, the Cochrane CF Group's register of RCTs contained 199 abstracts describing 180 RCTs. Abstracts were identified by handsearching 44 abstract books of three international CF conferences over a 30-year period. We searched the register for subsequent full reports of these RCTs and used survival analysis to investigate time to publication. Using the log-rank test, we examined 1) whether there is a difference in time to publication between reports where the investigators concluded that the test treatment was as effective as or better than the control treatment, and reports where it was not, and 2) whether there is a difference in time to publication according to sample size.Thirty-two percent of the 178 abstracts analyzed were subsequently published in full. Survival analysis indicated that the proportions published before 12 months, 2 years, and 5 years were 8.1%, 29%, and 40% respectively. No difference in time to publication was identified when the abstracts were stratified according to conclusions or sample size; no significant association (P0.05) existed between time to publication and both sample size and conclusions together.Only a small proportion of abstracts of RCTs presented at international conferences on CF are followed by full publication, and usually only after several years. Therefore, many potentially valuable studies do not reach a wide audience. However, we found no consistent factors which might delay or prevent publication.

Spirometry was performed before operation, soon after recovery ("early") and the day after ("late") general anaesthesia for elective surgery in 20 children with asthma and 20 matched children without asthma. Pulse oximetry was recorded on the first postoperative night. The mean early peak expiratory flow rate (PEFR) decreased in the asthmatics by 19.91 (95% confidence intervals (CI) 10.84-28.97)% and in the controls by 19.25 (10.70-27.80)%. The mean early FEV1 decreased in the asthmatics by 16.02 (9.29-22.75)% and in the controls by 11.03 (2.86-19.19)%. The mean late decrease from baseline PEFR for the asthmatics was 18.55 (11.23-25.87)% but only 14.93 (7.89-21.97)% for the controls. The mean late FEV1 was 8.2 (0.83-15.56)% below baseline in the asthmatics but only 6.82 (-0.79 to 14.42)% in the controls. There were no differences in overnight pulse oximetry. We conclude that healthy children exhibited a decrease in FEV1 and PEFR after general anaesthesia for elective surgery, but this decline did not appear to be any greater in well controlled asthmatic children compared with children who did not have asthma.

A retrospective serologic study was made of 67 heart-lung and 295 heart transplant recipients (with transplantations at Papworth Hospital, Cambridge, England) to determine the incidence and clinical impact of Epstein-Barr virus infection.Epstein-Barr virus capsid antigen immunofluorescence tests were performed, and the antibody avidity was determined by modifying the washing procedure to include a mild reducing agent (8M urea).This testing showed that 6.0% of the patients had primary Epstein-Barr virus infections, whereas 17.4% had the reactivation of a past infection. Primary infections were only detected in patients who were Epstein-Barr virus antibody-negative before transplantation, who had received an organ from an Epstein-Barr virus antibody-positive donor. Of the patients with serologically proven Epstein-Barr virus infections, 52.9% had symptoms. Although these were generally mild, five heart and two heart-lung transplant recipients had malignant lymphoma and one heart and one heart-lung transplant recipient had lymphoproliferative disease after Epstein-Barr virus infection. Additional four heart transplant recipients had lymphoma after transplantation. None of these four patients had evidence of active Epstein-Barr virus infection; one was Epstein-Barr virus antibody-negative during the study period and three had stable Epstein-Barr virus virus capsid antigen immunoglobulin G titers throughout.Epstein-Barr virus infection in organ transplant recipients may lead on to life-threatening lymphoproliferative disease or lymphoma. For this reason it may be beneficial to monitor patients after transplantation for evidence of Epstein-Barr virus infection and to follow the progress of those affected.

Introduction Corticosteroids are the main stay of preventative therapy for asthma-related symptoms. There is a wide range of inter-patient variability both in terms of response to therapy, and suppression of the HPA axis leading to potentially fatal adrenal suppression. A recently undertaken GWAS identified the GLCCI1 variant rs37973 as a biomarker for corticosteroid efficacy using FEV 1 response as the outcome measure. The aim of this study was two-fold: (a) to replicate the association with corticosteroid efficacy (using steroid dose and an increase in asthma exacerbations as surrogate measures) and (b) to determine whether the same variant is associated with adrenal suppression in asthmatic patients on inhaled corticosteroids. Methods The study included data on 402 asthmatic children (age 5–18yrs), who were recruited to the Pharmacogenetics of Adrenal Suppression with inhaled Steroids (PASS) study, all of whom were on long term corticosteroid therapy (>6 months), and had a clinically indicated low dose short Synacthen test (LDSST). Detailed history of their medication use and exacerbations were recorded for the 6 months prior to LDSST. Regression models, adjusted for significant clinical factors, were used to test for association between the SNP and each outcome. Results The rs37973 variant was associated with an increase in prescribed total inhaled/intranasal corticosteroid doses both before and after adjustment for body surface area. This association was significant when assuming both an additive mode of inheritance (p-value=0.020 for BSA adjusted total) as previously reported, and a recessive model (p-value =0.006 for BSA adjusted total). The variant was also associated with increased hospital admissions over the 6 month period (OR 2.16, 95% CI:1.10–4.33 when comparing homozygous states). There was no association with adrenal suppression (baseline or peak) or the number of rescue oral steroid courses. Conclusion In the first replication study in a European population, we have shown that the rs37973 SNP is associated with increased corticosteroid dose and an increase in asthma-related hospital admissions, further supporting the evidence that GLCCI1 is a determinant of steroid efficacy in asthma. However, this SNP was not associated with steroid-induced adrenal suppression, divorcing efficacy from toxicity, at least with respect to this gene.

Aims Rational use of medicines in children requires knowledge of both the efficacy and adverse drug reaction (ADR) profile of individual drugs. The Medicines and Healthcare Regulatory Authority (MHRA) in the UK runs a national spontaneous reporting system (Yellow Card Scheme) to collect ‘suspected’ ADRs for all medicines. To increase the data for paediatric medicines, current MHRA advice is to report all suspected ADRs in paediatric patients. Yellow Cards submitted in the UK between 2000 and 2009 were analysed. Methods Data on all UK spontaneous ‘suspected’ ADRs reported to the MHRA in patients ≤16 years from the years 2000–2009 were supplied in 2 datasets, inclusive and exclusive of vaccine related ADRs. Data, when provided on the Yellow Card by the reporter, included age, type of reaction, medication and type of reporter, but were unlinked. Medications were divided into therapeutic classes to aid specialists to determine rates of reporting in their area. Results From 2000to 2009, 222 755 Yellow Card reports were received by the MHRA, 31 726 (14.2%) were for children and young people Conclusions Reporting of ADRs is variable depending on the medication or therapeutic class, and overall underreporting is probably common. All suspected paediatric ADRs should continue to be reported to improve and optimise the evidence for the rational use of medicines in children.

In the 1980s heart-lung transplantation (HLT) [1, 2], evolved from an experimental and innovative stage to a clinical treatment. Despite improvements in survival and understanding of pathogenesis of the lung disease in HLT recipients, cytomegalovirus (CMV) infection remains an important cause of death and morbidity. Donor-acquired primary CMV disease may be effectively prevented by prospective donor and recipient matching. Considerable progress has been made in the diagnosis of CMV pneumonia by the use of trans-bronchial lung biopsy (TBB), and the antiviral drug ganciclovir provides effective treatment of reactivation or reinfection. However, the mechanisms and immunological response to CMV infection in this patient population remain poorly understood.

Background Clinical trials of regular therapies for children with asthma frequently measure outcomes reflecting short-term disease activity, but rarely assess functional status, quality of life (QoL), and long-term treatment effects.1 There is a lack of research assessing the importance of outcomes for children with asthma, from the perspective of clinicians, parents and young people.2 The authors aimed to identify the outcomes of most importance to these groups. Methods Paediatricians and specialist nurses, identified through the British Paediatric Respiratory Society, completed a two-round Delphi-survey. Parents, recruited in asthma clinics, participated in both rounds. Young people, 13 years or older, participated in the first round. Outcomes were considered for preschool and school-aged children separately. In Round 1, clinicians suggested important outcomes used in clinical practice. Parents and young people were asked how they judged whether they were satisfied with asthma medications. Responses were classified into corresponding outcomes by two researchers independently. In Round 2, participants were shown outcomes suggested by at least 10% of responders in Round 1. They scored the importance of each from 0–4, and selected the three most important. Results Forty-six clinicians completed Round 1. Forty-three completed Round 2. Thirty-eight parents and eleven young people completed Round 1. Fifty parents completed Round 2. Eighteen outcomes were listed in Round 2. The most important outcomes for school-aged and preschool children reflected clinical measures of disease activity (symptoms and exacerbations), QoL, activities of daily living and long-term effects of treatments. The results from parents and clinicians were generally concordant, but parents placed more emphasis on long-term effects of treatments. Conclusion Some outcomes which are rarely measured in clinical trials in children with asthma, namely, QoL, functional status and long-term effects of interventions, are very important to clinicians and parents of children with asthma. These outcomes should be measured in clinical trials. People involved in standardising outcomes for such trials should be aware of these findings.

A prospective study of 219 bronchoscopies in 54 heart-lung and in 2 single lung transplant recipients was undertaken over a 12-month period by a single operator. For histologic study, an average of 17.3 transbronchial biopsy specimens (range, 6 to 56) were taken from three lobes (or from two lobes and lingula of one lung). A further two specimens were taken for culture. The average procedure time was 14.4 minutes (SE 0.31). An estimate of the probability of rejection being missed, depending on the number of specimens taken and based on the method of Gilman and Wang, suggests 18 biopsy specimens are required to have 95% confidence of diagnosing rejection. Sensitivity for diagnosing rejection by histologic study of transbronchial biopsy specimens was 94%, and specificity was 90%. The simple grading of severity of rejection that was used was related both to the number of specimens demonstrating rejection and to the severity of graft airway mucosal inflammation seen at bronchoscopy. The major complication encountered, on 27 occasions, was bleeding of more than 100 ml. On no occasion did bleeding result in any long-term complication. Extensive transbronchial biopsy is a simple, relatively safe, and quick procedure, with a high sensitivity and specificity for diagnosing rejection and lung infection.

From March 1988 to March 1990, 11 children with cystic fibrosis (age 5-15 years) underwent combined heart-lung transplantation at our institutes. Maintenance immunosuppression consisted of cyclosporin and azathioprine with corticosteroids and antithymocyte globulin used perioperatively and during rejection episodes. Six patients (55%) survive from 1.5-23 months all of whom have improved life quality. Actuarial survival to 1 year was 55%. At six months after transplant, mean forced expiratory volume at one second was 73.5% of predicted normal, compared with 25% before transplant. There was one perioperative death, three later deaths associated with obliterative bronchiolitis at two, eight, and nine months, and one from mediastinitis at four months. Of the 15 children accepted for transplantation but not receiving grafts, 10 have died (eight within four months of being placed onto the transplant list). Early postoperative problems included acute reversible rejection (n = 10), meconium ileus equivalent (n = 3), and pancreatitis (n = 1). There was a high incidence of later pulmonary rejection with a mean of 5.7 episodes per patient in the first six months. Pulmonary infection occurred relatively infrequently, with Pseudomonas aeruginosa being the most common pathogen. Persistent diabetes mellitus requiring insulin occurred in four and systemic hypertension developed in one.

A 19-year-old girl was diagnosed as having primary pulmonary hypertension that was confirmed by right heart catheterization. Acute right heart failure was associated with syncope. Stabilization, while not achieved with intravenous epoprostenol (Prostacyclin) alone, was achieved with intravenous prostacyclin and nitroprusside. (Chest 1991; 99:1284-85)

Obliterative bronchiolitis is the major cause of death of long-term survivors of heart-lung transplantation. Of our first 75 patients who have received heart-lung transplantation, 38 have been followed for a year or longer. Eight patients developed clinical evidence of obliterative bronchiolitis within 15 months of transplantation, of whom four died with postmortem confirmation of extensive obliterative bronchiolitis, interstitial and pleural fibrosis, and vascular sclerosis in the heart and lungs. One further patient died before one year after chronic rejection. All nine patients had evidence on transbronchial biopsy of submucosal fibrosis and vascular sclerosis. Twelve of our remaining patients have shown similar areas of lung fibrosis on transbronchial biopsy, and the other eighteen are well and without fibrosis on transbronchial biopsy. Studies of the 274 biopsies obtained from 38 patients confirmed rejection on 182 occasions with more frequent, more persistent, and more severe rejection in the chronic rejection group than in the without-fibrosis or lung fibrosis groups. Opportunistic infection resulted in pneumonia on 19 occasions, and were most commonly found in lung fibrosis patients. We conclude that obliterative bronchiolitis is the likely outcome in patients with early, poorly controlled, severe rejection.

Domino transplantation provides a further source of hearts for transplantation (Dark 1990; Baumgartner 1989; Cavarrochi 1989). It is essential that neither donors nor recipients are disadvantaged as a result of this practice (Sutor 1988; Rhenman 1989). We have studied the first 28 donors and recipients of the domino procedure at our institute and compared them with comparable groups of heart-lung and heart transplant recipients not involved in the domino procedure. Comparison was made of ischaemic time of in-house and distant procurement hearts, of ischaemic time for donors and non-donors of domino hearts, time in hospital and early survival figures at 3 months after transplantation.

Chronic rejection is the major cause of death of long-term survivors of heart-lung transplantation. Of our 61 patients who have received heart-lung transplants, 29 have been followed up for a year or longer. Seven patients had clinical evidence of chronic rejection within 15 months of transplantations of these seven, four died with postmortem confirmation of extensive obliterative bronchiolitis, interstitial and pleural fibrosis, and vascular sclerosis in the heart and lungs. All seven patients had evidence on transbronchial biopsy specimens of submucosal fibrosis and vascular sclerosis. Twelve of our remaining patients have shown similar areas of lung fibrosis on transbronchial biopsy specimens, and the other 10 are well and without fibrosis seen on transbronchial biopsy specimens. Studies of the 201 biopsy specimens obtained from 29 patients confirmed rejection on 130 occasions, with more frequent, more persistent, and more severe rejection in the chronic-rejection group than in the without-fibrosis or lung-fibrosis group. Opportunistic infections resulted in pneumonia on 19 occasions, and these were most commonly found in patients with lung fibrosis. We conclude that chronic lung rejection is the likely outcome in patients with early, poorly controlled, severe rejection.