Admission to hospital for bronchiolitis in England: trends over five decades, geographical variation and association with perinatal characteristics and subsequent asthma.

BACKGROUND: Admission of infants to hospital with bronchiolitis consumes considerable healthcare resources each winter. We report an analysis of hospital admissions in England over five decades. METHODS: Data were analysed from the Hospital In-Patient Enquiry (HIPE, 1968-1985), Hospital Episode Statistics (HES, 1989-2011), Oxford Record Linkage Study (ORLS, 1963-2011) and Paediatric Intensive Care Audit Network (PICANet, 2003-2012). Cases were identified using International Classification of Diseases (ICD) codes in discharge records. Bronchiolitis was given a separate code in ICD9 (used in England from 1979). Geographical variation was analysed using Local Authority area boundaries. Maternal and perinatal risk factors associated with bronchiolitis and subsequent admissions for asthma were analysed using record-linkage. RESULTS: All-England HIPE and HES data recorded 468 138 episodes of admission for bronchiolitis in infants aged <1 year between 1979 and 2011. In 2011 the estimated annual hospital admission rate was 46.1 (95% CI 45.6 to 46.6) per 1000 infants aged <1 year. Between 2004 and 2011 the rates rose by an average of 1.8% per year in the all-England HES data, whereas admission rates to paediatric intensive care changed little (1.3 to 1.6 per 1000 infants aged <1 year). A fivefold geographical variation in hospital admission rates was observed. Young maternal age, low social class, low birth weight and maternal smoking were among factors associated with an increased risk of hospital admission with bronchiolitis. CONCLUSIONS: Hospital admissions for infants with bronchiolitis have increased substantially in recent years. However, cases requiring intensive care have changed little since 2004.

Tracheostomy in children admitted to paediatric intensive care.

PURPOSE: Tracheostomy is a common intervention for adults admitted to intensive care; many are performed early and most are percutaneous. Our study aimed to elucidate current practice and indications for children in the UK admitted to paediatric intensive care and undergoing tracheostomy. DESIGN: A questionnaire covering unit guidelines, practice, and the advantages and disadvantages of tracheostomy was sent to all UK paediatric intensive care units (PICUs) participating in the Paediatric Intensive Care Audit Network (PICANet). These results were combined with data from PICANet on all children in the UK reported to have had a tracheostomy performed during a PICU admission between 2005 and 2009 inclusive. RESULTS: Over 5 years, 1613 children had tracheostomies performed during their PICU admission (2.05% of all admissions). The death rate was 5.58% with tracheostomy versus 4.72% overall, but differences were not significant when risk-adjusted using the Paediatric Index of Mortality 2 (PIM2). All 29 units participating in PICANet responded to the survey. Prolonged invasive ventilation was an indication for tracheostomy in 25/29 units, but the definition varied between 14 and 90 days, and most respondents considered timing on an individual basis. Children undergoing tracheostomy during PICU admission account for 9% of PICU bed days in the UK. CONCLUSIONS: In contrast with current adult UK practice, tracheostomy for children admitted to intensive care is infrequent, performed late following admission and usually surgical. Practice varies significantly. The death rate for children having a tracheostomy performed was not significantly higher than for children admitted to PICU who did not undergo tracheostomy.

Calcium adjustment equations in neonates and children.

BACKGROUND: Calcium exists in human blood in a free form and in a form bound to plasma proteins, principally albumin. Since it is the ionized form that is biologically active, it has long been common practice to present calcium adjusted on the basis of serum albumin concentration. The concept of adjusted calcium has only been evaluated in adults. In this study, we evaluated the use of the adult-adjusted equation to report calcium in children. METHODS: We searched the laboratory information system over three teaching hospitals for young patients aged between newborn and 18 years old with a request for calcium and albumin analysis but with no evidence of disturbances of calcium homeostasis. These data were organized on the basis of age and was separated into four age groups (birth to 1 month old, 1 month to 1 year old, 1 to 5 years old and 5 to 18 years old). These data were subjected to regression analysis to derive the calcium-adjusted equation for each age group. RESULTS: There is an inverse relationship between the bias value and the age. The younger the age, the higher the difference between the adjusted calcium calculated by the adult equation and that calculated by the age-specific equation. This pattern was maintained on all sites. CONCLUSION: For all sites, the adult-adjusted calcium equation may be used to calculate the adjusted calcium for children aged one year old and above.

Gestational effects on host inflammatory response in normal and pre-eclamptic pregnancies.

OBJECTIVE: Pre-eclampsia (PET) remains a leading cause of maternal and neonatal morbidity and mortality. Although its pathophysiology involves an underlying inflammatory dysfunction, it is unclear how this may be affected by increasing gestational age, particularly in relation to the time of onset of disease. Murine studies have indicated that a progressive increase in serum inflammatory profile is a physiological feature of normal gestation. The present study aimed to investigate this phenomenon in women in relation to normal and pre-eclamptic pregnancies. STUDY DESIGN: Control and PET groups (each n=20) were divided into early and late pregnancy (before and after 34 weeks gestation, respectively). Whole blood was diluted 1:1 with RPMI 1640 medium with/without 1 microg/ml lipopolysaccharide at 37 degrees C for 24 h under a humidified 5% CO(2) atmosphere. Samples were collected at 0, 2, 6 and 24 h and analysed for interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon (IFN)-gamma, monocyte chemotactic protein (MCP-1), macrophage inflammatory protein (MIP)-1beta and tumour necrosis factor (TNF)-alpha by fluid-phase multiplex immunoassay. RESULTS: This study confirms that pregnancy features an increasing inflammatory response with advancing gestational age, which was seen in both control and PET pregnancies (P<0.01). CONCLUSIONS: This increase in inflammatory responsiveness with advancing gestation may provide an explanation for the incidence of late onset PET in the absence of placental pathology, as well as serving as a potential physiological priming mechanism geared towards increasing maternal sensitivity to the fetal triggers of labour.

Major effects of delayed graft function and cold ischaemia time on renal allograft survival.

BACKGROUND: There is mounting evidence from experimental and clinical studies that the quality of organs from cadaver donors may be influenced by events occurring around the time of brain death, and that these may affect transplant outcome. The aim of this study is to investigate the influence of donor factors on renal allograft outcome in a homogeneous cohort of 518 patients transplanted in a single centre over a 9 year period. METHODS: Endpoints of the study were delayed graft function (DGF), acute rejection (AR), 1 year graft survival and long-term survival of those grafts that reached 1 year. Multivariate analysis was performed to determine factors that may have influenced the graft outcome indicators. RESULTS: DGF was the major predictor of graft failure overall with cold ischaemia time (CIT) as an important independent factor. The level of histocompatibility did not influence graft survival. DGF was the major factor affecting 1 year graft survival (P<0.0005) with effects persisting beyond 1 year. DGF was significantly influenced by CIT, donor age, female kidney into male recipient and donor creatinine (P<0.05). Other donor factors and factors associated with donor management were not risk factors for DGF, rejection episodes or graft survival. The risk factors for a number of AR episodes were HLA-DR mismatch and DGF (P<0.005). When grafts surviving for 1 year were considered, only CIT, recipient age and creatinine at 1 year (P<0.05) were found to affect graft survival significantly. CONCLUSIONS: The results of this analysis of well-matched transplant recipients show that CIT and DGF are the most important predictors of poor short and long-term graft survival. Therefore, in order to improve the long-term survival of renal allografts efforts should focus on limiting CIT and the damage that occurs during this period and on improving our understanding of DGF.

Characterisation of collagen VI within the islet-exocrine interface of the human pancreas: implications for clinical islet isolation?

BACKGROUND: To optimize the methods used for human islet isolation for transplantation, it is important to improve our understanding of the structure of the islet-exocrine interface. In this study, the composition of collagen subtypes in the interface have been characterized and quantified in human pancreas. METHODS: Human adult pancreases were retrieved from older (mean age 55.7+/-3.0 yrs) and young donors (mean age 21.8+/-3.2 yrs). Tissue from the body of each pancreas was examined by quantitative immunohistochemistry. Collagen within the islet-exocrine interface was identified by immunolabeling for collagen I, IV, V or VI and islets identified either morphologically or by immunolabeling for insulin. Collagen subtypes were quantified and data expressed as collagen area at the interface relative to the islet area. Statistical analysis was by ANOVA or Mann Whitney U test. RESULTS: In older pancreases, collagen IV, V and VI were present throughout the islet-exocrine interface, whereas collagen I was more variable. The mean peri-islet collagen VI proportion was significantly greater than that of collagen I or IV. Mean islet area and the proportional collagen VI content in specimens from younger subjects were not significantly different to those in older subjects. CONCLUSIONS: Collagen VI is a major component of the islet-exocrine interface of the adult pancreas, the content being more than double that of collagen I or IV. However, the proportional collagen VI content was not dependent on the age of the donor. These data may facilitate the design of new collagenases, targeting major substrates such as collagen VI in order to improve clinical islet isolation.

Adverse outcome of human islet-allogeneic blood interaction.

BACKGROUND: A report of inflammatory damage when islets come into contact with allogeneic blood prompted us to confirm the finding. METHODS: Fresh handpicked human islets were incubated in blood group matched, nonsensitized allogeneic blood. Destruction was quantified by assaying the supernatants for proinsulin release and by blood clot histology. The effect on global hemostasis was assessed by thromboelastography (TEG), and heparin-bonded tubing was used to assess the effect on blood cellular counts. In separate experiments, islets were incubated in allogeneic blood with heparin or Reopro (monoclonal anti-GpIIbIIIa). Islets were also incubated in serum, and cryosections were stained for C1q, C4, C3, C5b-9, immunoglobulin (Ig)M, and IgG binding using immunohistochemistry. RESULTS: Histologic assessment showed severe destruction in 37% of islets in contact with allogeneic blood versus none in controls and a sevenfold increase in proinsulin release from controls (n = 6)(P < 0.005). TEG (n = 11) showed accelerated coagulation in the presence of islets (P < 0.001). Analysis of blood cellular counts (n = 3) showed consumption of platelets, neutrophils, and monocytes in the presence of islets (P < 0.001). Inhibition of coagulation with heparin (n = 3) or inhibition of platelet aggregation with Reopro (n = 3), separately or together (n = 3), did not make a substantial improvement in the destruction in terms of histology or proinsulin release. Immunohistochemical staining (n = 4) revealed C1q, C4, C3, and C5b-9 deposition along with IgG binding. IgM binding was weak if anything. CONCLUSION: This study confirms and extends the finding that human islet-allogeneic blood interaction results in significant destruction of islet tissue with activation of the coagulation cascade and platelet, neutrophil, and monocyte consumption. There was evidence for activation of complement by the classical pathway along with IgG binding.

The interaction between primate blood and mouse islets induces accelerated clotting with islet destruction.

BACKGROUND: Mouse islets transplanted under the renal subcapsular space of cynomolgus monkeys are subject to a form of hyperacute rejection, the mechanism of which is unclear. As islets are in contact with whole blood at the time of transplantation, the effect of platelets and the coagulation cascade on islet destruction was assessed. METHODS: Coagulation was assessed using thromboelastography on citrated/recalcified human blood samples with freshly isolated C57/Bl6 mouse islets. A dynamic islet perifusion system was used to assess the effect of islets on blood cells and coagulation factors. Cytotoxicity was evaluated using (51)Cr labelled islets incubated with human blood and islet destruction was also evaluated using a histological grading system. Continuous PO(2) measurements were made in a static incubation system to assess the role of hypoxia in islet destruction. RESULTS: Mouse islets incubated in human blood induced accelerated coagulation and rapid consumption of platelets within 15 min. Within 1 h of incubation, 52% of mouse islets exposed to xenogeneic human blood showed features of severe damage with necrosis when compared with islets incubated in syngeneic blood. Specific lysis of the xenogeneic islets was demonstrable (Mean percentage lysis: 48%, P < 0.05 vs. control) after 4 h incubation in human blood. Oxygen levels remained constant at a level adequate to maintain islet viability in separate experiments. CONCLUSION: Mouse islets induce rapid activation of the clotting cascade and platelet consumption in vitro when exposed to human blood, which correlated with histological evidence of significant destruction demonstrable within 1 h of exposure to human or non-human primate blood. This in vitro model has features which appear to correlate with the islet destruction seen in vivo and could be a useful model for the study of the mechanisms underlying the rapid destruction of xenogeneic islets in primate recipients.