Amanda Ogilvy-Stuart

Whole-genome sequencing for analysis of an outbreak of meticillin-resistant Staphylococcus aureus: a descriptive study

Summary Background The emergence of meticillin-resistant Staphylococcus aureus (MRSA) that can persist in the community and replace existing hospital-adapted lineages of MRSA means that it is necessary to understand transmission dynamics in terms of hospitals and the community as one entity. We assessed the use of whole-genome sequencing to enhance detection of MRSA transmission between these settings. Methods We studied a putative MRSA outbreak on a special care baby unit (SCBU) at a National Health Service Foundation Trust in Cambridge, UK. We used whole-genome sequencing to validate and expand findings from an infection-control team who assessed the outbreak through conventional analysis of epidemiological data and antibiogram profiles. We sequenced isolates from all colonised patients in the SCBU, and sequenced MRSA isolates from patients in the hospital or community with the same antibiotic susceptibility profile as the outbreak strain. Findings The hospital infection-control team identified 12 infants colonised with MRSA in a 6 month period in 2011, who were suspected of being linked, but a persistent outbreak could not be confirmed with conventional methods. With whole-genome sequencing, we identified 26 related cases of MRSA carriage, and showed transmission occurred within the SCBU, between mothers on a postnatal ward, and in the community. The outbreak MRSA type was a new sequence type (ST) 2371, which is closely related to ST22, but contains genes encoding Panton-Valentine leucocidin. Whole-genome sequencing data were used to propose and confirm that MRSA carriage by a staff member had allowed the outbreak to persist during periods without known infection on the SCBU and after a deep clean. Interpretation Whole-genome sequencing holds great promise for rapid, accurate, and comprehensive identification of bacterial transmission pathways in hospital and community settings, with concomitant reductions in infections, morbidity, and costs. Funding UK Clinical Research Collaboration Translational Infection Research Initiative, Wellcome Trust, Health Protection Agency, and the National Institute for Health Research Cambridge Biomedical Research Centre.

Early Insulin Therapy in Very-Low-Birth-Weight Infants

BACKGROUND Studies involving adults and children being treated in intensive care units indicate that insulin therapy and glucose control may influence survival. Hyperglycemia in very-low-birth-weight infants is also associated with morbidity and mortality. This international randomized, controlled trial aimed to determine whether early insulin replacement reduced hyperglycemia and affected outcomes in such neonates. METHODS In this multicenter trial, we assigned 195 infants to continuous infusion of insulin at a dose of 0.05 U per kilogram of body weight per hour with 20% dextrose support and 194 to standard neonatal care on days 1 to 7. The efficacy of glucose control was assessed by continuous glucose monitoring. The primary outcome was mortality at the expected date of delivery. The study was discontinued early because of concerns about futility with regard to the primary outcome and potential harm. RESULTS As compared with infants in the control group, infants in the early-insulin group had lower mean (+/-SD) glucose levels (6.2+/-1.4 vs. 6.7+/-2.2 mmol per liter [112+/-25 vs. 121+/-40 mg per deciliter], P=0.007). Fewer infants in the early-insulin group had hyperglycemia for more than 10% of the first week of life (21% vs. 33%, P=0.008). The early-insulin group had significantly more carbohydrate infused (51+/-13 vs. 43+/-10 kcal per kilogram per day, P<0.001) and less weight loss in the first week (standard-deviation score for change in weight, -0.55+/-0.52 vs. -0.70+/-0.47; P=0.006). More infants in the early-insulin group had episodes of hypoglycemia (defined as a blood glucose level of <2.6 mmol per liter [47 mg per deciliter] for >1 hour) (29% in the early-insulin group vs. 17% in the control group, P=0.005), and the increase in hypoglycemia was significant in infants with birth weights of more than 1 kg. There were no differences in the intention-to-treat analyses for the primary outcome (mortality at the expected date of delivery) and the secondary outcome (morbidity). In the intention-to-treat analysis, mortality at 28 days was higher in the early-insulin group than in the control group (P=0.04). CONCLUSIONS Early insulin therapy offers little clinical benefit in very-low-birth-weight infants. It reduces hyperglycemia but may increase hypoglycemia (Current Controlled Trials number, ISRCTN78428828.)

High incidence of obesity in young adults after treatment of acute lymphoblastic leukemia in childhood

To determine whether obesity complicated the treatment of childhood acute lymphoblastic leukemia, we studied the body mass index (BMI) of 63 female when and 51 male patients from the time of diagnosis of acute lymphoblastic leukemia to the time when final height was attained. The BMI z score was calculated for each patient at diagnosis, at end of treatment, and at attainment of final height. Obesity at attainment of final height was defined as a BMI greater than the 85th percentile of the normal reference population. At final height 23 of 51 male (45%) and 30 of 63 female patients (47%) were obese. Girls became obese between diagnosis and the end of chemotherapy (p = 0.02), after which they had no further increase, indicating that chemotherapy may have played a role in their obesity. Boys had a progressive and gradual increase in BMI z score through to attainment of final height. Obesity did not appear to be associated with growth hormone insufficiency, disproportionate growth, or abnormal timing of puberty. We conclude that approximately half the survivors of leukemia in childhood become obese young adults. Many of those treated with the more recent regimens studied are still only in their mid or preteen years and should be advised regarding a more active lifestyle and a healthy diet in an attempt to reduce the incidence of obesity.

Thyroid function after treatment of brain tumors in children

In 134 children who had been treated for a brain tumor not involving the hypothalamic-pituitary axis, thyroid function was assessed up to 24 years after treatment with cranial or craniospinal irradiation. In addition, 78 children received up to 2 years of cytotoxic chemotherapy. Of 85 children who received craniospinal irradiation, 30 (35%) had abnormalities of thyroid function, and 10 (20%) of 49 who received cranial irradiation had such abnormalities. Frank hypothyroidism developed in three children and thyrotoxicosis in one. Thirty-six children had an elevated thyroid-stimulating hormone level in the presence of a normal thyroxine level; in 16 of them the thyroid-stimulating hormone level subsequently returned to normal. Twenty-eight children who were treated between 1960 and 1970 were excluded from the analysis. Of 34 children who received cranial irradiation, five had thyroid dysfunction and 24 of 72 who received craniospinal irradiation had such dysfunction (p = 0.013). Thyroid dysfunction was present in 4 of 35 children who received no chemotherapy and in 25 of 71 who received chemotherapy (p = 0.014). Direct irradiation plus chemotherapy was more damaging than irradiation alone. These data confirm the high incidence of thyroid dysfunction when the thyroid gland is included in the radiation field. However, in a high proportion, the thyroid abnormalities are minor and revert to normal with time; life-long replacement therapy with thyroxine may be unnecessary.

The continuous glucose monitoring sensor in neonatal intensive care

Objective: To determine the feasibility of continuous glucose monitoring in the very low birthweight baby requiring intensive care, as these infants are known to be at high risk of abnormalities of glucose control. Method: Sixteen babies were studied from within 24 hours of delivery and for up to seven days. Results: The subcutaneous glucose sensors were well tolerated and readings were comparable to those on near patient whole blood monitoring devices. Conclusion: Continuous glucose monitoring is practical in neonates, giving detailed information about glucose control.

Prevalence and Determinants of Hyperglycemia in Very Low Birth Weight Infants: Cohort Analyses of the NIRTURE Study

OBJECTIVES To investigate the prevalence and determinants of hyperglycemia in the preterm population, as part of the Neonatal Insulin Therapy in Europe (NIRTURE) Trial. STUDY DESIGN We conducted prospective cohort analyses of continuous glucose monitoring data from control infants participating in an international randomized controlled trial. Data were collected from 188 very low birth weight infants (<1500 g). RESULTS In the first week of life, 80% of infants had evidence of glucose levels >8 mmol/L, and 32% had glucose levels >10 mmol/L >10% of the time. Independent risk factors for hyperglycemia included increasing prematurity, small size at birth, use of inotropes, lipid infusions, and sepsis. There was a lack of association between rate of dextrose infused and risk of hyperglycemia. CONCLUSION The prevalence of hyperglycemia in the very low birth weight infant is high, with marked variability in prevalence between infants, not simply related to rates of glucose infused, but to other potentially modifiable risk factors.

Disproportionate short stature after cranial irradiation and combination chemotherapy for leukaemia.

The effect of combination chemotherapy and cranial irradiation on final height and body proportions was retrospectively examined in a cohort of 142 children treated for acute lymphoblastic leukaemia (ALL). Eighty four children (48 girls, 36 boys) received 24 Gy cranial irradiation and 58 (35 girls, 23 boys) 18 Gy. None had received testicular or spinal irradiation. A significant reduction in standing height SD score from diagnosis to final height was seen in all groups. Of the 109 children in whom sitting height measurements were available, 88 (81%) had relatively shorter backs than legs and in 25 (23%) this disproportion was of a marked degree. After mathematical correction for sitting height loss there was no longer a significant reduction in standing height SD score at final height in all except the 24 Gy group of girls. These data suggest that disproportion is a common finding after treatment for ALL and that, at least in some children, much if not all of the height loss seen is due to a reduction in sitting height. Possible explanations for this disproportion include a disturbance of puberty or an effect of chemotherapy on spinal growth, or both.

Growth hormone deficiency (GHD) from birth to 2 years of age: diagnostic specifics of GHD during the early phase of life.

The first 2 years of life represent a transition period when growth changes from predominantly growth hormone (GH) independent to GH dependent. In the fetus, growth is influenced by genetic and environmental factors in addition to nutrition and growth factors including insulin. In infancy, nutrition remains an important determinant of growth. GH levels are high in mid-gestation and at birth, then fall sharply for the first few weeks and more slowly over the next few months reaching pre-pubertal levels by around the age of 6 months. GH deficiency (GHD) may present at birth with hypoglycaemia, micropenis or prolonged conjugated hyperbilirubinaemia. Although length at birth is usually within the normal centile ranges, post-natal growth failure can begin early and be profound.

Cancer risk following growth hormone use in childhood: implications for current practice.

The therapeutic use of growth hormone (GH) has caused concern, as it is anabolic and mitogenic, and its effector hormone, insulin-like growth factor (IGF)-I is anti-apoptotic. As both hormones can cause proliferation of normal and malignant cells, the possibility that GH therapy may induce cancer, increase the risk of tumour recurrence in those previously treated for a malignancy, or increase the risk of cancer in those with a predisposition, has resulted in concerns over its use. There are theoretical and epidemiological reasons that suggest GH and IGF-I may be important in tumour formation and proliferation. Malignant tumours have been induced in animals exposed to supraphysiological doses of GH, whereas hypophysectomy appears to protect animals from carcinogen-induced neoplasms. In vitro, proliferation and transformation of normal haemopoetic and leukaemic cells occurs with supraphysiological doses of GH, but not with physiological levels. IGF, IGF binding proteins (IGFBP) and IGFBP proteases influence the proliferation of cancer cells in vitro; however, GH is probably not involved in this process. Epidemiological studies have suggested an association between levels of IGF-I and cancer, and an inverse relationship between IGFBP-3 and cancer; however, these associations have been inconsistent. A number of studies have been undertaken to determine the risk of the development of cancer in children treated with GH, either de novo, or the recurrence of cancer in those previously treated for a malignancy. Despite early concerns following a report of a cluster of cases of leukaemia in recipients of GH, there appears to be no increased risk for the development of leukaemia in those treated with GH unless there is an underlying predisposition. Even in children with a primary diagnosis of cancer, subsequent GH use does not appear to increase the risk of tumour recurrence. However, a recent follow-up of pituitary GH recipients has suggested an increase in colorectal cancer. In addition, follow-up of oncology patients has suggested an increase in second neoplasms in those who also received GH therapy. These studies emphasise the importance of continued surveillance both internationally with established databases and also nationally through single-centre studies.

Management of hyperglycaemia in the preterm infant

In the fetus, the predominant energy supply is glucose transported across the placenta from the mother. As pregnancy progresses, the amount of glucose transported increases, with glycogen and fat stores being laid down, principally in the third trimester. In the well-term baby, there is hormonal and metabolic adaptation in the perinatal period to ensure adequate fuel supply to the brain and other vital organs after delivery, but in the preterm infant, abnormalities of glucose homeostasis are common. After initial hypoglycaemia, due to limited glycogen and fat stores, preterm babies often become hyperglycaemic because of a combination of insulin resistance and relative insulin deficiency. Hyperglycaemia is associated with increased morbidity and mortality in preterm infants, but what should be considered optimal glucose control, and how best to achieve it, has yet to be defined in these infants.