Clarissa Valim

Safety and Efficacy of a Fish-Oil–Based Fat Emulsion in the Treatment of Parenteral Nutrition–Associated Liver Disease

BACKGROUND. Parenteral nutrition–associated liver disease can be a progressive and fatal entity in children with short-bowel syndrome. Soybean-fat emulsions provided as part of standard parenteral nutrition may contribute to its pathophysiology. METHODS. We compared safety and efficacy outcomes of a fish-oil–based fat emulsion in 18 infants with short-bowel syndrome who developed cholestasis (serum direct bilirubin level of >2 mg/dL) while receiving soybean emulsions with those from a historical cohort of 21 infants with short-bowel syndrome who also developed cholestasis while receiving soybean emulsions. The primary end point was time to reversal of cholestasis (3 consecutive measurements of serum direct bilirubin level of ≤2 mg/dL). RESULTS. Among survivors, the median time to reversal of cholestasis was 9.4 and 44.1 weeks in the fish-oil and historical cohorts, respectively. Subjects who received fish-oil–based emulsion experienced reversal of cholestasis 4.8 times faster than those who received soybean emulsions and 6.8 times faster in analysis adjusted for baseline bilirubin concentration, gestational age, and the diagnosis of necrotizing enterocolitis. A total of 2 deaths and 0 liver transplantations were recorded in the fish-oil cohort and 7 deaths and 2 transplantations in the historical cohort. The provision of fish-oil–based fat emulsion was not associated with essential fatty acid deficiency, hypertriglyceridemia, coagulopathy, infections, or growth delay. CONCLUSIONS. Parenteral fish-oil–based fat emulsions are safe and may be effective in the treatment of parenteral nutrition–associated liver disease.

Mortality of necrotizing enterocolitis expressed by birth weight categories

PURPOSE Low birth weight is the most important risk factor for developing necrotizing enterocolitis (NEC). We aimed to establish birth weight-based benchmarks for in-hospital mortality in neonates with NEC. METHODS Five hundred eleven centers belonging to the Vermont Oxford Network prospectively evaluated 71,808 neonates with birth weight of 501 to 1500 g between January 2005 and December 2006. The primary outcome variable was in-hospital mortality. RESULTS Birth weight was divided into 4 categories by 250-g increments. The NEC risk (P < .001) and mortality (P < .001) decreased with higher birth weight category. Necrotizing enterocolitis was associated with a significant odds ratio for death for each category (P < .001). Across groups, the odds ratio for NEC mortality increased with higher birth weight category (category 1 = 1.6 vs category 4 = 9.9; P < .001). CONCLUSION The in-hospital mortality rate of neonates with NEC remains high and is significantly related to birth weight category. Although the risk and absolute mortality of NEC decrease with higher birth weight, the odds ratios indicate that NEC has a relatively greater impact upon mortality at higher birth weight. These data afford birth weight-based mortality benchmarks that may be useful in assessing single center NEC outcomes and facilitating comparisons between centers.

Parenteral Fish Oil Improves Outcomes in Patients with Parenteral Nutrition Associated Liver Injury

Objective:The objective was to determine the safety and efficacy of a fish oil-based intravenous lipid emulsion (ILE) in the treatment of parenteral nutrition-associated liver disease (PNALD). Summary and Background Data:PNALD can be a lethal complication in children with short bowel syndrome (SBS). ILE based on soybean oil administered with parenteral nutrition (PN) may contribute to its etiology. Methods:We performed an open-labeled trial of a fish oil-based ILE in 42 infants with SBS who developed cholestasis (serum direct bilirubin >2 mg/dL) while receiving soybean oil-based ILE. Safety and efficacy outcomes were compared with those from a contemporary cohort of 49 infants with SBS and cholestasis whose PN course included soybean ILE only. The primary efficacy end-point was time to reversal of cholestasis (direct bilirubin ≤2 mg/dL). Results:Three deaths and 1 liver transplantation occurred in the fish oil cohort, compared with 12 deaths and 6 transplants in the soybean oil cohort (P = 0.005). Among survivors not transplanted during PN, cholestasis reversed while receiving PN in 19 of 38 patients in the fish oil cohort versus 2 of 36 patients in the soybean oil cohort. Based on Cox models, subjects receiving fish oil-based ILE experienced reversal of cholestasis 6 times faster (95% CI: 2.0–37.3) than those receiving soybean oil-based ILE. The provision of fish oil-based ILE was not associated with hypertriglyceridemia, coagulopathy, or essential fatty acid deficiency. Moreover, hypertriglyceridemic events and abnormal international normalized ratio levels were more common among controls. Conclusions:Fish oil-based ILE is safe, may be effective in treating PNALD, and may reduce mortality and organ transplantation rates in children with SBS.

Improved survival in a multidisciplinary short bowel syndrome program

PURPOSE Pediatric short bowel syndrome (SBS) remains a management challenge with significant mortality. In 1999, we initiated a multidisciplinary pediatric intestinal rehabilitation program. The purpose of this study was to determine if the multidisciplinary approach was associated with improved survival in this patient population. METHODS The Center for Advanced Intestinal Rehabilitation includes dedicated staff in surgery, gastroenterology, nutrition, pharmacy, nursing, and social work. We reviewed the medical records of all inpatients and outpatients with severe SBS treated from 1999 to 2006. These patients were compared to a historical control group of 30 consecutive patients with severe SBS who were treated between 1986 and 1998. RESULTS Fifty-four patients with severe SBS managed by the multidisciplinary program were identified. Median follow-up was 403 days. The mean residual small intestinal length was 70 +/- 36 vs 83 +/- 67 cm in the historical controls (P = NS). Mean peak direct bilirubin was 8.1 +/- 7.9 vs 9.0 +/- 7.4 mg/dL in controls (P = NS). Full enteral nutrition was achieved in 36 (67%) of 54 patients with severe SBS vs 20 (67%) of 30 patients in the control group (P = NS). The overall survival rate, however, was 89% (48/54), which is significantly higher than in the historical controls (70%, 21/30; P < .05). CONCLUSIONS A multidisciplinary approach to intestinal rehabilitation allows for fully integrated care of inpatients and outpatients with SBS by fostering coordination of surgical, medical, and nutritional management. Our experience with 2 comparable cohorts demonstrates that this multidisciplinary approach is associated with improved survival.

Adverse Drug Events in the Outpatient Setting: An 11-Year National Analysis

Adverse drug events (ADEs) are a common complication of medical care resulting in high morbidity and medical expenditure. Population level estimates of outpatient ADEs are limited. Our objective was to provide national estimates and characterizations of outpatient ADEs and determine risk factors associated with these events.

Transition of adolescents with inflammatory bowel disease from pediatric to adult care: a survey of adult gastroenterologists.

Objectives: Transition of patients with inflammatory bowel disease (IBD) from pediatric to adult providers requires preparation. Gastroenterologists for adult patients (“adult gastroenterologists”) may have expectations of patients that are different from those of pediatric patients. We sought to explore the perspectives of adult gastroenterologists caring for adolescents and young adults with IBD, to improve preparation for transition. Materials and Methods: A survey sent to 1132 adult gastroenterologists caring for patients with IBD asked physicians to rank the importance of patient competencies thought necessary in successful transition to an adult practice. Providers reported which problems occurred in patients with IBD transitioning to their own practice. Adult gastroenterologists were asked about medical and developmental issues that are unique to adolescence. Results: A response rate of 34% was achieved. Adult gastroenterologists reported that young adults with IBD often demonstrated deficits in knowledge of their medical history (55%) and medication regimens (69%). In addition, 51% of adult gastroenterologists reported receiving inadequate medical history from pediatric providers. Adult providers were less concerned about the ability of patients to identify previous and current health care providers (19%), or attend office visits by themselves (15%). Knowledge of adolescent medical and developmental issues was perceived as important by adult gastroenterologists; however, only 46% felt competent addressing the developmental aspects of adolescents. Conclusions: For successful transition, adolescents and young adults with IBD need improved education about their medical history and medications. Pediatric providers need to improve communication with the receiving physicians. In addition, adult providers may benefit from further training in adolescent issues. Formal transition checklists and programs may improve the transition of patients with IBD from pediatric to adult care.

Genetic diversity and protective efficacy of the RTS,S/AS01 malaria vaccine

BACKGROUND The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. METHODS We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. RESULTS In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy. CONCLUSIONS These results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.).

Brain Swelling and Death in Children with Cerebral Malaria

BACKGROUND Case fatality rates among African children with cerebral malaria remain in the range of 15 to 25%. The key pathogenetic processes and causes of death are unknown, but a combination of clinical observations and pathological findings suggests that increased brain volume leading to raised intracranial pressure may play a role. Magnetic resonance imaging (MRI) became available in Malawi in 2009, and we used it to investigate the role of brain swelling in the pathogenesis of fatal cerebral malaria in African children. METHODS We enrolled children who met a stringent definition of cerebral malaria (one that included the presence of retinopathy), characterized them in detail clinically, and obtained MRI scans on admission and daily thereafter while coma persisted. RESULTS Of 348 children admitted with cerebral malaria (as defined by the World Health Organization), 168 met the inclusion criteria, underwent all investigations, and were included in the analysis. A total of 25 children (15%) died, 21 of whom (84%) had evidence of severe brain swelling on MRI at admission. In contrast, evidence of severe brain swelling was seen on MRI in 39 of 143 survivors (27%). Serial MRI scans showed evidence of decreasing brain volume in the survivors who had had brain swelling initially. CONCLUSIONS Increased brain volume was seen in children who died from cerebral malaria but was uncommon in those who did not die from the disease, a finding that suggests that raised intracranial pressure may contribute to a fatal outcome. The natural history indicates that increased intracranial pressure is transient in survivors. (Funded by the National Institutes of Health and Wellcome Trust U.K.).

Necrotising pneumonia is an increasingly detected complication of pneumonia in children

Necrotising pneumonia (NP) is a severe complication of community-acquired pneumonia characterised by liquefaction and cavitation of lung tissue. The present study describes the epidemiology, aetiology, management and outcomes of children hospitalised with NP over a 15-yr period. A retrospective observational study of NP cases was conducted from January 1990 to February 2005 analysing clinical presentation, laboratory data, hospital course and long-term follow-up. A total of 80 NP cases were identified, with the number of detected cases increasing from 12, in the period 1993–1996, to 40 in the period 2001–2004. In total, 69 (86%) cases had pleural effusion with a low pH (mean 7.08) and 38 (48%) patients had positive cultures, with Streptococcus pneumoniae as the predominant organism. Recently, other organisms, most notably methicillin-resistant Staphylococcus aureus, emerged. Patients had prolonged hospitalisations (median 12 days). A total of 69 patients required pleural interventions and those receiving chest drainage alone had similar outcomes to those managed surgically. All patients had full clinical resolution within 2 months of presentation. Necrotising pneumonia has increasingly been identified as a complication of paediatric pneumonia. Streptococcus pneumoniae remains the predominant organism, but since 2002, different bacteria have been isolated and the age range of cases has broadened. Despite the serious morbidity, massive parenchymal damage and prolonged hospitalisations, long-term outcome following necrotising pneumonia is excellent.

Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite

Through rapid genetic adaptation and natural selection, the Plasmodium falciparum parasite—the deadliest of those that cause malaria—is able to develop resistance to antimalarial drugs, thwarting present efforts to control it. Genome-wide association studies (GWAS) provide a critical hypothesis-generating tool for understanding how this occurs. However, in P. falciparum, the limited amount of linkage disequilibrium hinders the power of traditional array-based GWAS. Here, we demonstrate the feasibility and power improvements gained by using whole-genome sequencing for association studies. We analyzed data from 45 Senegalese parasites and identified genetic changes associated with the parasites’ in vitro response to 12 different antimalarials. To further increase statistical power, we adapted a common test for natural selection, XP-EHH (cross-population extended haplotype homozygosity), and used it to identify genomic regions associated with resistance to drugs. Using this sequence-based approach and the combination of association and selection-based tests, we detected several loci associated with drug resistance. These loci included the previously known signals at pfcrt, dhfr, and pfmdr1, as well as many genes not previously implicated in drug-resistance roles, including genes in the ubiquitination pathway. Based on the success of the analysis presented in this study, and on the demonstrated shortcomings of array-based approaches, we argue for a complete transition to sequence-based GWAS for small, low linkage-disequilibrium genomes like that of P. falciparum.