Sana Syed

Effect of case management on neonatal mortality due to sepsis and pneumonia.

BackgroundEach year almost one million newborns die from infections, mostly in low-income countries. Timely case management would save many lives but the relative mortality effect of varying strategies is unknown. We have estimated the effect of providing oral, or injectable antibiotics at home or in first-level facilities, and of in-patient hospital care on neonatal mortality from pneumonia and sepsis for use in the Lives Saved Tool (LiST).MethodsWe conducted systematic searches of multiple databases to identify relevant studies with mortality data. Standardized abstraction tables were used and study quality assessed by adapted GRADE criteria. Meta-analyses were undertaken where appropriate. For interventions with biological plausibility but low quality evidence, a Delphi process was undertaken to estimate effectiveness.ResultsSearches of 2876 titles identified 7 studies. Among these, 4 evaluated oral antibiotics for neonatal pneumonia in non-randomised, concurrently controlled designs. Meta-analysis suggested reductions in all-cause neonatal mortality (RR 0.75 95% CI 0.64- 0.89; 4 studies) and neonatal pneumonia-specific mortality (RR 0.58 95% CI 0.41- 0.82; 3 studies). Two studies (1 RCT, 1 observational study), evaluated community-based neonatal care packages including injectable antibiotics and reported mortality reductions of 44% (RR= 0.56, 95% CI 0.41-0.77) and 34% (RR =0.66, 95% CI 0.47-0.93), but the interpretation of these results is complicated by co-interventions. A third, clinic-based, study reported a case-fatality ratio of 3.3% among neonates treated with injectable antibiotics as outpatients. No studies were identified evaluating injectable antibiotics alone for neonatal pneumonia. Delphi consensus (median from 20 respondents) effects on sepsis-specific mortality were 30% reduction for oral antibiotics, 65% for injectable antibiotics and 75% for injectable antibiotics on pneumonia-specific mortality. No trials were identified assessing effect of hospital management for neonatal infections and Delphi consensus suggested 80%, and 90% reductions for sepsis and pneumonia-specific mortality respectively.ConclusionOral antibiotics administered in the community are effective for neonatal pneumonia mortality reduction based on a meta-analysis, but expert opinion suggests much higher impact from injectable antibiotics in the community or primary care level and even higher for facility-based care. Despite feasibility and low cost, these interventions are not widely available in many low income countries.FundingThis work was supported by the Bill & Melinda Gates Foundation through a grant to the US Fund for UNICEF, and to Saving Newborn Lives Save the Children, through Save the Children US.

Neonatal severe bacterial infection impairment estimates in South Asia, sub-Saharan Africa, and Latin America for 2010.

Background:Survivors of neonatal infections are at risk of neurodevelopmental impairment (NDI), a burden not previously systematically quantified and yet important for program priority setting. Systematic reviews and meta-analyses were undertaken and applied in a three-step compartmental model to estimate NDI cases after severe neonatal bacterial infection in South Asia, sub-Saharan Africa, and Latin America in neonates of >32 wk gestation (or >1,500 g).Methods:We estimated cases of sepsis, meningitis, pneumonia, or no severe bacterial infection from among estimated cases of possible severe bacterial infection ((pSBI) step 1). We applied respective case fatality risks ((CFRs) step 2) and the NDI risk among survivors (step 3). For neonatal tetanus, incidence estimates were based on the estimated deaths, CFRs, and risk of subsequent NDI.Results:For 2010, we estimated 1.7 million (uncertainty range: 1.1–2.4 million) cases of neonatal sepsis, 200,000 (21,000–350,000) cases of meningitis, 510,000 cases (150,000–930,000) of pneumonia, and 79,000 cases (70,000–930,000) of tetanus in neonates >32 wk gestation (or >1,500 g). Among the survivors, we estimated moderate to severe NDI after neonatal meningitis in 23% (95% confidence interval: 19–26%) of survivors, 18,000 (2,700–35,000) cases, and after neonatal tetanus in 16% (6–27%), 4,700 cases (1,700–8,900).Conclusion:Data are lacking for impairment after neonatal sepsis and pneumonia, especially among those of >32 wk gestation. Improved recognition and treatment of pSBI will reduce neonatal mortality. Lack of follow-up data for survivors of severe bacterial infections, particularly sepsis, was striking. Given the high incidence of sepsis, even minor NDI would be of major public health importance. Prevention of neonatal infection, improved case management, and support for children with NDI are all important strategies, currently receiving limited policy attention.

Environmental Enteric Dysfunction in Children.

ABSTRACT Diarrheal diseases are a major cause of childhood death in resource-poor countries, killing approximately 760,000 children younger than 5 years each year. Although deaths due to diarrhea have declined dramatically, high rates of stunting and malnutrition have persisted. Environmental enteric dysfunction (EED) is a subclinical condition caused by constant fecal-oral contamination with resultant intestinal inflammation and villous blunting. These histological changes were first described in the 1960s, but the clinical effect of EED is only just being recognized in the context of failure of nutritional interventions and oral vaccines in resource-poor countries. We review the existing literature regarding the underlying causes of and potential interventions for EED in children, highlighting the epidemiology, clinical and histologic classification of the entity, and discussing novel biomarkers and possible therapies. Future research priorities are also discussed.

Management of Acute Severe Colitis in Children With Ulcerative Colitis in the Biologics Era.

BACKGROUND AND OBJECTIVE: Approximately one-third of children with ulcerative colitis will experience at least 1 attack of acute severe colitis (ASC) before 15 years of age. Severe disease can be defined in children when Pediatric Ulcerative Colitis Activity Index is >65 and/or ≥6 bloody stools per day, and/or 1 of the following: tachycardia, fever, anemia, and elevated erythrocyte sedimentation rate with or without systemic toxicity. Our aim was to provide practical suggestions on the management of ASC in children. The goal of medical therapy is to avoid colectomy while preventing complications of disease, side effects of medications, and mortality. METHODS: A systematic search was carried out through Medline via PubMed to identify all articles published in English to date, based on the following keywords “ulcerative colitis,” “pediatric ulcerative colitis,” “biological therapy,” and “acute severe colitis.” Multidisciplinary clinical evaluation is recommended to identify early nonresponders to conventional treatment with intravenous corticosteroids, and to start, if indicated, second-line therapy or “rescue therapy,” such as calcineurin inhibitors (cyclosporine, tacrolimus) and anti–tumor necrosis factor molecules (infliximab). RESULTS: Pediatric Ulcerative Colitis Activity Index is a valid predictive tool that can guide clinicians in evaluating response to therapy. Surgery should be considered in the case of complications or rapid clinical deterioration during medical treatment. CONCLUSIONS: Several pitfalls may be present in the management of ASC, and a correct clinical and therapeutic approach is recommended to reduce surgical risk.

Iodine and the "near" eradication of cretinism.

The eradication of intellectual disability from iodine deficiency in Western countries is one of the great public health triumphs of 20th-century child health care.1 Yet the problem persists today in many parts of the world.2 This article explores why a strategy so successful in the West has proven difficult to export to certain other contexts and how new kinds of thinking may point the way forward. As recently as the late 19th century, American pediatricians were familiar with the dwarfism and severe mental deficiency associated with the syndrome that had long been called “cretinism”. The 1920 edition of L. Emmett Holt’s3 influential textbook The Diseases of Infancy and Childhood described these children as “dull, placid, and good-natured, rarely troublesome or excitable; and when fifteen or eighteen years old they appear like children of three or four years” (Figure 1). Pediatricians in those times were aware that the short stature and coarse facial features of cretinism could be lessened by the early administration of thyroid extract, with Holt describing a change in the entire appearance of the child and a loss of “the idiotic expression of the features.” However, treatment did not prevent children from developing mental deficiency. FIGURE 1 Images from the 1920 edition of The Diseases of Infancy and Childhood, by L. Emmett Holt: A, A typical cretin at 2½ years old; B, The same patient at 6 years of age, illustrating the effect of thyroid treatment. Prenatal iodine deficiency, and the resulting fetal hypothyroidism that caused cretinism, vanished … Address correspondence to Sana Syed, MD, Children’s Healthcare of Atlanta, 2015 Upper Gate Dr NE, Atlanta, GA 30322. E-mail: sana.syed{at}emory.edu

Determinants of Anemia among School-Aged Children in Mexico, the United States and Colombia

Anemia affects approximately 25% of school-aged children (SAC—aged 5.00–14.99 years) globally. We determined in three countries the prevalence and determinants of anemia in SAC. Data on sociodemographics, inflammation and nutrition status were obtained from the 2006 Mexican National Nutrition Survey, the 2003-6 US National Health and Nutrition Examination Surveys, and the 2010 Encuesta Nacional de Nutrición Situación Colombia. In the US, vitamin A and iron deficiency (ID) were available only for girls aged 12.00–14.99 years to which our analysis was limited. Associations were evaluated by country using multivariable logistic regression adjusting for confounders and complex survey design. The prevalence of anemia and ID were: Mexico 12% (ID 18%), n = 3660; US 4% (ID 10%), n = 733; and Colombia 4% (ID 9%), n = 8573. The percentage of anemia associated with ID was 22.4% in Mexico, 38.9% in the US and 16.7% in Colombia. In Mexico, anemia was associated with ID (adjusted OR: 1.5, p = 0.02) and overweight (aOR 0.4, p = 0.007). In the US, anemia was associated with black race/ethnicity (aOR: 14.1, p < 0.0001) and ID (aOR: 8.0, p < 0.0001). In Colombia, anemia was associated with black race/ethnicity (aOR: 1.6, p = 0.005), lowest socio-economic status quintile (aOR: 1.8, p = 0.0005), ID (aOR: 2.7, p < 0.0001), and being stunted (aOR: 1.6, p = 0.02). While anemia was uniformly associated with iron deficiency in Mexico, Columbia, and the United States, other measured factors showed inconsistent associations with anemia. Additional data on anemia determinants in SAC are needed to guide interventions.

Pilot Study Evaluating Efficacy of 2 Regimens for Hypovitaminosis D Repletion in Pediatric Inflammatory Bowel Disease

Objectives: Vitamin D is critical for skeletal health; hypovitaminosis D is common in pediatric inflammatory bowel disease (IBD), yet optimal repletion therapy is not well studied. We aimed to conduct a pilot trial comparing the efficacy of 2 vitamin D regimens of weekly dosing for the repletion of hypovitaminosis D in pediatric IBD. Methods: Subjects identified from our IBD clinic with 25-hydroxyvitamin D (25[OH]D) concentrations <30 ng/mL were randomized to 10,000 (n = 18) or 5000 (n = 14) IU of oral vitamin D3/10 kg body weight per week for 6 weeks. Serum 25(OH)D, Ca, and parathyroid hormone concentrations were measured at baseline, week 8, and week 12. Results: In the higher dosing group, serum 25(OH)D increased from 23.7 ± 8.5 ng/mL at baseline to 49.2 ± 13.6 ng/mL at 8 weeks; P < 0.001. In the lower dosing group, serum 25(OH)D increased from 24.0 ± 7.0 ng/mL at baseline to 41.5 ± 9.6 ng/mL at 8 weeks; P < 0.001. At 12 weeks, serum 25(OH)D concentrations were 35.1 ± 8.4 and 30.8 ± 4.2 ng/mL for the higher and lower dose regimens, respectively. Mean serum Ca and parathyroid hormone concentrations did not significantly change during the study. No patient exhibited hypercalcemia, and no serious adverse events occurred. Conclusions: Both treatment arms were safe and effective at normalizing vitamin D nutriture in pediatric IBD. Although significant repletion of 25(OH)D concentration was achieved in both dosing groups at 8 weeks, this effect was lost by the 12-week follow-up. Maintenance vitamin D therapy following initial repletion is likely required to maintain long-term normalized vitamin D status.

Use of Reticulocyte Hemoglobin Content in the Assessment of Iron Deficiency in Children with Inflammatory Bowel Disease

Background: Iron deficiency and anemia affect up to 50% to 75% of patients with inflammatory bowel disease (IBD). Iron deficiency in IBD may be difficult to diagnose because of the effect of inflammation on iron status biomarkers. Thus, there is a need for better methods to accurately determine iron status in IBD. Objective: The aim of the study was to investigate the association of inflammation with hemoglobin content of reticulocytes (CHr) and the utility of CHr in comparison to standard iron biomarkers. Methods: We conducted a cross-sectional study of children with IBD. Iron biomarkers (CHr, ferritin, soluble transferrin receptor [sTfR], hepcidin, hemoglobin) were measured along with systemic biomarkers of inflammation (C-reactive protein, &agr;1-acid glycoprotein]. Spearman correlations were used to evaluate the relation of inflammation and iron biomarkers. The criterion standard for iron deficiency was defined as inflammation-corrected ferritin <15 &mgr;g/L or sTfR >8.3 mg/L. Receiver operating characteristic curves were used to estimate the prognostic values of all iron biomarkers to identify patients with iron deficiency. Results: We analyzed data in 62 children ages 5 to 18 years. Sixty-nine percent of our subjects had Crohn disease and 31% had ulcerative colitis, of which 42% were girls and 53% African American. The prevalence of anemia was 32%, of iron deficiency was 52% using ferritin <15 &mgr;g/L or sTfR >8.3 mg/L, 39% using red blood cell distribution width of >14.5%, 26% using body iron stores of <0 mg/kg body weight, 25% using CHr of <28 pg, and 11% using mean corpuscular volume of <75 fL/cell. The prevalence of elevated CRP or AGP was 48%. After correcting ferritin and sTfR levels for inflammation, the prevalence of iron deficiency was 68%. CHr was correlated with C-reactive protein (rs −0.44, P < 0.001) and &agr;1-acid glycoprotein (rs −0.37, P < 0.05). The optimal prognostic value for inflammation-adjusted CHr to predict iron deficiency was 34 pg (area under the receiver operating characteristic of 0.70), with 88% sensitivity and 30% specificity. Conclusions: Iron deficiency and anemia are common in this pediatric IBD cohort. All explored iron biomarkers, including CHr, were affected by inflammation and should be adjusted. A single iron biomarker is unlikely to best predict iron deficiency in pediatric IBD. Iron intervention studies are needed to examine the response of iron biomarkers to iron supplementation in the setting of inflammation.

Vitamin D Status Is Associated with Hepcidin and Hemoglobin Concentrations in Children with Inflammatory Bowel Disease.

Background: Anemia, iron deficiency, and hypovitaminosis D are well-known comorbidities in inflammatory bowel disease (IBD). Epidemiologic studies have linked vitamin D deficiency with increased risk of anemia, and in vitro studies suggest that vitamin D may improve iron recycling through downregulatory effects on hepcidin and proinflammatory cytokines. Methods: We aimed to investigate the association of vitamin D status with inflammation, iron biomarkers, and anemia in pediatric IBD. Cross-sectional data were obtained from N = 69 patients with IBD aged 5 to <19 years. Iron biomarkers (ferritin, soluble transferrin receptor), and 25-hydroxyvitamin D (25(OH)D), inflammatory biomarkers (C-reactive protein and &agr;-1-acid glycoprotein), hepcidin, and hemoglobin were collected. Iron biomarkers were regression corrected for inflammation. Multivariable logistic/linear models were used to examine the associations of 25(OH)D with inflammation, iron status, hepcidin, and anemia. Results: Approximately 50% of subjects were inflamed (C-reactive protein >5 mg/L or &agr;-1-acid glycoprotein >1 g/L). Iron deficiency prevalence (inflammation-corrected ferritin <15 &mgr;g/L or soluble transferrin receptor >8.3 mg/L) was 67%; anemia was 36%, and vitamin D insufficiency (25(OH)D <30 ng/mL) was 77%. In linear regression models, vitamin D insufficiency was associated with increased hepcidin levels (&bgr; [SE] = 0.6 [0.2], P = 0.01) and reduced hemoglobin (&bgr; [SE] = −0.9 [0.5], P = 0.046), controlling for age, sex, race, insurance status, body mass index for age, inflammation, disease diagnosis (ulcerative colitis versus Crohns disease), and disease duration, compared with 25(OH)D ≥30 ng/mL. Conclusions: Our results suggest that concentrations of 25(OH)D ≥30 ng/mL are associated with lower hepcidin and higher hemoglobin levels. Further research is needed to clarify the association of vitamin D with inflammation, iron status, and anemia in pediatric IBD.

Authorship Concerns and Who Truly Owns a Research Idea

Researchers often face dilemmas about authorship. When the researchers are graduate students, fellows, or junior faculty, the dilemmas might involve discussions about fair criteria for more senior faculty to be acknowledged as key contributors or authors on manuscripts. This “Ethics Rounds” presents a case in which a fellow faced such a dilemma. We review current journal guidelines for authorship and some ethical considerations that should help make this process more streamlined.