Pneumococcal infections in children with sickle cell disease before and after pneumococcal conjugate vaccines.

Children with sickle cell disease (SCD) are at increased risk of invasive pneumococcal disease (IPD). Over 25 years, the Georgia Emerging Infections Program/Centers for Disease Control and Prevention Active Bacterial Core Surveillance network identified 104 IPD episodes among 3707 children with hemoglobin SS (HbSS) or HbSC aged <10 years, representing 6% of IPD in Black or African American children residing in Metropolitan Atlanta (reference population). Children with IPD and HbSS/SC were older than those with IPD in the reference population (P < .001). From 1994-1999 to 2010-2018, IPD declined by 87% in children with HbSS aged 0 to 4 years, and by 80% in those aged 5 to 9 years. However, IPD incidence rate ratios when comparing children with SCD with the reference population increased from 20.2 to 29.2 over these periods. Among children with HbSS and IPD, death declined from 14% to 3% after 2002, and meningitis declined from 16% to 8%. Penicillin resistance was more prevalent in children with SCD before 7-valent pneumococcal conjugate vaccine (PCV7) licensure. After 2010, all IPD serotypes were not included in the 13-valent PCV (PCV13). Within 3 years of vaccination, the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) against non-PCV13 serotypes included in PPSV23 plus 15A/15C was 92% (95% confidence interval, 40.8- 99.0, P = .014; indirect-cohort effect adjusted for age and hydroxyurea). PPSV23 would cover 62% of non-PCV13 serotype IPD in children with SCD, whereas PCV15, PCV20, and PCV21/V116 (in development) could cover 16%, 51%, and 92%, respectively. Although less frequent, IPD remains a life-threatening risk in children with SCD. Effective vaccines with broader coverage could benefit these children.

Avances en el diagnóstico y tratamiento de deficiencia de hierro y anemia ferropenica / Advances in the diagnosis and treatment of iron deficiency and iron deficiency anemia

RESUMEN Deficiencia de hierro (DH) y anemia ferropénica (AF) continúan siendo problemas de salud de magnitud en el mundo y afectan especialmente a niños preescolares y mujeres embarazadas. Este artículo tiene como objetivos: a) Describir las pruebas de laboratorio diagnóstico de AF y los factores que influyen en los niveles de ferritina y otros biomarcadores del estado del hierro; b) Presentar avances en el metabolismo del hierro, i.e. el rol regulador esencial de la hepcidina en la absorción y utilización del hierro; c) Describir el impacto que estos avances han tenido en el diseño de investigaciones clínicas comparando la absorción del hierro asociada con esquemas de ingesta diaria versus días alternados; d) Describir las situaciones clínicas en las cuales hierro endovenoso está indicado como tratamiento secundario o de primera línea. Los conceptos y sugerencias expresados en este artículo están basados en literatura actualizada y la experiencia clínica de los autores.

ABSTRACT Iron deficiency (ID) and iron deficiency anemia (IDA) are still major health problems worldwide, affecting especially preschool children and pregnant women. The objectives of this article are: a) To describe the laboratory tests for diagnosing IDA and the factors that may influence results of the serum ferritin and the other iron biomarkers ; b) To present advances in iron metabolism, i.e. the critical regulatory role of hepcidin in the absorption and utilization of iron ; c) To describe the impact this new knowledge has had in the design of clinical investigations comparing the absorption of iron following oral supplementation given in consecutive days vs. alternate days schedules; and, d) To describe the clinical situations in which intravenous iron is indicated as secondary or first-line treatment. The concepts expressed and the suggestions made in this article are based on updated literature and the clinical experience of the authors.

Influenza vaccination rates and hospitalizations among Medicaid enrollees with and without sickle cell disease, 2009-2015.

BACKGROUND: Personswith sickle cell disease (SCD) face increased risks for pulmonary and infection-related complications. This study examines influenza vaccination coverage and estimates influenza-related morbidity among Medicaid enrollees with and without SCD. PROCEDURE: Influenza vaccination coverage and hospitalizations related to influenza and pneumonia/acute chest syndrome (ACS) during each influenza season from 2009-2010 to 2014-2015 were assessed among enrollees in the IBM MarketScan® Multi-State Medicaid Database. Enrollees with SCD were identified as enrollees with greater than or equal to three claims listing SCD within a 5-year period during 2003-2017. Vaccinations were identified in outpatient claims. Hospitalizations associated with influenza or pneumonia/ACS were identified using inpatient claims. This study includes a series of cross-sectional assessments by season. RESULTS: From 2009-2010 through 2014-2015 seasons, the SCD sample ranged from 5044 to 8651 enrollees; the non-SCD sample ranged from 1,841,756 to 3,796,337 enrollees. Influenza vaccination coverage was higher among enrollees with SCD compared with enrollees without SCD for all seasons (24.5%-33.6% and 18.2%-22.0%, respectively). Age-standardized rates of influenza-related hospitalizations were 20-42 times higher among SCD enrollees compared with non-SCD enrollees, and ACS/pneumonia hospitalizations were 18-29 times higher. Among enrollees with SCD, influenza-related hospitalization rates were highest among children aged 0-9 years. Among enrollees without SCD, influenza-related hospitalization rates were highest among adults aged 40-64 years. CONCLUSIONS: Although vaccine coverage was higher in persons with versus without SCD, efforts to increase influenza coverage further are warranted for this high-risk group, who experienced markedly higher rates of influenza and ACS/pneumonia hospitalizations during each season.

Observed and expected frequencies of structural hemoglobin variants in newborn screening surveys in Africa and the Middle East: deviations from Hardy-Weinberg equilibrium.

PURPOSE: Our objective was to compare observed and expected genotype proportions from newborn screening surveys of structural hemoglobin variants. METHODS: We conducted a systematic review of newborn screening surveys of hemoglobins S and C in Africa and the Middle East. We compared observed frequencies to those expected assuming Hardy-Weinberg equilibrium (HWE). Significant deviations were identified by an exact test. The fixation index FIS was calculated to assess excess homozygosity. We compared newborn estimates corrected and uncorrected for HWE deviations using demographic data. RESULTS: Sixty samples reported genotype counts for hemoglobin variants in Africa and the Middle East. Observed and expected counts matched in 27%. The observed number of sickle cell anemia (SCA) individuals was higher than expected in 42 samples, reaching significance (P < 0.05) in 24. High FIS values were common across the study regions. The estimated total number of newborns with SCA, corrected based on FIS, was 33,261 annual births instead of 24,958 for the 38 samples across sub-Saharan Africa and 1,109 annual births instead of 578 for 12 samples from the Middle East. CONCLUSION: Differences between observed and expected genotype frequencies are common in surveys of hemoglobin variants in the study regions. Further research is required to identify and quantify factors responsible for such deviations. Estimates based on HWE might substantially underestimate the annual number of SCA-affected newborns (up to one-third in sub-Saharan Africa and one-half in the Middle East).

Contribution of Sickle Cell Disease to the Pediatric Stroke Burden Among Hospital Discharges of African-Americans-United States, 1997-2012.

BACKGROUND: Approximately 10-20% of children with sickle cell disease (SCD) develop stroke, but few consistent national estimates of the stroke burden for children with SCD exist. The purpose of this study is to determine the proportion of diagnosed stroke among African-American pediatric discharges with and without SCD. PROCEDURE: Records for African-Americans aged 1-18 years in the Kids' Inpatient Database (KID) 1997-2012 with ≥1 ICD-9-CM diagnosis code for stroke were included. Data were weighted to provide national estimates. A total of 2,994 stroke cases among African-American children were identified. Diagnoses co-existing with ischemic or hemorrhagic stroke were frequency ranked separately. RESULTS: From 1997 through 2012, SCD was present in 24% of stroke discharges, with 89% being ischemic stroke. For hospital discharges of African-American children, SCD is the highest co-existing risk factor for ischemic stroke (29%). Stroke in children with SCD occurred predominantly in children aged 5-9 years, older than previously reported. The trend of stroke discharges significantly decreased for children with SCD from 1997 to 2012 for children aged 10-14 years. CONCLUSIONS: SCD is a leading risk factor to pediatric stroke in African-American children. Reducing the number of strokes among children with SCD would have a significant impact on the rate of strokes among African-American children. Preventative intervention may be modifying initial age of presentation of stroke in children with SCD.

Plasma BDNF and PDGF-AA levels are associated with high TCD velocity and stroke in children with sickle cell anemia.

Sickle cell anemia (SCA) associated cerebrovascular disease includes vascular remodeling, abnormal cerebral blood flow (CBF) and infarction. We studied the relationships between plasma brain derived neurotropic factor (BDNF), platelet derived growth factors (PDGF-AA and -AB/BB) and high trans-cranial Doppler (TCD) velocity, an indication of CBF velocity. Baseline plasma samples from 39 children (19 SCA with abnormal/high TCD [SATCD], 13 SCA with normal TCD [SNTCD] and 7 healthy non-SCA), were assayed for BDNF, PDGF-AA and -AB/BB plus 11 other cytokines. The sensitivity, specificity and usefulness of these biomarkers for stroke prediction was investigated. All subject groups were of similar age and gender distribution. Mean BDNF was significantly higher among SATCD than SNTCD (p=0.004) as was mean PDGF-AA (p=0.001). Similarly, mean PDGF-AA was higher among SCA subjects who developed stroke than those who did not (p=0.012). Elevated BDNF and PDGF-AA were good predictors of the presence of abnormally high CBF velocity and were both associated with severity of anemia. Elevated PDGF-AA predicted risk for stroke development. Stroke incidence and high TCD velocity were associated with elevated BDNF and PDGF-AA. These findings suggest a role for BDNF and PDGF-AA in the patho-physiological mechanism of cerebrovascular disease in SCA.

Genetic polymorphisms linked to susceptibility to malaria.

The influence of host genetics on susceptibility to Plasmodium falciparum malaria has been extensively studied over the past twenty years. It is now clear that malaria parasites have imposed strong selective forces on the human genome in endemic regions. Different genes have been identified that are associated with different malaria related phenotypes. Factors that promote severity of malaria include parasitaemia, parasite induced inflammation, anaemia and sequestration of parasitized erythrocytes in brain microvasculature.Recent advances in human genome research technologies such as genome-wide association studies (GWAS) and fine genotyping tools have enabled the discovery of several genetic polymorphisms and biomarkers that warrant further study in host-parasite interactions. This review describes and discusses human gene polymorphisms identified thus far that have been shown to be associated with susceptibility or resistance to P. falciparum malaria. Although some polymorphisms play significant roles in susceptibility to malaria, several findings are inconclusive and contradictory and must be considered with caution. The discovery of genetic markers associated with different malaria phenotypes will help elucidate the pathophysiology of malaria and enable development of interventions or cures. Diversity in human populations as well as environmental effects can influence the clinical heterogeneity of malaria, thus warranting further investigations with a goal of developing new interventions, therapies and better management against malaria.

Serum ferritin level changes in children with sickle cell disease on chronic blood transfusion are nonlinear and are associated with iron load and liver injury.

Chronic blood transfusion is increasingly indicated in patients with sickle cell disease. Measuring resulting iron overload remains a challenge. Children without viral hepatitis enrolled in 2 trials for stroke prevention were examined for iron overload (STOP and STOP2; n = 271). Most received desferrioxamine chelation. Serum ferritin (SF) changes appeared nonlinear compared with prechelation estimated transfusion iron load (TIL) or with liver iron concentrations (LICs). Averaged correlation coefficient between SF and TIL (patients/observations, 26 of 164) was r = 0.70; between SF and LIC (patients/observations, 33 of 47) was r = 0.55. In mixed models, SF was associated with LIC (P = .006), alanine transaminase (P = .025), and weight (P = .026). Most patients with SF between 750 and 1500 ng/mL had a TIL between 25 and 100 mg/kg (72.8% +/- 5.9%; patients/observations, 24 of 50) or an LIC between 2.5 and 10 mg/g dry liver weight (75% +/- 0%; patients/observations, 8 of 9). Most patients with SF of 3000 ng/mL or greater had a TIL of 100 mg/kg or greater (95.3% +/- 6.7%; patients/observations, 7 of 16) or an LIC of 10 mg/g dry liver weight or greater (87.7% +/- 4.3%; patients/observations, 11 of 18). Although SF changes are nonlinear, levels less than 1500 ng/mL indicated mostly acceptable iron overload; levels of 3000 ng/mL or greater were specific for significant iron overload and were associated with liver injury. However, to determine accurately iron overload in patients with intermediately elevated SF levels, other methods are required. These trials are registered at www.clinicaltrials.gov as #NCT00000592 and #NCT00006182.

Effectiveness of the 7-valent pneumococcal conjugate vaccine in children with sickle cell disease in the first decade of life.

BACKGROUND: The incidence of and mortality from invasive pneumococcal disease are significantly higher in children with sickle cell disease than in the general pediatric population. The objective of this population-based study was to assess the effect of pneumococcal conjugate vaccine on rates of invasive pneumococcal disease among children with sickle cell disease. PATIENTS AND METHODS: Records, including the history of pneumococcal conjugate vaccine administration, of 1247 children born after 1983 residing in metropolitan Atlanta, Georgia, with confirmed hemoglobinopathies were linked to an active surveillance database for invasive pneumococcal disease for the period of January 1, 1995, through January 1, 2003. The incidence of invasive pneumococcal disease and the percentage of rate reduction were estimated before and after pneumococcal conjugate vaccine licensure. Survival analysis was used to estimate the effect of pneumococcal conjugate vaccine on invasive pneumococcal disease rates while accounting for herd immunity. RESULTS: A significant decline in invasive pneumococcal disease in children with sickle cell disease < or = 10 years of age was noted after pneumococcal conjugate vaccine licensure, from 1.7 infections per 100 person-years (1995-2000) to 0.5 infections per 100 person-years (2001-2002), which represents a 68% reduction. The effectiveness of > or = 1 dose of pneumococcal conjugate vaccine was estimated by crude analysis to be 84.5% and by stratified survival analysis to be 81.4% when controlling for the presence of herd immunity in the 2 years after pneumococcal conjugate vaccine licensure. Serotype 6A invasive pneumococcal disease represented 36% of invasive pneumococcal disease before pneumococcal conjugate vaccine licensure and 0% after pneumococcal conjugate vaccine licensure, suggesting a protective effect against this pneumococcal conjugate vaccine-related serotype. CONCLUSIONS: Invasive pneumococcal disease significantly decreased in children with sickle cell disease < or = 10 years of age after pneumococcal conjugate vaccine licensure. Pneumococcal conjugate vaccine was effective even when controlling for herd immunity. Extending guideline recommendations for catch-up vaccination beyond 4 years of age should be considered.

Identification of unrelated cord blood units for hematopoietic stem cell transplantation in children with sickle cell disease.

This study examined the theoretical availability of compatible unrelated umbilical cord blood (UCB) units for hematopoietic stem cell transplantation (HSCT) of children with sickle cell disease (SCD), matched for DRB1 at high resolution. UCB units registered via Bone Marrow Donors Worldwide were matched with patients who had been previously typed for possible HSCT. Suitable matching was determined after typing at antigen level at A and B loci and allele-level typing at DRB1. Forty patients met criteria for analysis. All matched at four of six loci with at least two UCB units, and 50% (n = 20) matched at five of six loci with at least one unit. In patients matched at four loci or more, significantly more units per patient (median 19 vs. 2 units; P = 0.03) at higher cell dose (median 205 vs. 113 best nucleated cell dose per unit; P < 0.01) were identified compared with patients matched at five loci or more. Hypothetically, at a dose of at least 5 x 10 nucleated cells/kg, 54% of patients weighing 40 kg would match with units at four or more of six loci and 5% at five or more of six loci. This study suggests that cord blood units matching at four or more of six HLA loci at acceptable cell doses can be identified for a majority of children with SCD weighing 40 kg or less. Availability of units matched at five or more of six HLA loci was more limited. Defining procedure-related risks and benefits remains a challenge.

Invasive pneumococcal infections in children with sickle cell disease in the era of penicillin prophylaxis, antibiotic resistance, and 23-valent pneumococcal polysaccharide vaccination.

Rates and severity of pneumococcal infections in children with sickle cell disease were examined before licensure of pneumococcal-conjugated vaccine (PVC). Rates of peak invasive infection rates in 1-year-old children with hemoglobin SS and mortality in those 0 to 10 years of age were 36.5 to 63.4 and 1.4 to 2.8 per 1000 person-years, respectively (>10 and 100 times as frequent as in the general population). Overall, 71% of serotyped isolates (n=80) were PVC serotypes and 71% of nonvaccine serotype strains were penicillin-sensitive. Clinical presentation in children with hemoglobin SS (n=71; more with hypotension) and hemoglobin SC (n=18; more with acute chest syndrome, otitis media) differed. Penicillin nonsusceptibility (38% of isolates) varied between geographic study sites. Penicillin prophylaxis appeared less effective against intermediate and resistant strains. Of all infected children, meningitis developed in 20% and 15% died (hemoglobin SS, n=15 and 11; hemoglobin SC, n=1 each). Factors associated with death included age >4 years (58%), serotype 19F, and not being followed by a hematologist (42% each). The pneumococcal-polysaccharide vaccine was 80.4% effective within 3 years after vaccination (95% CI, 39.7, 93.6). Children with sickle cell disease of all ages may benefit from PVC boosted with polysaccharide vaccination.