Gut permeability is associated with lower insulin sensitivity in youth with perinatally acquired HIV.

The relationships between alterations in the intestinal barrier, and bacterial translocation with the development of metabolic complications in youth with perinatally acquired HIV (YPHIV) have not been investigated. The PHACS Adolescent Master Protocol enrolled YPHIV across 15 U.S. sites, including Puerto Rico, from 2007 to 2009. For this analysis, we included YPHIV with HIV viral load 1000 c/ml or less, with at least one measurement of homeostatic assessment of insulin resistance (HOMA-IR) or nonhigh density lipoprotein (non-HDLc) between baseline and year 3 and plasma levels of intestinal fatty-acid binding protein (I-FABP), lipopolysaccharide-binding protein (LBP), and zonulin levels at baseline. We fit linear regression models using generalized estimating equations to assess the association of baseline log 10 gut markers with log 10 HOMA-IR and non-HDLc at all timepoints. HOMA-IR or non-HDLc was measured in 237, 189, and 170 PHIV at baseline, Yr2, and Yr3, respectively. At baseline, median age (Q1, Q3) was 12 years (10, 14), CD4 + cell count was 762 cells/µl (574, 984); 90% had HIV RNA less than 400 c/ml. For every 10-fold higher baseline I-FABP, HOMA-IR dropped 0.85-fold at baseline and Yr2. For a 10-fold higher baseline zonulin, there was a 1.35-fold increase in HOMA-IR at baseline, 1.23-fold increase in HOMA-IR at Yr2, and 1.20-fold increase in HOMA-IR at Yr3 in adjusted models. For a 10-fold higher baseline LBP, there was a 1.23-fold increase in HOMA-IR at baseline in the unadjusted model, but this was slightly attenuated in the adjusted model. Zonulin was associated with non-HDLc at baseline, but not for the other time points. Despite viral suppression, intestinal damage may influence downstream insulin sensitivity in YPHIV.

Longitudinal changes in body fat and metabolic complications in young people with perinatally acquired HIV.

BACKGROUND: The role of body fat on metabolic complications remains poorly understood in young people living with perinatally acquired HIV (YPHIV). OBJECTIVE: Our objective was to assess the association of changes in adiposity over 2 years with metabolic outcomes in YPHIV. METHODS: The PHACS Adolescent Master Protocol (AMP) study enrolled YPHIV from 2007 to 2009 across 15 US sites, including Puerto Rico. We included YPHIV aged 7-19 years with body composition data assessed by whole-body dual-energy X-ray absorptiometry (DXA) at baseline and 2 years later. Metabolic outcomes included homeostatic model assessment of insulin resistance (HOMA-IR) and non-high-density lipoprotein cholesterol (non-HDL-C). We fitted linear regression models to assess the association of increase in body fat over 2 years with metabolic outcomes at years 2 and 3. RESULTS: In all, 232 participants had a second DXA and either HOMA-IR or non-HDL-C measured at year 2. Participant characteristics at the first DXA were: age 12 years (9-14) [median (Q1-Q3)], 69% Black, and median CD4 count 714 cells/µL; 70% with HIV RNA <400 copies/mL. In adjusted analyses for every 1% increase in body fat from baseline to year 2, HOMA-IR was higher by 1.03-fold at year 3 (95% CI: 1.00, 1.05). We observed that for every 1% increase in body fat from baseline to year 2, non-HDL-C was 0.72 mg/dL higher at year 2 (95% CI: -0.04-1.49) and 0.81 mg/dL higher at year 3 (95% CI: -0.05-1.66). CONCLUSIONS: Increases in adiposity over time may lead to downstream decreased insulin sensitivity and dyslipidaemia in YPHIV.

Report of Haemophilus Influenzae serotype a intracranial infections in older children.

Introduction: Haemophilus influenzae (Hi) is subdivided into typeable (a-f) and non-typeable groups. Hi serotype b (Hib) has historically been one of the important pathogens responsible for invasive infection. However, after widespread Hib vaccination, the emergence of other Hi serotypes, specifically Hi serotype a (Hia), was noted during the last few decades, mostly in children younger than 5 years of age. Case presentation: We present two cases of severe intracranial infections with detected Hia in patients > 5 years of age within a short time frame and within the same geographic area. Conclusion: Epidemiological studies and surveillance on Hia-related illnesses in all age groups worldwide are needed to better understand the clinical and epidemiological characteristics of Hia. This can establish a platform to develop a candidate vaccine against Hia that might protect children of all ages.

Gut Dysfunction Markers Are Associated With Body Composition in Youth Living With Perinatally Acquired Human Immunodeficiency Virus.

BACKGROUND: The association between gut dysfunction and body fat composition in youth living with perinatal human immunodeficiency virus infection (YPHIV) has not been investigated. METHODS: We included YPHIV aged 7-19 years from the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol with plasma available within 6 months of baseline whole-body dual energy x-ray absorptiometry (DXA) and HIV RNA ≤1000 copies/mL within 3 months of baseline DXA and a second DXA 2 years later. Plasma markers of bacterial translocation and gut barrier dysfunction (lipopolysaccharide binding protein [LBP], zonulin, and intestinal fatty acid binding protein [I-FABP]) were measured at baseline by enzyme-linked immunosorbent assay and log10 transformed. Adiposity outcomes included percentage total body, truncal, and extremity fat in kilograms from DXA. Linear regression models were fit using generalized estimating equations to assess associations of baseline gut markers (log10) on adiposity outcomes at baseline and 2 years, adjusted for demographic variables, current antiretroviral therapy exposure, and physical activity. RESULTS: Two hundred sixty-one youth were included; 128 had a second DXA. Median age at first DXA was 12 years (interquartile range, 10-14 years), 49% were female, and 69% were Black. After adjustment for potential confounders, log10 LBP was positively associated with percentage total body fat at baseline (ß = 4.08, P < .01) and zonulin with adiposity measures at both time points (ß = .94 to 6.50, P ≤ .01). I-FABP was inversely associated with percentage total body fat at baseline and year 2 (ß = -2.36 and -3.01, respectively, P ≤ .02). CONCLUSIONS: Despite viral suppression, gut damage and the resultant bacterial translocation are associated with body composition measures in YPHIV.

Antimicrobial stewardship program in pediatric medicine.

The rising threats from antimicrobial resistance due to inappropriate utilization of antimicrobial agents in health care including the pediatric population has been a topic of concern at the global level for the last several decades. The antimicrobial stewardship program (ASP) is a multidisciplinary institutional initiative focusing primarily on the improvement of antimicrobial prescribing practices and limiting inappropriate use. ASPs play an important role in the implementation of healthcare strategies in pediatrics worldwide to reduce antimicrobial resistance. Many published reports demonstrate how adapted ASPs in pediatrics result in improvement of unnecessary antimicrobial utilization, decreasing drug resistance and treatment failure, minimization of adverse clinical outcomes, decreasing healthcare costs and hospital length of stay, and optimization of diagnostic strategies. However, some barriers in pediatric ASP still exist. This narrative review describes core elements of ASP, the impact of implemented ASPs on pediatric healthcare, and challenges of pediatric ASP as seen by the authors.

Utilizing Virtual Exchange to Sustain Global Health Partnerships in Medical Education.

Integrating global health (GH) training in medical education has become prevalent in the United States over the last two decades. Many medical school graduates participate in some type of international learning experience during their undergraduate/graduate training, with plans to make this a part of their life-long learning experiences. Recognizing this trend, many pediatric national organizations, such as the American Academy of Pediatrics, the Association of Pediatric Program Directors, and the American Board of Pediatrics, have developed initiatives integrating GH education into existing curricula. We report our experience with using virtual learning on a cloud-based platform to remain connected with our GH training partners, and utilize this opportunity to further strengthen our existing relationships during the ongoing COVID-19 pandemic. Overall, our experience thus far shows that this is an effective way to maintain communication even when international travel is not possible. It allows for the ongoing exchange of ideas and the development of long-term sustainable relationships. There are many important lessons our trainees can learn from such partnerships.

Allergic fungal rhinosinusitis presenting with intracranial spread along large sphenoidal emissary foramen.

A 13-year-old girl was admitted for headache, right periorbital swelling and erythema. CT imaging demonstrated right orbital preseptal cellulitis, severe pansinusitis and suspected epidural abscess. Brain MRI and sinus CT confirmed an epidural abscess in the right middle cranial fossa and a second extra-cranial abscess in the right infratemporal fossa along with large right sphenoidal emissary foramen. Drainage from sinus surgery confirmed allergic fungal rhinosinusitis. She was treated with prednisone and voriconazole.

Fractures in children and adolescents living with perinatally acquired HIV.

BACKGROUND: Across numerous settings, bone mineral density for age and sex is lower in children/adolescents living with perinatally-acquired HIV (PHIV) compared to uninfected peers. We assessed incidences of any fracture/any long bone fracture, and osteoporosis prevalence in PHIV and HIV-exposed uninfected (PHEU) participants in the Pediatric HIV/AIDS Cohort Study (PHACS). METHODOLOGY: Lifetime history of fracture events from birth up to age 20 years was obtained by chart review and/or interview, including age at fracture, mechanism, and bone(s) fractured. Poisson regression models were fit comparing fracture incidence by HIV status adjusted for age, sex, and race, with effect modification by age (<6, ≥6 yr). RESULTS: PHIV (N = 412) were older (median 17.5 vs 16.7 yr) and more frequently reported black race (72% vs 61%) than PHEU children/adolescents (N = 206). 17% of PHIV and 12% of PHEU ever reported a fracture. Among children <6 yr, the adjusted incidence rate ratio of ≥1 fracture was higher (7.23; 95% CI 0.98, 53.51) in PHIV than PHEU, but similar among children/adolescents ≥6 years (1.20; 95% CI: 0.77, 1.87). Results were similar for long bone fracture. The most common fracture mechanisms were falling to the ground from a standing height (23.6% PHIV vs 8.8% PHEU) and sports injuries (21.3% vs 32.4%), and the most commonly fractured sites were the forearm and small bones of the wrist/hands. None of the children had osteoporosis. CONCLUSIONS: Among children/adolescents ≥6 yr of age, fractures were similar by perinatal HIV status. Prospective, targeted collection of fracture history will be necessary to determine rates of fracture as PHIV and PHEU age into adulthood. SUMMARY: Lifetime fracture history was collected in children/adolescents living with perinatally-acquired HIV (PHIV) and HIV-exposed uninfected (PHEU) children from birth up to age 20 years. Fracture incidence was higher in PHIV compared to PHEU among children <6 years old, but not among older children/adolescents.

Primer in Patient Safety Concepts: Simulation Case-Based Training for Pediatric Residents and Fellows.

Introduction: Health care quality and patient safety remain one of the core areas of focus for the Accreditation Council for Graduate Medical Education. In addition to using the traditional approach to teaching patient safety, disclosure of a safety event and introduction to the concepts of just culture and safely doing less add a unique perspective to our module. Methods: This 4-hour learning activity was conducted using a formal PowerPoint presentation, simulation, and interactive discussion/debriefing. The presentation reviewed safety concepts and introduced learners to the concepts of just culture and safely doing less. The first case was a standard scenario in which participants assessed a sick but stable child and evaluated the use of premature closure bias that might preclude them from making the correct diagnosis. The second case represented disclosure of a medical error. Participants were evaluated on their communication/professionalism skills and challenged to discover overuse as one of the root causes of medication error. Pre- and posttest surveys were used for learner evaluation. Results: Participants showed significant improvement on content-based questions, increasing from 51.7% to 69.3% correct (p < .001). After Bonferroni correction, only the question on overdiagnosis showed significant improvement (p = .001). Participants reported significantly increased confidence in all areas evaluated (p < .001). Discussion: Participants placed high value on the workshop. The question on overdiagnosis showed significant improvement on the posttest. The concepts of patient safety, just culture, and safely doing less can be introduced to learners at a formative stage in their career through simulation.

Associations of Low Vitamin D and Elevated Parathyroid Hormone Concentrations With Bone Mineral Density in Perinatally HIV-Infected Children.

BACKGROUND: Perinatally HIV-infected (PHIV) children have, on average, lower bone mineral density (BMD) than perinatally HIV-exposed uninfected (PHEU) and healthy children. Low 25-hydroxy vitamin D [25(OH)D] and elevated parathyroid hormone (PTH) concentrations may lead to suboptimal bone accrual. METHODS: PHIV and PHEU children in the Pediatric HIV/AIDS Cohort Study had total body (TB) and lumbar spine (LS) BMD and bone mineral content (BMC) measured by dual-energy x-ray absorptiometry; BMD z-scores (BMDz) were calculated for age and sex. Low 25(OH)D was defined as ≤20 ng/mL and high PTH as >65 pg/mL. We fit linear regression models to estimate the average adjusted differences in BMD/BMC by 25(OH)D and PTH status and log binomial models to determine adjusted prevalence ratios of low 25(OH)D and high PTH in PHIV relative to PHEU children. RESULTS: PHIV children (n = 412) were older (13.0 vs. 10.8 years) and more often black (76% vs. 64%) than PHEU (n = 207). Among PHIV, children with low 25(OH)D had lower TB-BMDz [SD, -0.38; 95% confidence interval (CI), -0.60 to -0.16] and TB-BMC (SD, -59.1 g; 95% CI, -108.3 to -9.8); high PTH accompanied by low 25(OH)D was associated with lower TB-BMDz. Among PHEU, children with low 25(OH)D had lower TB-BMDz (SD, -0.34; 95% CI, -0.64 to -0.03). Prevalence of low 25(OH)D was similar by HIV status (adjusted prevalence ratio, 1.00; 95% CI, 0.81 to 1.24). High PTH was 3.17 (95% CI, 1.25 to 8.06) times more likely in PHIV children. CONCLUSIONS: PHIV and PHEU children with low 25(OH)D may have lower BMD. Vitamin D supplementation trials during critical periods of bone accrual are needed.

Growth at 2 Years of Age in HIV-exposed Uninfected Children in the United States by Trimester of Maternal Antiretroviral Initiation.

BACKGROUND: Abnormal childhood growth may affect future health. Maternal tenofovir (TFV) use was associated with lower body length and head circumference at 1 year of age in HIV-exposed uninfected (HEU) US children. METHODS: We studied 509 HEU children in the US-based Surveillance Monitoring of Antiretroviral Therapy Toxicities cohort whose HIV-infected mothers were not using antiretrovirals at the last menstrual period and began combination antiretroviral therapy (cART) in pregnancy (cART initiators). We examined adjusted associations between antiretrovirals and Centers for Disease Control 2000 growth Z scores at 2 years of age within trimester of cART initiation: weight (weight Z score), length (length Z score), weight-for-length [weight-for-length Z score (WFLZ)], triceps skinfold Z score (TSFZ) and head circumference (head circumference Z score). RESULTS: Mothers mean age was 28.6 years; 57% were black non-Hispanic and 19% delivered at <37 weeks gestation. At 2 years, mean weight Z score, length Z score, WFLZ and head circumference Z score were above average (P < 0.05), whereas TSFZ (P = 0.57) did not differ from average. WFLZ was >1.64 standard deviation (SD) (>95th percentile) in 13%. Among children of first-trimester cART initiators, TFV+emtricitabine-exposed children had slightly higher mean WFLZ (0.45 SD; 95% confidence interval: -0.10 to 1.00) and lower TSFZ (-0.55 SD; 95% confidence interval: -1.07 to -0.02) compared with zidovudine+lamivudine-exposed children. TSFZ was lower in those exposed to boosted protease inhibitors. In contrast, growth in children of second trimester cART initiators did not differ by antiretroviral exposures. CONCLUSION: Growth was above average in HEU; 13% were obese. Maternal TFV use was not associated with lower length or head circumference at 2 years of age, as hypothesized, but may be related to greater weight among those exposed to cART early in pregnancy.

Vitamin D Deficiency in HIV-Infected Children.

OBJECTIVES: Improvement in life expectancy with the use of combination antiretroviral therapy has come with the recognition of the complications associated with chronic human immunodeficiency virus infection. Vitamin D has been of particular interest because of its effect on bone health and immune functions. The purpose of this study was to assess vitamin D status in children in relation to the duration and severity of their human immunodeficiency virus infection and nutritional status, as well as to determine whether there was any effect of seasonality. METHODS: The study design was cross-sectional and all children 0 to 21 years of age were eligible to participate. RESULTS: A total of 59 participants provided informed consent, with 54 subjects completing all study activities. Thirteen (24.1%) had sufficient vitamin D levels, 13 (24.1%) had insufficient levels, and 28 (51.9%) had deficient levels per the guidelines of the Endocrine Society. In our univariate analysis, younger age was associated with higher vitamin D levels (P = 0.030). Higher CD4 counts were associated with higher vitamin D levels (P = 0.018). A significant association between the vitamin D intake per day and vitamin D level was seen (P = 0.013). In the multivariate analysis, the best ordinal logistic regression model had the CD4 count as predictor (P < 0.005), higher CD4 counts were associated with decreased odds of vitamin D deficiency (odds ratio 0.47, 95% confidence interval 0.28-0.80). CONCLUSIONS: Vitamin D deficiency was common among the patients included in this study.

Contraception for HIV-Infected Adolescents.

Access to high-quality reproductive health care is important for adolescents and young adults with HIV infection to prevent unintended pregnancies, sexually transmitted infections, and secondary transmission of HIV to partners and children. As perinatally HIV-infected children mature into adolescence and adulthood and new HIV infections among adolescents and young adults continue to occur in the United States, medical providers taking care of such individuals often face issues related to sexual and reproductive health. Challenges including drug interactions between several hormonal methods and antiretroviral agents make decisions regarding contraceptive options more complex for these adolescents. Dual protection, defined as the use of an effective contraceptive along with condoms, should be central to ongoing discussions with HIV-infected young women and couples wishing to avoid pregnancy. Last, reproductive health discussions need to be integrated with discussions on HIV care, because a reduction in plasma HIV viral load below the level of detection (an "undetectable viral load") is essential for the individual's health as well as for a reduction in HIV transmission to partners and children.

Immunization Update V.

With all the new vaccines and strategies for prevention, the most important challenge that one continues to talk about globally and at home is the one presented by ongoing transmission of diseases for which excellent vaccines already exist. As pediatricians, this presents a constant reminder to keep the conversation about the importance of vaccine-preventable diseases with the patients and their families going at every possible opportunity possible. One needs to constantly remind oneself that every case of a vaccine-preventable disease is a missed opportunity for prevention. One must also have a broader perspective for global eradication of vaccine-preventable disease and advocate for availability of vaccines globally at affordable cost and encourage local vaccine development.

Elevated aspartate aminotransferase-to-platelet ratio index in perinatally HIV-infected children in the United States.

Elevated aspartate aminotransferase-to-platelet ratio index may signal liver fibrosis. Among 397 US children with perinatal HIV infection, at baseline was >1.5 in 0.8% [95% confidence interval (CI), 0.2-2.2%) and >0.5 in 6.5% (95% CI, 4.3-9.4%); incidence on study was 0.5 (95% CI, 0.2-1.2) and 6.4 (95% CI, 4.8-8.3) per 100 person-years, respectively. Long-term liver outcomes after perinatal HIV infection warrant further study.

Human immunodeficiency virus and the central nervous system.

Human immunodeficiency virus (HIV) continues to infect large numbers of people, including children, worldwide. The virus produces much of its clinical impact by infecting cellular components of the immune system. However, HIV also has the propensity to infect the brain, where it can induce substantial pathology and impair brain function. Highly active antiretroviral therapy has reduced the severity and prevalence of HIV-associated neurocognitive disorders. Nevertheless, substantial morbidity and mortality continue to stem from HIV infection of the nervous system. This article reviews the pathogenesis of HIV-induced central nervous system disease, the pathological and clinical effects of HIV infection within the brain, and the controversies and challenges of the use of highly active antiretroviral therapy for prevention and treatment of HIV-induced central nervous system dysfunction.

Pediatric HIV Infection.

As this article was written, celebrating another World AIDS Day, which falls on December 1 each year, was just days away. Not only is this a time to reflect on all the success with the treatment and management of HIV infection, in particular MTCT but also a time to reflect on the challenges ahead. As champions of children, pediatricians need to be more vocal in educating patients, families, and their communities about the risks of sexually transmitted infections and HIV infection and the need for testing as part of routine primary care. This needs to be the norm rather than the exception. All persons should be aware of their HIV status; until and unless this approach is taken, new infections will continue to be seen in young people, and even those who are aware of their status will continue to be wary of seeking care.

Primary amebic meningoencephalitis: a case report and literature review.

Primary amebic meningoencephalitis (PAM) is a rare but nearly always fatal disease caused by infection with Naegleria fowleri, a thermophilic, free-living ameba found in freshwater environments. Cases of N. fowleri infection have been reported from many of the southern-tier states in the United States, with Florida and Texas disproportionately represented among them. Primary amebic meningoencephalitis presents clinically in a fashion that may be indistinguishable from bacterial and viral meningitis. Unfortunately, because the disease is so rare, PAM is often excluded from the differential diagnosis of children with meningitis resulting in delayed diagnostic and therapeutic efforts.Pediatric acute care practitioners in emergency departments, general pediatric wards, and critical care units, especially those practicing in the southern United States, should be familiar with the risk factors for acquisition of PAM, its clinical presentation, and the fact that common empiric treatment of bacterial meningitis will not treat N. fowleri. Herein, we present the case of an adolescent who died of PAM and review the (a) epidemiology, (b) pathophysiology, (c) available diagnostic modalities, (d) treatment options, and (e) outcomes of patients treated for N. fowleri infection of the central nervous system.