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1.  [No title available] 
PMCID: PMC3875831  PMID: 23799515
2.  [No title available] 
PMCID: PMC3917323  PMID: 24418836
3.  [No title available] 
PMCID: PMC3947201  PMID: 23934204
4.  [No title available] 
PMCID: PMC3947204  PMID: 24061274
5.  Revisiting Pneumonia and Exposure Status in Infants Born to HIV-Infected Mothers 
The Pediatric infectious disease journal  2014;33(1):10.1097/INF.0b013e31829f0ade.
HIV-exposed uninfected infants are an increasing population. Past analyses have often categorized these infants as uninfected leading to inaccurate conclusions. We present a HIV exposure, rather than infection, based reanalysis of treatment failure among children with pneumonia to show that failure odds among HIV-exposed uninfected infants are intermediate between their unexposed and infected counterparts. Additional prospective studies aimed at better understanding this population are needed.
doi:10.1097/INF.0b013e31829f0ade
PMCID: PMC3868946  PMID: 24352190
HIV-exposed uninfected; pneumonia
6.  Population Pharmacokinetics of Intravenous Acyclovir in Preterm and Term Infants 
Background
Acyclovir is used to treat herpes infections in preterm and term infants; however, the influence of maturation on drug disposition and dosing requirements is poorly characterized in this population.
Methods
We administered intravenous acyclovir to preterm and term infants <31 days postnatal age and collected plasma samples. We performed a population pharmacokinetic analysis. The primary pharmacodynamic target was acyclovir concentration ≥3 mg/L for ≥50% of the dosing interval. The final model was simulated using infant data from a clinical database.
Results
The analysis included 28 infants (median 30 weeks gestation). Acyclovir pharmacokinetics was described by a 1-compartment model: clearance (L/h/kg) = 0.305 × (postmenstrual age [PMA]/31.3 weeks)3.02. This equation predicts a 4.5-fold increase in clearance from 25 to 41 weeks PMA. With proposed dosing, the pharmacodynamic target was achieved in 91% of infants: 20 mg/kg every 12 hours in infants <30 weeks PMA; 20 mg/kg every 8 hours in infants 30 to <36 weeks PMA; 20 mg/kg every 6 hours in infants 36–41 weeks PMA.
Conclusions
Acyclovir clearance increased with infant maturation. A dosing strategy based on PMA accounted for developmental changes in acyclovir disposition to achieve the surrogate pharmacodynamic target in the majority of infants.
doi:10.1097/01.inf.0000435509.75114.3d
PMCID: PMC3904301  PMID: 24346595
herpes simplex virus; preterm infants; acyclovir
7.  Temporal Trends in Emergency Department Visits for Bronchiolitis in the United States, 2006-2010 
Background
To examine temporal trends in emergency departments (ED) visits for bronchiolitis among US children between 2006 and 2010.
Methods
Serial, cross-sectional analysis of the Nationwide Emergency Department Sample, a nationally-representative sample of ED patients. We used ICD-9-CM code 466.1 to identify children <2 years of age with bronchiolitis. Primary outcome measures were rate of bronchiolitis ED visits, hospital admission rate, and ED charges.
Results
Between 2006 and 2010, weighted national discharge data included 1,435,110 ED visits with bronchiolitis. There was a modest increase in the rate of bronchiolitis ED visits, from 35.6 to 36.3 per 1000 person-years (2% increase; Ptrend=0.008), due to increases in the ED visit rate among children from 12 months to 23 months (24% increase; Ptrend<0.001). By contrast, there was a significant decline in the ED visit rate among infants (4% decrease; Ptrend<0.001) Although unadjusted admission rate did not change between 2006 and 2010 (26% in both years), admission rate declined significantly after adjusting for potential patient- and ED-level confounders (adjusted OR for comparison of 2010 with 2006, 0.84; 95%CI, 0.76-0.93; P<0.001). Nationwide ED charges for bronchiolitis increased from $337 million to $389 million (16% increase; Ptrend<0.001), adjusted for inflation. This increase was driven by a rise in geometric mean of ED charges per case from $887 to $1059 (19% increase; Ptrend<0.001).
Conclusions
Between 2006 and 2010, we found a divergent temporal trend in the rate of bronchiolitis ED visits by age group. Despite a significant increase in associated ED charges, ED-associated hospital admission rates for bronchiolitis significantly decreased over this same period.
doi:10.1097/INF.0b013e3182a5f324
PMCID: PMC3984903  PMID: 23934206
bronchiolitis; emergency department; incidence; hospitalization; charge
8.  Etiology of Bacteremia in Young Infants in Six Countries 
Background:
Neonatal illness is a leading cause of death worldwide; sepsis is one of the main contributors. The etiologies of community-acquired neonatal bacteremia in developing countries have not been well characterized.
Methods:
Infants <2 months of age brought with illness to selected health facilities in Bangladesh, Bolivia, Ghana, India, Pakistan and South Africa were evaluated, and blood cultures taken if they were considered ill enough to be admitted to hospital. Organisms were isolated using standard culture techniques.
Results:
Eight thousand eight hundred and eighty-nine infants were recruited, including 3177 0–6 days of age and 5712 7–59 days of age; 10.7% (947/8889) had a blood culture performed. Of those requiring hospital management, 782 (54%) had blood cultures performed. Probable or definite pathogens were identified in 10.6% including 10.4% of newborns 0–6 days of age (44/424) and 10.9% of infants 7–59 days of age (39/358). Staphylococcus aureus was the most commonly isolated species (36/83, 43.4%) followed by various species of Gram-negative bacilli (39/83, 46.9%; Acinetobacter spp., Escherichia coli and Klebsiella spp. were the most common organisms). Resistance to second and third generation cephalosporins was present in more than half of isolates and 44% of the Gram-negative isolates were gentamicin-resistant. Mortality rates were similar in hospitalized infants with positive (5/71, 7.0%) and negative blood cultures (42/557, 7.5%).
Conclusions:
This large study of young infants aged 0–59 days demonstrated a broad array of Gram-positive and Gram-negative pathogens responsible for community-acquired bacteremia and substantial levels of antimicrobial resistance. The role of S. aureus as a pathogen is unclear and merits further investigation.
doi:10.1097/INF.0000000000000549
PMCID: PMC4272225  PMID: 25389919
Neonatal sepsis; infant; neonate; bacteremia; Staphylococcus aureus
9.  Mortality and Long-Term Virologic Outcomes in Children and Infants Treated with Lopinavir/Ritonavir 
Background
There is scant data on young children receiving protease inhibitor (PI)-based therapy in real-life resource-limited settings and on the optimal timing of therapy among children who survive infancy. Our aim was to evaluate outcomes at the Hospital del Niño, Panama, where children have been routinely treated with lopinavir/ritonavir (LPV/r)-based therapy since 2002.
Methods
Retrospective cohort analysis of all HIV-infected children enrolled in care between January 1, 1991 and June 1, 2011. Kaplan-Meier method and Cox proportional hazards regression were used to evaluate death, virologic suppression, and virologic rebound.
Results
Of 399 children contributing 1,944 person-years of follow-up, 254 (63.7%) were treated with LPV/r and 94 (23.6%) were never treated with antiretrovirals (ARVs). Among infants, improved survival was associated with male gender (HRdeath 0.54, 95% CI 0.32–0.92) and treatment with highly active antiretroviral therapy (HAART) (HRdeath 0.32, 95% CI 0.12–0.83), while residence outside of Panama City was associated with poorer survival (HRdeath 1.72, 95% CI 1.01–2.94). Among children who survived to 1 year of age without exposure to ARVs, LPV/r-based therapy improved survival (HRdeath 0.07, 95% CI 0.01–0.33). Virologic suppression was achieved in 42.1%, 70.5%, and 85.1% by 12, 24 and 60 months of follow up among children treated with LPV/r. Virologic suppression was not associated with prior ARV exposure or age at initiation of therapy but was associated with residence outside of Panama City (HRsuppression 1.93, 95% CI 1.19–3.14). Patients with a baseline viral load > 100,000 copies/mL were less likely to achieve suppression (HRsuppression 0.37, 95% CI 0.21–0.66). No children who achieved virologic suppression after initiating LPV/r died.
Conclusions
LPV/r-based therapy improved survival not only in infants but also in children over 1 year of age. Age at initiation of LPV/r-based therapy or prior ARVs did not impact virologic outcomes.
doi:10.1097/INF.0b013e3182a09276
PMCID: PMC3883902  PMID: 23799516
Children; HIV-infection; mortality; virologic outcomes; Lopinavir/Ritonavir
10.  Novel Inflammatory Markers, Clinical Risk Factors, and Virus Type Associated with Severe Respiratory Syncytial Virus Infection 
Background
Virus-induced inflammation contributes to respiratory syncytial virus (RSV) pathogenesis. We sought to determine the specific mediators that are associated with more severe illness in young children.
Methods
Children ≤ 5 yrs of age seen in our emergency department for respiratory symptoms from September 1998 to May 2008 were eligible for enrollment. Nasopharyngeal (NP) wash samples were collected from all eligible patients, and clinical data were recorded. Individuals were included in this study if NP wash samples were positive for RSV only. Patients enrolled in the study were stratified by disease severity, defined as mild (not hospitalized), moderate (hospitalized), or severe (requiring ICU stay). Concentrations of individual inflammatory biomarkers in NP wash fluids were determined using the Luminex human 30-plex assay.
Results
851 patients met study criteria; 268 (31.5%) with mild, 503 (59.1%) with moderate, and 80 (9.4%) with severe illness. As expected, illness severity was directly associated with young age, prematurity, heart or lung disease, infection with RSV group A, and elevated concentrations of interleukin (IL)-2R, IL-6, CXCL8, tumor necrosis factor (TNF)-α, interferon (IFN)-α, CCL3, CCL4, and CCL2. In addition, we report several novel and mechanistically important inflammatory biomarkers of severe RSV disease, including IL-1β, IL1-RA, IL-7, epidermal growth factor (EGF), and hepatocyte growth factor (HGF).
Conclusions
In a large, longitudinal study (10 years, 851 enrolled patients) limited to RSV infection only, in which well-known risk factors are confirmed, we identified five novel biomarkers specifically of severe disease. These markers may ultimately serve to elucidate disease mechanisms.
doi:10.1097/INF.0b013e3182a14407
PMCID: PMC3883981  PMID: 23804121
Respiratory syncytial virus; innate immunity; illness severity; hepatocyte growth factor
11.  Hoarseness as a Presenting Sign in Children with Kawasaki Disease 
We noted that many patients with Kawasaki disease (KD) were hoarse at presentation and thus evaluated the frequency of hoarseness in children with acute KD. New onset hoarseness was noted in 86 of 287 (30%) prospectively assessed KD patients. Laryngoscopic examination of three hoarse patients with acute KD revealed edema and erythema of the larynx.
doi:10.1097/INF.0b013e3182a0960b
PMCID: PMC3887132  PMID: 23811742
Kawasaki Disease; hoarseness; coronary artery dilatation; vasculitis
12.  The Acceptability and Feasibility of Routine Pediatric HIV Testing in an Outpatient Clinic in Durban, South Africa 
Background
Limited access to HIV testing of children impedes early diagnosis and access to antiretroviral therapy. Our objective was to evaluate the feasibility and acceptability of routine pediatric HIV testing in an urban, fee-for-service, outpatient clinic in Durban, South Africa.
Methods
We assessed the number of patients (0–15 years) who underwent HIV testing upon physician referral during a baseline period. We then established a routine, voluntary HIV testing study for pediatric patients, regardless of symptoms. Parents/caretakers were offered free rapid fingerstick HIV testing of their child. For patients <18 months, the biological mother was offered HIV testing and HIV DNA polymerase chain reaction was used to confirm the infant’s status. The primary outcome was the HIV testing yield, defined as the average number of positive tests per month during the routine compared with the baseline period.
Results
Over a 5-month baseline testing period, 931 pediatric patients registered for outpatient care. Of the 124 (13%) patients who underwent testing on physician referral, 21 (17%, 95% confidence interval: 11–25%) were HIV infected. During a 13-month routine testing period, 2790 patients registered for care and 2106 (75%) were approached for participation. Of these, 1234 were eligible and 771 (62%) enrolled. Among those eligible, 637 (52%, 95% confidence interval: 49–54%) accepted testing of their child or themselves (biological mothers of infants <18 months). There was an increase in the average number of HIV tests during the routine compared with the baseline HIV testing periods (49 versus 25 tests/month, P = 0.001) but no difference in the HIV testing yield during the testing periods (3 versus 4 positive HIV tests/month, P = 0.06). However, during the routine testing period, HIV prevalence remains extraordinarily high with 39 (6%, 95% confidence interval: 4–8%) newly diagnosed HIV-infected children (median 7 years, 56% female).
Conclusions
Targeted and symptom-based testing referral identifies an equivalent number of HIV-infected children as routine HIV testing. Routine HIV testing identifies a high burden of HIV and is a feasible and moderately acceptable strategy in an outpatient clinic in a high prevalence area.
doi:10.1097/INF.0b013e31829ba34b
PMCID: PMC3895104  PMID: 23694834
routine HIV testing; pediatric; adolescent; South Africa; outpatient clinic
13.  Human Milk Galectin-3 Binding Protein and Breastfeeding-Associated HIV Transmission 
Analysis of milk from 247 HIV-infected Zambian mothers showed that Galectin-3 Binding Protein (Gal3BP) concentrations were significantly higher among HIV-infected mothers who transmitted HIV through breastfeeding (6.51±2.12 ug/mL) than among non-transmitters but were also correlated with higher milk and plasma HIV RNA copies/ml and lower CD4+ cell counts. The association between Gal3BP and postnatal transmission was attenuated after adjustment for milk and plasma HIV load and CD4+ cell counts. This suggests that although milk Gal3BP is a marker of advanced maternal disease, it does not independently modify transmission risk.
doi:10.1097/INF.0b013e3182a6e0a8
PMCID: PMC3907473  PMID: 23899964
HIV transmission; breastfeeding; Galectin-3 Binding Protein; oral transmission
14.  Executive Summary: 2013 Update of the Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children 
This executive report provides an overview of the 2013 update of the Department of Health and Human Services (DHHS) Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children in the United States. The full text of the guidelines is available online at www.aidsinfo.nih.gov and as a supplement to the Pediatric Infectious Disease Journal. These guidelines are intended for use by clinicians and other health-care workers providing medical care for HIV-exposed and HIV-infected children in the United States. A separate document providing recommendations for prevention and treatment of OIs among HIV-infected adults and postpubertal adolescents (Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents) was prepared by a working group of adult HIV and infectious disease specialists and is also available at www.aidsinfo.nih.gov.
The guidelines were developed by a panel of specialists in pediatric HIV infection and infectious diseases (the Panel on Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children) from the U.S. government and academic institutions, under the auspices of the NIH Office for AIDS Research (OAR). For each OI, one or more pediatric specialists with subject-matter expertise reviewed the literature for new information since the last guidelines were published (2009) and then proposed revised recommendations for review by the full Panel. After these reviews and discussions, the guidelines underwent further revision, with review and approval by the Panel, followed by review by CDC subject matter experts, and final review and endorsement by NIH, CDC, the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA), the Pediatric Infectious Disease Society (PIDS), and the American Academy of Pediatrics (AAP). Treatment of OIs is an evolving science, and availability of new agents or clinical data on existing agents may change therapeutic options and preferences. As a result, these recommendations will need to be periodically updated. Interim updates to recommendations will be posted on the www.aids.nih.gov website as needed and the full guidelines document will continue to be reviewed and updated every 2–3 years. Consultation with an expert in the management of HIV infection and OIs in children is also encouraged.
doi:10.1097/INF.0000000000000080
PMCID: PMC3937852  PMID: 24569304
15.  Lower Vancomycin Serum Trough Concentrations Might Not Be the Answer 
doi:10.1097/INF.0000000000000003
PMCID: PMC3937855  PMID: 24569315
Vancomycin; MRSA; AUC
16.  Immunogenicity of Haemophilus influenzae Type b Protein Conjugate Vaccines in Very Low Birth Weight Infants 
doi:10.1097/01.inf.0000437263.04493.7c
PMCID: PMC3960569  PMID: 24569312
Infant; premature; infant; very low birth weight; Haemophilus influenzae vacines; immunization; vaccines
17.  Acute Viral Respiratory Illnesses in Andean Children: a Household-Based Cohort Study 
Background
Few community studies have measured the incidence, severity, and etiology of acute respiratory illness (ARI) among children living at high-altitude in remote rural settings.
Methods
We conducted active, household-based ARI surveillance among children aged <3 years in rural highland communities of San Marcos, Cajamarca, Peru from May 2009 through September 2011 (RESPIRA-PERU study). ARI (defined by fever or cough) were considered lower respiratory tract infections (LRTI) if tachypnea, wheezing, grunting, stridor, or retractions were present. Nasal swabs collected during ARI episodes were tested for respiratory viruses by real-time reverse-transcriptase polymerase chain reaction. ARI incidence was calculated using Poisson regression.
Results
During 755.1 child-years of observation among 892 children in 58 communities, 4,475 ARI were observed, yielding an adjusted incidence of 6.2 ARI/child-year (95% CI 5.9 – 6.5). Families sought medical care for 24% of ARI, 4% were classified as LRTI, and 1% led to hospitalization. Two of five deaths among cohort children were attributed to ARI. One or more respiratory virus was detected in 67% of 3957 samples collected. Virus-specific incidence rates per 100 child-years were: rhinovirus, 236; adenovirus, 73; parainfluenza virus, 46; influenza, 37; respiratory syncytial virus, 30; and human metapneumovirus, 17. Respiratory syncytial virus, metapneumovirus, and parainfluenza virus 1-3 comprised a disproportionate share of LRTI compared to other etiologies.
Conclusions
In this high-altitude rural setting with low population density, ARI in young children were common, frequently severe, and associated with a number of different respiratory viruses. Effective strategies for prevention and control of these infections are needed.
doi:10.1097/INF.0000000000000135
PMCID: PMC4223552  PMID: 24378948
influenza; respiratory syncytial virus; human metapneumovirus; acute respiratory infection; Peru
18.  Prevalence of Vitamin D Deficiency among Perinatally HIV-Infected Thai Adolescents Receiving Antiretroviral Therapy 
The Pediatric infectious disease journal  2013;32(11):10.1097/INF.0b013e31829e7a5c.
We assessed the prevalence of vitamin D deficiency among 101 perinatally HIV-infected Thai adolescents receiving antiretroviral therapy. Median age was 14.3 (IQR 13.0–15.7) years and 90% had a HIV RNA <50 copies/mL. The median (IQR) 25-hydroxyvitamin D (25-OHD) level was 24.8 (6.9–46.9) ng/mL; 25 (24.7%) had vitamin D deficiency (25-OHD< 20 ng/ml) and 47 (46.5%) had insufficiency (25-OHD 20–30 ng/ml). Adolescents with vitamin D deficiency had significantly higher parathyroid hormone levels (54.9 vs. 40.2 pg/mL, P<0.007). No associations between vitamin D deficiency and body mass index, bone mineral density, efavirenz use, HIV RNA, CD4, or self-reported sunlight exposure were observed.
doi:10.1097/INF.0b013e31829e7a5c
PMCID: PMC3806192  PMID: 24145954
Vitamin D Insufficiency; Vitamin D Deficiency; Adolescents; Human Immunodeficiency Virus; Osteopenia; Bone Health; Bone Mineral Density
19.  Non- Protective Responses to Pediatric Vaccines Occur in Children Who are Otitis Prone 
The Pediatric infectious disease journal  2013;32(11):10.1097/INF.0b013e31829e887e.
Objective
We recently found that children who experience recurrent otitis media despite individualized care (stringently-defined otitis prone, sOP) do not develop an antibody response to several vaccine candidate protein antigens expressed by Streptococcus pneumonia (Spn) and Haemophilus influenzae (Hi). Here we sought to determine if these same children also failed to develop antibody to routine pediatric vaccinations.
Study Design
140 sera collected from children age 6–24 months were analyzed. sOP (n=34) and age-matched non-sOP (n=34) children were assessed for IgG concentrations to diphtheria toxoid (DT), tetanus toxoid (TT), pertussis toxoid (PT), filamentous hemagglutinin (FHA), pertactin (PRN) (DTaP), polio, hepatitis B, Hi type b capsule (PRP) and Streptococcus pneumoniae (Spn) capsular polysaccharide conjugate vaccine.
Results
IgG protective titers to DT (p=0.006), TT (p<0.0001), PT (p<0.0001), FHA (p=0.001), PRN (p=0.005), hepatitis B (p<0.0001), polio 3 (p= 0.03) and Spn 23F (p=0.01) but not polio 1,2, PRP or Spn 6B, and 14 were decreased in sOP versus non-sOP children using generalized estimating equations. A high percentage of sOP children had non-protective antibody values that persisted until 24 months of age despite routine boosters.
Conclusion
sOP children may fail to achieve protective antibody concentrations after several routine vaccinations.
doi:10.1097/INF.0b013e31829e887e
PMCID: PMC3884640  PMID: 24141796
vaccination; immunity; acute otitis media; pertussis; polio; hepatitis B; pneumococcal conjugate vaccine; dipththeria; tetanus; Haemophilus influenzae type b vaccine; immune deficiency
21.  The Relationship between Vitamin D Status and HIV-Related Complications in HIV-infected Children and Young Adults 
Background
In HIV-infected adults, we and others have shown that vitamin D deficiency is independently associated with increased carotid intima-media thickness (cIMT), a surrogate marker for cardiovascular disease (CVD). This study explored for the first time the relationship between vitamin D and CVD risk in HIV-infected youth.
Methods
This is a cross-sectional assessment of cIMT, inflammation, metabolic markers and vitamin D status in HIV-infected youth and healthy controls. We measured serum 25-hydroxyvitamin D (25(OH)D), fasting lipids, insulin, glucose, inflammatory markers, and cIMT.
Results
30 HIV–infected subjects and 31 controls were included. Among HIV-infected subjects, median age was 11 years (37% males; 73% black; similar to controls). HIV-infected subjects’ mean (standard deviation) serum 25(OH)D was 24 (35) ng/mL; 70% had 25(OH)D <20 ng/mL (deficient), 23% between 20–30 ng/mL (insufficient), and 7% >30 ng/mL (sufficient); proportions were similar to controls (P=0.17). After adjusting for season, sex and race, there was no difference in serum 25(OH)D between groups (P=0.11). Serum 25(OH)D was not significantly correlated with cIMT, inflammatory markers, or lipids. Serum 25(OH)D was negatively correlated with body mass index, insulin resistance, HIV duration, and cumulative use of antiretroviral therapy, non- and nucleoside reverse transcriptase inhibitors.
Conclusions
Most HIV-infected youth have vitamin D deficiency or insufficiency. Despite no direct association between serum 25(OH)D and cIMT, there were notable associations with some CVD risk factors, particularly inverse correlation with insulin resistance. Studies are needed to determine whether CVD risk, including insulin resistance, could be improved with vitamin D supplementation.
doi:10.1097/INF.0b013e318286c793
PMCID: PMC3750101  PMID: 23360833
HIV; children and adolescents; vitamin D deficiency; cardiovascular disease; insulin resistance
22.  Vitamin D Related Host Genetic Variants Alter HIV Disease Progression in Children 
The Pediatric infectious disease journal  2013;32(11):10.1097/INF.0b013e31829e4d06.
Background
Vitamin D deficiency is common in HIV infection and has been associated with advanced disease. This study investigated whether vitamin D related genetic variants were associated with disease progression in HIV-infected children.
Methods
The Fok-I (C/T), Bsm-I (G/A), GC (A/C), DHCR7 (G/T) and CYP2R1 (G/A) genetic variants were detected by RT-PCR in HIV-infected children who participated in the PACTG P152 and P300 protocols which pre-dated the availability of effective combination antiretroviral therapy. The primary endpoints included time to progression to the first HIV-related disease end-point (≥2 OI's, weight-growth failure) or death, which constituted the progression-free-survival. Analyses were performed for age >2 years and ≤2 years separately adjusting for race and treatment effect.
Results
Of the 998 children evaluated, 139 experienced HIV disease progression. For children >2 years, rapid disease progression was associated with the DHCR7 G allele compared to the T allele (G/G vs. T/T: HR=5.0, p=0.035, G/T vs. T/T: HR=4.5, p=0.042, G/G+G/T vs. T/T: HR=4.8, p=0.036), and the Bsm-I A allele compared to the G allele (A/G vs. G/G: HR=2.2, p=0.014 and A/G+A/A vs. G/G: HR=2.0, p=0.026). In children ≤2 years, the Bsm-I A allele increased the risk of disease progression in Hispanics (A/A vs. G/A+G/G: HR=2.8, p=0.03; A/A vs. G/G: HR=2.8, p=0.046) and whites (A/A vs. G/G: HR=6.6, p=0.025; A/A vs. G/A+G/G: HR=3.6, p=0.038).
Conclusions
Vitamin D related host genetic variants that alter the availability and activity of vitamin D are associated with risk of HIV disease progression in children, and may vary by age and race.
doi:10.1097/INF.0b013e31829e4d06
PMCID: PMC3811908  PMID: 23736144
Vitamin D; Human immunodeficiency virus; HIV; Vitamin D receptor; pediatric AIDS; host genetics
23.  Safety and Pharmacokinetic Profiles of Repeated-Dose Micafungin in Children and Adolescents Treated for Invasive Candidiasis 
The Pediatric infectious disease journal  2013;32(11):10.1097/INF.0b013e31829efd14.
Background
Micafungin is an echinocandin with proven efficacy against a broad range of fungal infections, including those caused by Candida species.
Objective
To evaluate the safety and pharmacokinetics of once-daily 3 mg/kg and 4.5 mg/kg micafungin in children with proven, probable, or suspected invasive candidiasis.
Methods
Micafungin safety and pharmacokinetics were assessed in two Phase I, open-label, repeat-dose trials. In Study 2101, children aged 2–16 years were grouped by weight to receive 3 mg/kg (≥25 kg) or 4.5 mg/kg (<25 kg) intravenous micafungin for 10–14 days. In Study 2102, children aged 4 months to <2 years received 4.5 mg/kg micafungin. Study protocols were otherwise identical.
Results
Safety was analyzed in seventy-eight and nine children in Studies 2101 and 2102, respectively. Although adverse events were experienced by most children (2101: n = 62; 2102: n = 9), micafungin-related adverse events were less common (2101: n = 28; 2102: n = 1), and the number of patients discontinuing due to adverse events was low (2101: n = 4; 2102: n = 1). The most common micafungin-related adverse events were infusion-associated symptoms, pyrexia, and hypomagnesemia (Study 2101), and liver function abnormalities (Study 2102). The micafungin pharmacokinetic profile was similar to that seen in other studies conducted in children, but different than that observed in adults.
Conclusions
In this small cohort of children, once-daily doses of 3 mg/kg and 4.5 mg/kg micafungin were well tolerated. Pharmacokinetic data will be combined in a population pharmacokinetic analysis to support U.S. dosing recommendations in children.
doi:10.1097/INF.0b013e31829efd14
PMCID: PMC3818701  PMID: 23958810
candidiasis; children; micafungin; pharmacokinetics; safety
24.  Relationship with Original Pathogen in Recurrence of Acute Otitis Media after Completion of Amoxicillin/Clavulanate: Bacterial Relapse or New Pathogen 
The Pediatric infectious disease journal  2013;32(11):10.1097/INF.0b013e31829e3779.
Objective
We sought to determine whether recurrent AOM (rAOM) occurring within 30 days of amoxicillin/clavulanate treatment was caused by bacterial relapse or new pathogens.
Methods
Pneumococcal conjugate vaccinated children, age 6–36 months, enrolled in a prospective, longitudinal study experiencing rAOM < 1 month after completing amoxicillin/clavulanate therapy were studied. AOM episodes occurred between June 2006–Nov 2012. Multi locus sequence typing was used to genotype isolates.
Results
66 children were in the study cohort; 63 otopathogens were recovered from middle ear fluid after tympanocentesis. Nontypeable H. influenzae (NTHi) accounted for 47% of initial AOMs vs. 15% by S. pneumoniae (Spn), p<0.0001. NTHi accounted for 42% of rAOM vs. 24% by Spn (p-value =0.04). NTHi was the main otopathogen that caused true bacteriologic relapses (77%). Beta lactamase-producing NTHi and penicillin nonsusceptible Spn were not more common in rAOM than initial AOM infections. Among 21 paired (initial and rAOM events) NTHi isolates genotyped, 13 (61.9%) were the same organism; 1 of 9 (11.1%) of paired Spn isolates was the same (p-value =0.017). rAOM occurring within a week of stopping amoxicillin/clavulanate was a different pathogen in 21% of cases, 8–14 days later in 33%, 15–21 days in 41% and 22–30 days in 57% (p =0.04).
Conclusions
In amoxicillin/clavulanate treated children, NTHi was the main otopathogen that caused true bacteriologic relapses. New pathogens causing rAOM vs. persistence of the initial pathogen significantly increased week to week. Neither relapses nor new infections were caused more frequently by beta lactamase producing NTHi or penicillin nonsusceptible Spn.
doi:10.1097/INF.0b013e31829e3779
PMCID: PMC3845822  PMID: 23736142
Recurrent AOM; Non-typeable Haemophilus influenzae; Streptococcus pneumoniae; Bacterial Relapse
25.  Detection of Secretory Immunoglobulin A in Human Colostrum as Mucosal Immune Response against Proteins of the Type Three Secretion System of Salmonella, Shigella and Enteropathogenic Escherichia Coli 
Background
Some enteropathogens use the type three secretion system (T3SS) to secrete proteins that allows them to interact with enterocytes and promote bacterial attachment or intracellular survival. These proteins are Salmonella invasion proteins (Sip), invasion plasmid antigens (Ipa) of Shigella and E. coli secreted proteins (Esp) of enteropathogenic E. coli (EPEC). There are no previous studies defining the presence of colostral sIgA against all these three major enteric pathogens.
Objective
To evaluate the presence of sIgA in colostrum against proteins of the T3SS of Salmonella, Shigella and EPEC.
Methods
We collected 76 colostrum samples from puerperal women in Lima, Peru. These samples were reacted with T3SS proteins extracted from bacterial culture supernatants and evaluated by Western Blot.
Results
Antibodies were detected against Salmonella antigens SipA in 75 samples (99%), SipC in 62 (82%) and SipB in 31 (41%); against Shigella antigens IpaC in 70 (92%), IpaB in 68 (89%), IpaA in 66 (87%) and IpaD in 41 (54%); and against EPEC EspC in 70 (92%), EspB-D in 65 (86%) and EspA in 41 (54%). 10% of samples had antibodies against all proteins evaluated; and 42% against all except one protein. There was no sample negative to all these proteins.
Conclusions
The extraordinarily high frequency of antibodies in colostrum of puerperal women detected in this study against these multiple enteric pathogens, shows evidence of immunological memory and prior exposure to these pathogens, in addition to its possible protective role against infection.
doi:10.1097/INF.0b013e318293306c
PMCID: PMC3776007  PMID: 23538526
Colostrum; sIgA; T3SS; Salmonella; Shigella; EPEC

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