The Role of Breast Milk in Infectious Disease.

Human milk has many advantageous anti-infective and immunologic properties, making it the ideal nutritional source to optimize the well-being of infants. There are certain infectious circumstances where breast milk feedings should be withheld or strict precautions followed, and this article addresses these rare events. Contamination and misadministration when handling human milk is also a safety concern, especially when caring for vulnerable preterm infants. This article addresses ways to decrease these occurrences to maintain the inherent anti-infectious properties of human milk and preserve the health of our neonatal population.

Ten Years of Newborn Screening for Severe Combined Immunodeficiency (SCID) in Massachusetts.

BACKGROUND: Massachusetts began newborn screening (NBS) for severe combined immunodeficiency (SCID) using measurement of T-cell receptor excision circles (TRECs) from dried blood spots. OBJECTIVE: We describe developments and outcomes from the first 10 years of this program (February 1, 2009, to January 31, 2019). METHODS: TREC values, diagnostic, and outcome data from all patients screened for SCID were evaluated. RESULTS: NBS of 720,038 infants prompted immunologic evaluation of 237 (0.03%). Of 237, 9 were diagnosed with SCID/leaky SCID (4% of referrals vs 0.001% general population). Another 7 were diagnosed with other combined immunodeficiencies, and 3 with athymia. SCID/leaky SCID incidence was approximately 1 in 80,000, whereas approximately 1 in 51,000 had severe T-cell lymphopenia for which definitive treatment was indicated. All patients with SCID/leaky SCID underwent hematopoietic cell transplant or gene therapy with 100% survival. One patient with athymia underwent successful thymus transplant. No known cases of SCID were missed. Compared with outcomes from the 10 years before SCID NBS, survival trended higher (9 of 9 vs 4 of 7), likely due to a lower rate of infection before treatment. CONCLUSIONS: Our data support a single NBS testing-and-referral algorithm for all gestational ages. Despite lower median TREC values in premature infants, the majority for all ages are well above the TREC cutoff and the algorithm, which selects urgent (undetectable TREC) and repeatedly abnormal TREC values, minimizes referral. We also found that low naïve T-cell percentage is associated with a higher risk of SCID/CID, demonstrating the utility of memory/naïve T-cell phenotyping as part of follow-up flow cytometry.

Identification of High-Yield Targets for Antimicrobial Stewardship Program Efforts Within a Nonfreestanding Children's Hospital.

OBJECTIVES: Identify diagnoses with the highest likelihood of prompting antimicrobial stewardship program (ASP) recommendations and lowest probability of recommendation acceptance, investigate the impact of provider years in practice on recommendation receipt and acceptance, and simultaneously assess the influence of patient and provider-level variables associated with recommendations within a nonfreestanding children's hospital. METHODS: Retrospective cohort study of antibiotic courses reviewed by the ASP staff from December 1, 2014 to November 30, 2016. Poisson regression was used to detect associations between diagnoses, provider years in practice, and the probability of recommendation receipt and acceptance. Multivariable logistic regression was used to simultaneously examine the influence of patient and provider-level characteristics on recommendation probability. RESULTS: A total of 938 inpatient encounters and 1170 antibiotic courses were included. Diagnoses were associated with provider receipt (P < .001) and acceptance (P < .001) of recommendations, with ear, nose, and throat and/or sinopulmonary diagnoses most likely to prompt recommendations (56%; 95% confidence interval [CI], 48-64) and recommendations for neonatal and/or infant diagnoses accepted least often (67%; 95% CI, 58-76). No associations were initially found between provider experience and recommendation receipt or acceptance, although multivariable analysis revealed a trend between increasing years in practice and recommendation likelihood (P = .001). Vancomycin usage (64%; 95% CI, 56-72) and ear, nose, and throat and/or sinopulmonary diagnoses (56%; 95% CI, 47-65) had the highest probability of a recommendation. Sensitivity analyses revealed that use of diagnosis-related clinical practice guidelines decreased recommendations and increased acceptance rates, especially for the surgery diagnosis category. CONCLUSIONS: High-yield targets for ASP activities at our nonfreestanding children's hospital were identified. Clinical practice guidelines have the potential to decrease ASP workload, and their development should be particularly encouraged for ASPs with limited resources.

Implementation and Impact of an Antimicrobial Stewardship Program at a Non-freestanding Children's Hospital.

OBJECTIVES: Pediatric Antimicrobial Stewardship Programs (ASP) have been associated with improvements in antibiotic utilization and patient outcomes; however, ASP studies originating from non-freestanding children's hospitals are lacking. In this study, we present the implementation and impact of a multidisciplinary ASP that employs a collaborative physician and pharmacist driven thrice-weekly prospective audit-with-feedback approach at a non-freestanding children's hospital. METHODS: Implementation was assessed via descriptive design. Pediatric inpatients maintained on predefined targeted antibiotics of interest for 48 to 72 hours preceding ASP review were eligible for inclusion. Outcomes evaluated included ASP recommendation and provider acceptance rates (overall and by antibiotic and provider specialty). Impact was examined using an interrupted time series design (with a preimplementation period of August 1, 2013, to July 31, 2014 and postimplementation period of December 1, 2014 to May 31, 2016). Eligibility included all targeted antibiotic usage among pediatric inpatients, with a control group comprising those who received antibiotics requiring preauthorization. Outcomes analyzed included days of antibiotic therapy per 1000 patient days (DOT/1000 PD) and 30-day hospital readmission rates over time. RESULTS: Postimplementation, 882 antibiotic reviews were performed on 637 patients, with 327 recommendations generated. Reviews of patients maintained on vancomycin and clindamycin, and of those under care of intensivist and hospitalist physicians, were most likely to prompt recommendations. A mean targeted antibiotic usage decrease of 24.8 DOT/1000 PD (95% confidence interval, -62 to 14) was observed postimplementation, with no change in 30-day readmissions (0.64% during both periods). CONCLUSIONS: ASP implementation at a non-freestanding children's hospital was feasible and allowed for identification of areas for targeted quality improvement, while demonstrating modest antibiotic use reduction without adversely impacting patient care.

Reduced frequencies of polyfunctional CMV-specific T cell responses in infants with congenital CMV infection.

PURPOSE: CMV infection remains a priority for vaccine development. Vaccination of infants could modify congenital infection and provide lifetime immunity. Properties of CMV-specific T cells associated with control of viral replication in early life have not been fully defined. METHODS: CMV-specific CD4 and CD8 T cell responses were investigated in infants with congenital CMV infection and compared to adults with primary or chronic infection. PBMC were stimulated with UL83 (pp65) or UL122 (IE-2) peptide pools then stained with antibodies to markers of T cell subset (CD4 or CD8), phenotype (CD45RA, CCR7), or function (MIP1ß, CD107, IFNγ, IL2) for flow cytometry analysis. RESULTS: Detection of CMV pp65-specific CD4 T cells was less common in infants than adults. Responder cells were primarily effector memory (EM, CD45RA-CCR7-) in adults, but mixed memory subsets in infants. Detection of CMV pp65-specific CD8 T cells did not differ between the groups, but infants had lower frequencies of total responding cells and of MIP1ß- or CD107-expressing cells. Responder cells were EM or effector memory RA (CD45RA + CCR7-) in all groups. Polyfunctional T cells were less commonly detected in infants than adults. Responses to IE-2 were detected in adults but not infants. All infants had detectable circulating CMV DNA at initial study (versus 60 % of adults with primary infection) despite longer duration of CMV infection. CONCLUSIONS: Reduced frequencies and altered functional profile of CMV-specific CD4 and CD8 T cell responses were detected in infants compared to adults, and were associated with persistent CMV DNA in peripheral blood.

Rapid intrahost evolution of human cytomegalovirus is shaped by demography and positive selection.

Populations of human cytomegalovirus (HCMV), a large DNA virus, are highly polymorphic in patient samples, which may allow for rapid evolution within human hosts. To understand HCMV evolution, longitudinally sampled genomic populations from the urine and plasma of 5 infants with symptomatic congenital HCMV infection were analyzed. Temporal and compartmental variability of viral populations were quantified using high throughput sequencing and population genetics approaches. HCMV populations were generally stable over time, with ~88% of SNPs displaying similar frequencies. However, samples collected from plasma and urine of the same patient at the same time were highly differentiated with approximately 1700 consensus sequence SNPs (1.2% of the genome) identified between compartments. This inter-compartment differentiation was comparable to the differentiation observed in unrelated hosts. Models of demography (i.e., changes in population size and structure) and positive selection were evaluated to explain the observed patterns of variation. Evidence for strong bottlenecks (>90% reduction in viral population size) was consistent among all patients. From the timing of the bottlenecks, we conclude that fetal infection occurred between 13-18 weeks gestational age in patients analyzed, while colonization of the urine compartment followed roughly 2 months later. The timing of these bottlenecks is consistent with the clinical histories of congenital HCMV infections. We next inferred that positive selection plays a small but measurable role in viral evolution within a single compartment. However, positive selection appears to be a strong and pervasive driver of evolution associated with compartmentalization, affecting ≥ 34 of the 167 open reading frames (~20%) of the genome. This work offers the most detailed map of HCMV in vivo evolution to date and provides evidence that viral populations can be stable or rapidly differentiate, depending on host environment. The application of population genetic methods to these data provides clinically useful information, such as the timing of infection and compartment colonization.

Metabolic abnormalities in human immunodeficiency virus-infected children: two-year follow-up.

BACKGROUND: HIV-associated lipodystrophy (LD) manifests with fat maldistribution, dyslipidemia, and insulin resistance in some HIV-infected children on antiretroviral therapy. AIM: To assess whether lipid abnormalities in patients with HIV are stable over time. PATIENTS: The perinatally HIV-infected cohort at a medium-sized urban US teaching hospital. METHODS: This prospective, observational study consisted of five visits (at entry and 3, 6, 24, and 30 months after entry) during which fasting venous blood samples were drawn for HIV-1 RNA, CD4 lymphocytes, lipid profile, free fatty acids (FFA), glucose, insulin, and adiponectin. IGF-I/IGFBP-3 levels were measured at the first and fifth visits. RESULTS: Of 36 study participants, seven were lipodystrophic, and 30 patients completed all five study visits. LDL-cholesterol, total cholesterol (TC), triglycerides (TG), and FFA levels were significantly higher in patients taking protease inhibitors (PIs). Patients with LD had higher TC and TG levels (both p < 0.05), and higher FFA (p = 0.0532). Adiponectin levels did not differ between PI/non-PI and LD/non-LD groups. HDL-cholesterol seemed to decrease, and FFA to increase over time. All IGF-I and all but one IGFBP-3 level were within normal range for age and Tanner stage. CONCLUSION: Dyslipidemia remained relatively constant over our study period. Adiponectin was not useful as a marker of LD in our population.

Response to an education program for parents about adult pertussis vaccination.

We designed a prospective study to evaluate the effectiveness of an educational intervention designed to increase awareness and knowledge of pertussis among parents and grandparents of newborns. We also evaluated its effect on their willingness to receive the tetanus toxoid-diphtheria toxoid-acellular pertussis vaccine. There was a statistically significant (P < .05) increase in participants' knowledge about pertussis and in their willingness to receive vaccination after our education program. However, follow-up several months after participants underwent the intervention revealed that only 12 (8%) of 150 participants had been vaccinated.

Cytomegalovirus (CMV) IE1- and pp65-specific CD8+ T cell responses broaden over time after primary CMV infection in infants.

Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in young children. We have previously shown that CD8+ T cell responses to CMV pp65 or IE1 protein were readily detectable in children with congenital or postnatal CMV infection. Here, we have further characterized the evolution of the peptide specificity of these responses in 7 infants<6 months of age at the start of the study. Thirteen pp65 and 15 IE1 peptides (median, 5 peptides/infant) were targeted, and most (61%) represented sequences not previously reported. Peptide specificity remained stable or broadened over time despite the clearance of CMV viremia. Loss of peptide recognition was not observed. Responses with the highest functional peptide avidity were not necessarily detected earliest. These data provide additional evidence that young infants can generate diverse CMV-specific CD8+ T cell responses but show that early responses may exhibit relatively focused peptide specificity and lower peptide avidity.

Management of influenza symptoms in healthy children: cost-effectiveness of rapid testing and antiviral therapy.

OBJECTIVE: To determine the cost-effectiveness of rapid testing and antiviral therapy for children of different ages with symptoms of influenza. DESIGN: Cost-effectiveness analysis from the societal perspective using a decision model based on published data. SETTING: Physician's office during an influenza A epidemic. PARTICIPANTS: Hypothetical children aged 2, 7, and 15 years. INTERVENTIONS: Rapid testing or clinical diagnosis followed by treatment with amantadine hydrochloride or oseltamivir phosphate compared with no antiviral therapy. OUTCOME MEASURES: Costs and quality-adjusted life expectancy. RESULTS: Empirical therapy with antiviral medication resulted in the greatest quality-adjusted life expectancy in all age groups. Compared with not treating, antiviral therapy improved quality-adjusted life expectancy by 0.003 quality-adjusted life-year by shortening the duration of illness and preventing otitis media. In young children it saved up to USD 121 per child mostly by avoiding parental work loss. Excluding work loss, antiviral therapy improved quality-adjusted life expectancy at a cost of USD 800 to 1800 per quality-adjusted life-year saved. Compared with amantadine, oseltamivir was not cost-effective when influenza A predominated. The incremental cost-effectiveness of oseltamivir fell below USD 50 000 per quality-adjusted life-year saved when the proportion of influenza B exceeded 14% for a 2-year-old, 27% for a 7-year-old, or 43% for a 15-year-old. Rapid testing was cost-effective only when the probability of influenza was 60% or less. CONCLUSIONS: For children presenting with influenza symptoms during a local influenza outbreak, treatment with antiviral therapy appears to offer the best outcome and often saves money. The choice of antiviral drug should be based on the prevalence of influenza B.

Improvement of motor development and postural control following intervention in children with sensorineural hearing loss and vestibular impairment.

OBJECTIVE: The purpose of this study was to determine the effect of exercise intervention on the progressive motor development delay and postural control impairments in children with sensorineural hearing loss and concurrent vestibular impairment. METHODS: Twenty-one children with sensorineural hearing loss and vestibular impairment were randomly assigned to two groups (exercise and placebo) matched for age and gross motor development level. Exercise intervention consisted of compensatory training, emphasizing enhancement of visual and somatosensory function, and balance training. Placebo intervention focused on language development activities. Each intervention was administered three times weekly for 12 weeks. Motor development and posturography testing was completed pre- and post-intervention. To examine the mechanisms of change, somatosensory, visual and vestibular functional effectiveness ratios were calculated from posturography stability scores. Children in the placebo group later participated in exercise intervention, and a second post-test completed. Data were analyzed by group, as well as merged once all had received exercise intervention. RESULTS: Post-intervention, motor development scores significantly improved in the exercise, not the placebo group (P=0.004). Although not significant, improvement in posturography scores were evident in the exercise group. Once the post-exercise data from both groups were merged (n=21), improvements in these scores were significant (< or =0.02). The difference from the normative sample was eliminated. CONCLUSIONS: Exercise intervention focused on the enhancement of sensory integrative postural control abilities is effective for the arrest of the progressive motor development delay in children with sensorineural hearing loss and vestibular impairment.

Evidence of human immunodeficiency virus-associated lipodystrophy syndrome in children treated with protease inhibitors.

We conducted a prospective evaluation for evidence of the HIV-associated lipodystrophy syndrome of 26 children infected with HIV-1. Six children had evidence of body fat redistribution. Nine children showed laboratory evidence of insulin resistance. All children with body fat distribution or insulin resistance had been treated with protease inhibitors. Children treated with protease inhibitors had higher total cholesterol, higher low density lipoprotein-cholesterol and higher triglycerides than untreated children.