Site-specific development and progressive maturation of human tissue-resident memory T cells over infancy and childhood.

Infancy and childhood are critical life stages for generating immune memory to protect against pathogens; however, the timing, location, and pathways for memory development in humans remain elusive. Here, we investigated T cells in mucosal sites, lymphoid tissues, and blood from 96 pediatric donors aged 0-10 years using phenotypic, functional, and transcriptomic profiling. Our results revealed that memory T cells preferentially localized in the intestines and lungs during infancy and accumulated more rapidly in mucosal sites compared with blood and lymphoid organs, consistent with site-specific antigen exposure. Early life mucosal memory T cells exhibit distinct functional capacities and stem-like transcriptional profiles. In later childhood, they progressively adopt proinflammatory functions and tissue-resident signatures, coincident with increased T cell receptor (TCR) clonal expansion in mucosal and lymphoid sites. Together, our findings identify staged development of memory T cells targeted to tissues during the formative years, informing how we might promote and monitor immunity in children.

Distinct Localization, Transcriptional Profiles, and Functionality in Early Life Tonsil Regulatory T Cells.

CD4+ regulatory T cells (Tregs) are key orchestrators of the immune system, fostering the establishment of protective immunity while preventing deleterious responses. Infancy and childhood are crucial periods of rapid immunologic development, but how Tregs mediate immune responses at these earliest timepoints of human life is poorly understood. In this study, we compare blood and tissue (tonsil) Tregs across pediatric and adult subjects to investigate age-related differences in Treg biology. We observed increased FOXP3 expression and proportions of Tregs in tonsil compared with paired blood samples in children. Within tonsil, early life Tregs accumulated in extrafollicular regions with cellular interactions biased toward CD8+ T cells. Tonsil Tregs in both children and adults expressed transcriptional profiles enriched for lineage defining signatures and canonical functionality compared with blood, suggesting tissue as the primary site of Treg activity. Early life tonsil Tregs transcriptional profiles were further defined by pathways associated with activation, proliferation, and polyfunctionality. Observed differences in pediatric tonsil Treg transcriptional signatures were associated with phenotypic differences, high proliferative capacity, and robust production of IL-10 compared with adult Tregs. These results identify tissue as a major driver of Treg identity, provide new insights into developmental differences in Treg biology across the human lifespan, and demonstrate unique functional properties of early life Tregs.

Developmental Regulation of Effector and Resident Memory T Cell Generation during Pediatric Viral Respiratory Tract Infection.

Viral respiratory tract infections (VRTI) remain a leading cause of morbidity and mortality among infants and young children. In mice, optimal protection to VRTI is mediated by recruitment of effector T cells to the lungs and respiratory tract, and subsequent establishment of tissue resident memory T cells (Trm), which provide long-term protection. These critical processes of T cell recruitment to the respiratory tract, their role in disease pathogenesis, and establishment of local protective immunity remain undefined in pediatric VRTI. In this study, we investigated T cell responses in the upper respiratory tract (URT) and lower respiratory tract (LRT) of infants and young children with VRTI, revealing developmental regulation of T cell differentiation and Trm generation in situ. We show a direct concurrence between T cell responses in the URT and LRT, including a preponderance of effector CD8+ T cells that was associated with disease severity. During infant VRTI, there was an accumulation of terminally differentiated effector cells (effector memory RA+ T cells) in the URT and LRT with reduced Trm in the early neonatal period, and decreased effector memory RA+ T cell and increased Trm formation with age during the early years of childhood. Moreover, human infant T cells exhibit increased expression of the transcription factor T-bet compared with adult T cells, suggesting a mechanism for preferential generation of effector over Trm. The developmental regulation of respiratory T cell responses as revealed in the present study is important for diagnosing, monitoring, and treating VRTI in the critical early life stages.

Human γδ T cells in diverse tissues exhibit site-specific maturation dynamics across the life span.

During ontogeny, γδ T cells emerge from the thymus and directly seed peripheral tissues for in situ immunity. However, their functional role in humans has largely been defined from blood. Here, we analyzed the phenotype, transcriptome, function, and repertoire of human γδ T cells in blood and mucosal and lymphoid tissues from 176 donors across the life span, revealing distinct profiles in children compared with adults. In early life, clonally diverse Vδ1 subsets predominate across blood and tissues, comprising naïve and differentiated effector and tissue repair functions, whereas cytolytic Vδ2 subsets populate blood, spleen, and lungs. With age, Vδ1 and Vδ2 subsets exhibit clonal expansions and elevated cytolytic signatures, which are disseminated across sites. In adults, Vδ2 cells predominate in blood, whereas Vδ1 cells are enriched across tissues and express residency profiles. Thus, antigenic exposures over childhood drive the functional evolution and tissue compartmentalization of γδ T cells, leading to age-dependent roles in immunity.

SARS-CoV-2 infection and recovery in children: Distinct T cell responses in MIS-C compared to COVID-19.

SARS-CoV-2 infection for most children results in mild or minimal symptoms, though in rare cases severe disease can develop, including a multisystem inflammatory syndrome (MIS-C) with myocarditis. Here, we present longitudinal profiling of immune responses during acute disease and following recovery in children who developed MIS-C, relative to children who experienced more typical symptoms of COVID-19. T cells in acute MIS-C exhibited transient signatures of activation, inflammation, and tissue residency which correlated with cardiac disease severity, while T cells in acute COVID-19 upregulated markers of follicular helper T cells for promoting antibody production. The resultant memory immune response in recovery showed increased frequencies of virus-specific memory T cells with pro-inflammatory functions in children with prior MIS-C compared to COVID-19 while both cohorts generated comparable antibody responses. Together our results reveal distinct effector and memory T cell responses in pediatric SARS-CoV-2 infection delineated by clinical syndrome, and a potential role for tissue-derived T cells in the immune pathology of systemic disease.

Mental Health in the Medical Home: A Longitudinal Curriculum for Pediatric Residents on Behavioral and Mental Health Care.

Introduction: Currently, a pediatric mental and behavioral health crisis exists, driven by increasing stressors among children coupled with a paucity of psychiatric providers who treat children. Pediatric primary care providers can play a critical role in filling this gap, yet trainees feel uncomfortable screening for, identifying, and managing mental and behavioral health conditions among their patients. Thus, expanding training for pediatricians in this domain is critical. Methods: We created a longitudinal integrated mental and behavioral health curriculum for pediatric residents at NewYork-Presbyterian/Columbia University Irving Medical Center with a logic model contextualizing outpatient pediatric care as a framework for the development and planned evaluation. We devised a comprehensive set of materials, with presentations on topics including attention deficit hyperactivity disorder and anxiety disorders. Workflows and escalation pathways promoting collaboration among interdisciplinary providers were implemented. We evaluated residents' and faculty members' participation in the curriculum and their perception of curricular gaps. Results: Approximately 155 pediatric residents participated in the curriculum from 2017 to 2021, reflecting robust curricular exposure. Few residents and no preceptors perceived mental and behavioral health as a curricular gap. Discussion: Our curriculum is feasible and can be adapted to a variety of educational settings. Its use of a logic model for development, implementation, and ongoing evaluation grounds the curriculum in educational theory and can address curricular gaps. The framework can be adapted to suit the needs of other institutions' educational and practice settings and equip pediatric trainees with the skills to promote patient mental health and well-being.

An Innovative Model for Providing Dermatology Services Within Primary Care.

OBJECTIVE: Dermatologic complaints are common in outpatient pediatrics. However, pediatric dermatology specialty care can be difficult to access. We aimed to test the feasibility of co-locating dermatology services within primary care and increase the proportion of patients treated for basic skin complaints within the medical home while decreasing wait times. METHODS: The Rapid Assessment of Skin Health (RASH) clinic was created within a hospital-based primary care clinic in 11/2013. The clinic was staffed by 2 pediatricians trained in the dermatology department and supported with specialist advice as needed. Referral volume and wait times to dermatology and RASH clinic were tracked for visits between 11/1/12 and 10/31/18. A chart review was also conducted on a subset of RASH clinic visits. Primary care providers (PCPs) were surveyed about their experiences. RESULTS: Fifty-eight percent of patients referred for a dermatologic complaint were scheduled in RASH clinic. Wait times for new patient appointments in RASH clinic were significantly shorter than for new dermatology appointments in the previous 12 months (mean 36 days vs 65 days, P < .001). The monthly number of referrals to dermatology also decreased significantly after the RASH clinic opened (24/month vs 12/month, P < .001). Ten percent of RASH patients were referred on to dermatology. In a survey of PCPs (N = 67), 76% said the RASH clinic was "extremely/very helpful." CONCLUSIONS: Providing dermatologic care to low or moderate complexity patients within the medical home is feasible and leads to better access to care. This innovative model could be spread to other clinics and subspecialties.

Managing the COVID-19 Pandemic Using Quality Improvement Principles: A New York City Pediatric Primary Care Experience.

In the setting of COVID-19, pediatric primary care in New York City faced multiple challenges, requiring large-scale practice reorganization. We used quality improvement principles to implement changes to care delivery rapidly. METHODS: Plan-do-study-act cycles were used, based on primary drivers of consolidation, reorganization of in-person and urgent care, telehealth expansion, patient outreach, mental health linkages, team communication, and safety. RESULTS: The average visit volume in pediatrics decreased from 662 per week to 370. Telehealth visits increased from 2 to 140 per week, whereas urgent in-person visits decreased from 350 to 8 per week. Adolescent visits decreased from 57 to 46 per week. Newborn Clinic visits increased from 37 per week to 54. Show rates increased significantly for pediatrics and adolescent (P = 0.003 and P = 0.038, respectively). CONCLUSIONS: Quality improvement methodology allowed for the consolidation of pediatric primary care practices during the first wave of the COVID-19 pandemic, ensuring care for patients while prioritizing safety, evidence-based practices, and available resources.

The Relationship Between Linkages to Behavioral Health Services in Pediatric Primary Care and Reductions in Non-urgent Emergency Department Visits Among Vulnerable Children.

The integration of behavioral health (BH) services within pediatric primary care has been utilized as a way to address young children's social-emotional needs. This study aimed to examine whether linking at-risk young children to BH services is associated with a reduction in "non-urgent" emergency department (ED) visits. BH teams integrated in a pediatric clinic conducted socio-emotional screening in children 6-65 months of age and tracked ED utilization for children with positive screening. The results indicated that children with positive screening are less likely to have a non-urgent ED visit than children with negative screening with concerns (NWC) and are more likely to be connected to services. Among children in the NWC group, those connected to services were less likely to have non-urgent ED visits than those not connected to services. These findings suggest that integrated behavioral health care has the potential to reduce non-urgent ED visits among at-risk children.

Why Parents Use the Emergency Department Despite Having a Medical Home.

Despite having a medical home, pediatric patients continue emergency department (ED) utilization for various reasons. This study examines parental reasons associated with the decision to seek ED care in a group of low-income, inner-city, publicly insured children. Surveys were conducted with parents of children (age = 0-19 years) presenting to a community-based clinic, which has an established medical home model with enhanced access. Most patients (88.3%) had a pediatrician, and nearly all (93.3%) reported a visit to the ED; most (75.7%) were aware of clinic walk-in hours, but less than half (42.6%) were aware of an after-hours phone line. There was no difference in those who were aware of walk-in hours or an after-hours phone line and a reported ED visit. Half of the parents (52.5%) thought their child's medical problem was serious. In addition to providing enhanced efforts, medical homes should strive to make families aware of increased access.

Office-Based Educational Handout for Influenza Vaccination: A Randomized Controlled Trial.

OBJECTIVES: To assess the impact of a parent educational intervention about influenza disease on child vaccine receipt. METHODS: A convenience sample of parents of children ≥6 months old with a visit at 2 New York City pediatric clinics between August 2016 and March 2017 were randomly assigned (1:1:1) to receive either usual care, an educational handout about influenza disease that was based on local data, or an educational handout about influenza disease that was based on national data. Parents received the handout in the waiting room before their visit. Primary outcomes were child influenza vaccine receipt on the day of the clinic visit and by the end of the season. A multivariable logistic regression was used to assess associations between intervention and vaccination, with adjustment for variables that were significantly different between arms. RESULTS: Parents who received an intervention (versus usual care) had greater odds of child influenza vaccine receipt by the end of the season (74.9% vs 65.4%; adjusted odds ratio 1.68; 95% confidence interval: 1.06-2.67) but not on the day of the clinic visit. Parents who received the national data handout (versus usual care) had greater odds of child influenza vaccine receipt on the day of the clinic visit (59.0% vs 52.6%; adjusted odds ratio 1.79; 95% confidence interval: 1.04-3.08) but not by the end of the season. CONCLUSIONS: Providing an educational intervention in the waiting room before a pediatric provider visit may help increase child influenza vaccine receipt.

Improving rates of ferrous sulfate prescription for suspected iron deficiency anaemia in infants.

BACKGROUND: Iron deficiency anaemia (IDA) in infancy is prevalent and associated with impaired neurodevelopment; however, studies suggest that treatment and follow-up rates are poor. OBJECTIVES: To improve the rate of ferrous sulfate prescription for suspected IDA among infants aged 8-13 months to 75% or greater within 24 months. METHODS: We implemented a multidisciplinary process improvement effort aimed at standardising treatment for suspected IDA at two academic paediatric primary care clinics. We developed a clinical pathway with screening and treatment recommendations, followed by multiple plan-do-study-act cycles including provider education, targeted reminders when ferrous sulfate was not prescribed and development of standardised procedures for responding to abnormal lab values. We tracked prescription and screening rates using statistical process control charts. In post hoc analyses, we examined rates of haemoglobin (Hgb) recheck and normalisation for the preintervention versus postintervention groups. RESULTS: The prescription rate for suspected IDA increased from 41% to 78% following implementation of the intervention. Common reasons for treatment failure included prescription of a multivitamin instead of ferrous sulfate, and Hgb not flagged as low by the electronic medical record. Screening rates remained stable at 89%. Forty-one per cent of patients with anaemia in the preintervention group had their Hgb rechecked within 6 months, compared with 56% in the postintervention group (p<0.001). Furthermore, 30% of patients with anaemia in the postintervention group had normalised their Hgb by 6 months, compared with 20% in the preintervention group (p<0.05). CONCLUSIONS: A multipronged interdisciplinary quality improvement intervention enabled: (1) development of standardised practices for treating suspected IDA among infants aged 8-13 months, (2) improvement of prescription rates and (3) maintenance of high screening rates. Rates of Hgb recheck and normalisation also increased in the intervention period.​.