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Lower respiratory tract infections (LRTIs) remain the leading cause of infant morbidity and mortality worldwide and affect long-term respiratory health. Identifying immunological determinants of LRTI susceptibility may help stratify disease risk and identify therapies. This study aimed to identify neonatal immunological factors predicting LRTI risk in infancy. Cord blood plasma from 191 neonates from the Boston Birth Cohort was analyzed for 28 soluble immune factors. LRTI was defined as bronchiolitis, bronchitis, or pneumonia during the first year of life. Welch's t-test demonstrated significantly higher log10 transformed concentrations of IL-17 and IFNγ in the LRTI group compared to neonates without LRTI in the first year of life (p < 0.05). Risk associations were determined using multivariate survival models. There were 29 infants with LRTIs. High cord blood levels of IFNγ (aHR = 2.35, 95% CI 1.07–5.17), TNF-β (aHR = 2.86, 95% CI 1.27–6.47), MIP-1α (aHR = 2.82, 95% CI 1.22–6.51), and MIP-1β (aHR = 2.34, 95% CI 1.05–5.20) were associated with a higher risk of LRTIs. RANTES was associated with a lower risk (aHR = 0.43, 95% CI 0.19–0.97). Soluble immune factors linked to antiviral immunity (IFNγ) and cytokines mediating inflammatory responses (TNF-β), and cell homing (MIP-1α/b), at birth were associated with an increased risk of LRTIs during infancy. [ABSTRACT FROM AUTHOR]

Background. Cytokine storm syndromes (CSS) are life-threatening systemic inflammatory disorders caused by immune system dysregulation. They can lead to organ failure and are triggered by various factors, including infections, malignancy, inborn errors of immunity, and autoimmune conditions. Trisomy 21 (TS21), also known as Down syndrome, is a genetic disorder associated with immune dysfunction, increased infection susceptibility, and inflammation. While TS21 has been linked to infectious-triggered hyperinflammation, its role as a primary cause of CSS has not been confirmed. Case Presentation. We present a case of a 16-year-old male with TS21 with fever, rash, joint pain, and abdominal symptoms. Extensive investigations ruled out infections, autoimmune conditions, malignancies, and inborn errors of immunity as triggers for a CSS. The patient's symptoms improved with treatment using IL-1 inhibition and corticosteroids. Conclusions. This case reinforces that TS21 is an immune dysregulation disorder and highlights the importance of considering CSS in TS21 patients, even when triggers are unclear. The positive response to IL-1 inhibition in this patient suggests that dysregulation of the IL-1 superfamily and the NLRP3 inflammasome may contribute to CSS in TS21. This finding raises the possibility of using IL-1 inhibition as a treatment approach for CSS in TS21 patients. [ABSTRACT FROM AUTHOR]

In addition to being a vital organ for gas exchange, the lung is a crucial immune organ continuously exposed to the external environment. Genetic defects that impair immune function, called inborn errors of immunity (IEI), often have lung disease as the initial and/or primary manifestation. Common types of lung disease seen in IEI include infectious complications and a diverse group of diffuse interstitial lung diseases. Although lung damage in IEI has been historically ascribed to recurrent infections, contributions from potentially targetable autoimmune and inflammatory pathways are now increasingly recognized. This article provides a practical guide to identifying the diverse pulmonary disease patterns in IEI based on lung imaging and respiratory manifestations, and integrates this clinical information with molecular mechanisms of disease and diagnostic assessments in IEI. We cover the entire IEI spectrum, including immunodeficiencies and immune dysregulation with monogenic autoimmunity and autoinflammation, as well as recently described IEI with pulmonary manifestations. Although the pulmonary manifestations of IEI are highly relevant for all age groups, special emphasis is placed on the pediatric population, because initial presentations often occur during childhood. We also highlight the pivotal role of genetic testing in the diagnosis of IEI involving the lungs and the critical need to develop multidisciplinary teams for the challenging evaluation of these rare but potentially life-threatening disorders. [ABSTRACT FROM AUTHOR]

Byline: Ping Liu, PhD (Department of Clinical Pharmacology Pfizer Global Research and Development, Groton/New London, Connecticut, Ping.Liu@pfizer.com); Grover Foster, PhD (Department of Clinical Sciences, Pfizer, Inc, New York); Robert R. [...]

Over the past two decades, several studies have positioned early-life microbial exposure as a key factor for protection or susceptibility to respiratory diseases. Birth cohorts have identified a strong link between neonatal bacterial colonization of the nasal airway and gut with the risk for respiratory infections and childhood asthma. Translational studies have provided companion mechanistic insights on how viral and bacterial exposures in early life affect immune development at the respiratory mucosal barrier. In this review, we summarize and discuss our current understanding of how early microbial--immune interactions occur during infancy, with a particular focus on the emergent paradigm of "innate immune training". Future human-based studies including newborns and infants are needed to inform the timing and key pathways implicated in the development, maturation, and innate training of the airway immune response, and how early microbiota and virus exposures modulate these processes in the respiratory system during health and disease. [ABSTRACT FROM AUTHOR]

Introduction: IFN lambda (type III‐IFN‐λ1) is a molecule primarily produced by epithelial cells that provides an important first‐line defence against viral respiratory infections and has been linked to the pathogenesis of viral‐induced wheezing in early life. The goal of this study was to better understand the regulation of innate IFN‐lambda responses in vitro in primary human infant airway epithelial cells (AECs) and in vivo using nasal aspirates during viral respiratory infections. Methods: IFN‐lambda protein levels were quantified: (a) in human infant AECs exposed to (poly(I:C) dsRNA) under different experimental conditions (n = 8 donors); and (b) in nasal aspirates of young children (≤3 years) hospitalized with viral respiratory infection (n = 138) and in uninfected controls (n = 74). In vivo IFN‐lambda airway levels during viral infections were correlated with individual characteristics and respiratory disease parameters. Results: Our in vitro experiments showed that the poly(I:C)‐induced innate production of IFN lambda in human infant AECs is regulated by (a) p38‐MAPK/NF‐kB dependent mechanism; and (b) exposure to pro‐inflammatory signals such as IL1β. Our in vivo studies demonstrated that (a) infants (<18 months) had higher virus‐induced IFN‐lambda airway secretion; (b) subjects with RSV infection showed the highest IFN‐lambda airway levels; and (c) individuals with the highest virus‐induced IFN‐lambda levels (>90th percentile) had higher viral loads and were more likely to have respiratory sick visits within 12 months of discharge (OR = 5.8). Conclusion: IFN‐lambda responses to dsRNA in the human infant airway epithelium are regulated by p38‐MAPK and NF‐kB signalling. High in vivo IFN‐lambda production is influenced by virus type and associated with recurrent respiratory sick visits in young children. [ABSTRACT FROM AUTHOR]

The molecular machinery controlling immune development has been extensively investigated. Studies in animal models and adult individuals have revealed fundamental mechanisms of disease and have been essential to understanding how humans sense and respond to cellular stress, tissue damage, pathogens and their environment. Nonetheless, our understanding of how immune responses originate during human development is just starting to emerge. In particular, studies to unveil how environmental and other non-heritable factors shape the immune system at the beginning of life offer great promise to yield important knowledge about determinants of normal inter-individual immune variation and to prevent and treat many human diseases. In this review, we summarize our current understanding of some of the mechanisms determining early life antibody production as a model of an immune process with sequential molecular checkpoints susceptible to influence by non-heritable factors. We discuss the potential of epigenomics as a valuable approach that may reveal not only relevant gene-environment interactions but important clues about immune developmental processes and homeostasis in early life. We then highlight the novel paradigm of human immunology as a complex field that nowadays requires a longitudinal systems-biology approach to understand normal variation and developmental changes during the first few years of life. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRs) control gene expression and the development of the immune system and antiviral responses. MiR-155 is an evolutionarily-conserved molecule consistently induced during viral infections in different cell systems. Notably, there is still an unresolved paradox for the role of miR-155 during viral respiratory infections. Despite being essential for host antiviral TH1 immunity, miR-155 may also contribute to respiratory disease by enhancing allergic TH2 responses and NFkB-mediated inflammation. The central goal of this study was to define how airway miR-155 production is related to TH1, TH2, and pro-inflammatory cytokine responses during naturally occurring viral respiratory infections in young children. Methods: Normalized nasal airway levels of miR-155 and nasal protein levels of IFN-γ, TNF-α, IL-1β, IL-13, IL-4 were quantified in young children (≤2 years) hospitalized with viral respiratory infections and uninfected controls. These data were linked to individual characteristics and respiratory disease parameters. Results: A total of 151 subjects were included. Increased miR-155 levels were observed in nasal samples from patients with rhinovirus, RSV and all respiratory viruses analyzed. High miR-155 levels were strongly associated with high IFN-γ production, increased airway TH1 cytokine polarization (IFN-γ/IL-4 ratios) and increased pro-inflammatory responses. High airway miR-155 levels were linked to decreased respiratory disease severity in individuals with high airway TH1 antiviral responses. Conclusions: The airway secretion of miR-155 during viral respiratory infections in young children is associated with enhanced antiviral immunity (TH1 polarization). Further studies are needed to define additional physiological roles of miR-155 in the respiratory tract of human infants and young children during health and disease. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with immune dysregulation and increased risk of infections. The presence of autoantibodies and immunoglobulin abnormalities indicates B-cell and antibody-secreting cell (ASC) dysfunction. We hypothesize that soluble factors associated with B-cell and ASC activity are decreased in RA patients and that this is linked to higher susceptibility to infections.Methods: Using the Johns Hopkins Arthritis Cohort and Biorepository, we contrasted serum protein levels of soluble factors involved in B-cell activation (CD40, CD40L) and B-cell/ASC homing (CXCL10, CXCL11, and CXCL13) or survival (BAFF, APRIL, TACI, and BCMA) in 10 healthy subjects and 23 adult RA patients (aged 24-65 years). We subdivided RA patients into those with (n = 17) and those without infections (n = 6) within a 2-year period. In order to reduce the effect of RA treatment, we only included patients receiving methotrexate monotherapy or no RA treatments at baseline. Soluble serum protein levels of B-cell/ASC factors were quantified by multiplex immunoassays.Results: We identified that (1) serum levels of soluble BCMA, APRIL, CD40, and CD40L were significantly decreased in RA patients relative to healthy individuals; (2) serum soluble BCMA, predominantly released by ASC, correlated with serum concentrations of class-switched immunoglobulins, IgG and IgA; and (3) RA patients with a history of infections had significantly lower soluble BCMA levels compared with healthy donors and with RA patients without infections.Conclusions: Our study using soluble factors linked to B-cell/ASC activation and survival suggests that there is a paucity of ASC in a subset of RA patients and that this may be linked to altered antibody production and increased risk of infections. Further delineating the link between ASC and infection susceptibility in RA may optimize disease management and provide novel insights into disease pathogenesis that are susceptible to intervention. [ABSTRACT FROM AUTHOR]

The article presents a study examine the thymic stromal lymphopoietin (TSLP) production in the human infant airway epithelium and clinical relevance during viral respiratory infections. It discusses how human airway epithelial cells (AECs) derived from adults with asthma have confirmed that type 2 airway epithelial cytokines, such as TSLP (thymic stromal lymphopoietin), are key mediators in the pathogenesis of the disease.

Abstract Patients with common variable immunodeficiency (CVID) have a higher incidence of rheumatologic disorders. To delineate this clinical association, we investigated the phenotypic features of patients with CVID affected by these conditions. Methods We conducted a retrospective analysis of 870 pediatric and adult patients with CVID included in the United States Immunodeficiency Network (USIDNET) registry. Outcomes included clinical characteristics (age, gender, ethnicity, rheumatologic diagnosis, and comorbidities), infectious history and basic immunophenotype (serum immunoglobulin levels, CD19+ B cells, and CD4/CD8 ratio) in patients with CVID and rheumatologic disorders compared to those with non-inflammatory CVID. Demographic and clinical data were compared using chi-square, Fisher's exact or Wilcoxon-Mann-Whitney tests. Non-parametric tests, single and multiple logistic regression models were used to evaluate the relationship between CVID-associated rheumatologic disorders and basic immunophenotypic parameters (IgA, IgM, CD19+ B-cell counts, and CD4/CD8 ratios). Results Physician-reported rheumatic diseases were present in 5.9% of patients with CVID (n = 51) included in the registry. Although CVID affects both sexes equally, and patients are of predominantly White-Caucasian ethnicity, there were more females (3.3:1 female to male ratio) and increased proportion of non-white patients in the rheumatologic disease group (p < 0.05). Specific disorders included: inflammatory arthritis (n = 18), Sjogren's syndrome (n = 11), SLE (n = 8), Raynaud's syndrome (n = 8), vasculitis (n = 9), MCTD (n = 3), and other (n = 5). In about one-third of patients, a rheumatologic condition was associated with an additional inflammatory complication or malignancy. In regards to the immunophenotype parameters compared (CD19+ B-cell counts, CD4/CD8 ratio, IgA, and IgM), no significant differences were demonstrated between the two groups. Conclusion Our findings highlight the coexistence of primary antibody immunodeficiencies and systemic rheumatologic disorders, describe the spectrum of rheumatologic manifestations, and contrast differences in relevant demographic, clinical and immunophenotype parameters in the largest registry of CVID patients in the U.S. In spite of its limitations, our study details the intersection of systemic autoimmunity and CVID and provides valuable insights into these two groups of disorders. Further delineating the link between systemic autoimmunity and humoral immunodeficiencies can provide novel insights into the immune abnormalities underlying these related conditions. [ABSTRACT FROM AUTHOR]

Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) is a rare disorder of immune dysregulation caused by mutations in the autoimmune regulator (AIRE) gene. Individuals affected with APECED develop a clinical syndrome characterized by ectodermal abnormalities, autoantibody production, and organspecific autoimmune manifestations. Inflammatory arthritis is usually not described as a part of the syndrome, and only sporadic cases are reported. We describe the case of a preschool-age girl who presented with hypoparathyroidism, hepatitis, interstitial pneumonitis, and chronic polyarthritis at 4 years of age and was found to have two compound heterozygous disease-associated mutations in the AIRE gene. We also conducted a literature review of the main characteristics of inflammatory arthritis in APECED patients. Our case and review demonstrate that (1) inflammatory arthritis, although rare, can be an early manifestation of APECED; (2) the diagnosis of APECED should be considered if mucocutaneous candidiasis, multiple organ-specific autoimmune manifestations, polyendocrinopathy, especially hypoparathyroidism or adrenal failure, or ectodermal dystrophy accompany joint symptoms; and (3) genotyping interpretation should take into account that mutations are found in the 14 exons of the gene, compound heterozygosity is common, and in some cases, only one or no mutated alleles are found. [ABSTRACT FROM AUTHOR]

Background: Innate immune responses are fine-tuned by small noncoding RNA molecules termed microRNAs (miRs) that modify gene expression in response to the environment. During acute infections, miRs can be secreted in extracellular vesicles (EV) to facilitate cell-to-cell genetic communication. The purpose of this study was to characterize the baseline population of miRs secreted in EVs in the airways of young children (airway secretory microRNAome) and examine the changes during rhinovirus (RV) infection, the most common cause of asthma exacerbations and the most important early risk factor for the development of asthma beyond childhood. Methods: Nasal airway secretions were obtained from children (≤3 yrs. old) during PCR-confirmed RV infections (n = 10) and age-matched controls (n = 10). Nasal EVs were isolated with polymer-based precipitation and global miR profiles generated using NanoString microarrays. We validated our in vivo airway secretory miR data in an in vitro airway epithelium model using apical secretions from primary human bronchial epithelial cells (HBEC) differentiated at air-liquid interface (ALI). Bioinformatics tools were used to determine the unified (nasal and bronchial) signature airway secretory miRNAome and changes during RV infection in children. Results: Multiscale analysis identified four signature miRs comprising the baseline airway secretory miRNAome: hsa-miR-630, hsa-miR-302d-3p, hsa- miR-320e, hsa-miR-612. We identified hsa-miR-155 as the main change in the baseline miRNAome during RV infection in young children. We investigated the potential biological relevance of the airway secretion of hsa-mir-155 using in silico models derived from gene datasets of experimental in vivo human RV infection. These analyses confirmed that hsa-miR-155 targetome is an overrepresented pathway in the upper airways of individuals infected with RV. Conclusions: Comparative analysis of the airway secretory microRNAome in children indicates that RV infection is associated with airway secretion of EVs containing miR-155, which is predicted in silico to regulate antiviral immunity. Further characterization of the airway secretory microRNAome during health and disease may lead to completely new strategies to treat and monitor respiratory conditions in all ages. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) is a prevalent pathogen in the immunocompromised host and invasive pneumonia is a feared complication of the virus in this population. In this pediatric case series we characterized CMV lung infection in 15 non-HIV infected children (median age 3 years; IQR 0.2-4.9 years), using current molecular and imaging diagnostic modalities, in combination with respiratory signs and symptoms. The most prominent clinical and laboratory findings included cough (100%), hypoxemia (100%), diffuse adventitious breath sounds (100%) and increased respiratory effort (93%). All patients had abnormal lung images characterized by ground glass opacity/consolidation in 80% of cases. CMV was detected in the lung either by CMV PCR in bronchoalveolar lavage (82% detection rate) or histology/immunohistochemistry in lung biopsy (100% detection rate). CMV caused respiratory failure in 47% of children infected and the overall mortality rate was 13.3%. Conclusion: CMV pneumonia is a potential lethal disease in non-HIV infected children that requires a high-index of suspicion. Common clinical and radiological patterns such as hypoxemia, diffuse adventitious lung sounds and ground-glass pulmonary opacities may allow early identification of CMV lung infection in the pediatric population, which may lead to prompt initiation of antiviral therapy and better clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Rhinitis and obstructive sleep apnea (OSA) often coexist during childhood. To delineate this clinical association, we examined OSA severity and polysomnogram (PSG) features in children with rhinitis and OSA. Given that rapid-eye-movement (REM) sleep is characterized by nasal congestion, we hypothesized that children with rhinitis have more REM-related breathing abnormalities. Methods: We conducted a retrospective cross-sectional analysis of 145 children with PSG-diagnosed OSA. Outcomes included PSG parameters and obstructive apnea-hypopnea index (OAHI) during REM and non-REM. Linear multivariable models examined the joint effect of rhinitis and OSA parameters with control for potential confounders. Results: Rhinitis was present in 43% of children with OSA (n = 63) but overall OAHI severity was unaffected by the presence of rhinitis. In contrast, OAHI during REM sleep in children with moderate-severe OSA was significantly increased in subjects with rhinitis and OSA (44.1/hr; SE = 6.4) compared with those with OSA alone (28.2/hr; SE = 3.8). Conclusion: Rhinitis is highly prevalent in children with OSA. Although OSA is not more severe in children with rhinitis, they do have a distinct OSA phenotype characterized by more REM-related OSA. Further research is needed to delineate the link between REM-sleep and the physiology of the nose during health and disease. [ABSTRACT FROM AUTHOR]

Rationale. The sleep-related factors thatmodulate the nocturnal worsening of asthma in children are poorly understood. This study addressed the hypothesis that asthmatic children have a REM sleep-related vulnerability trait that is independent of OSA. Methods. We conducted a retrospective cross-sectional analysis of pulse-oximetry signals obtained during REM and NREM sleep in control and asthmatic children (η = 134). Asthma classification was based on preestablished clinical criteria. Multivariate linear regression model was built to control for potential confounders (significance level P = 0.05). Results. Our data demonstrated that (1) baseline nocturnal respiratory parameters were not significantly different in asthmatic versus control children, (2) the maximal % of SaO2 desaturation during REM, but not during NREM, was significantly higher in asthmatic children, and (3) multivariate analysis revealed that the association between asthma and REM-related maximal % SaO2 desaturation was independent of demographic variables. Conclusion. These results demonstrate that children with asthma have a REM-related vulnerability trait that impacts oxygenation independently of OSA. Further research is needed to delineate the REM sleep neurobiological mechanisms that modulate the phenotypical expression of nocturnal asthma in children. [ABSTRACT FROM AUTHOR]

Chronic granulomatous disease (CGD) is characterized by inherited immune defects resulting from mutations in the NADPH oxidase complex genes. The X-linked type of CGD is caused by defects in the CYBB gene that encodes gp91-phox, a fundamental component of the NADPH oxidase complex. This mutation originates the most common and severe form of CGD, which typically has absence of NADPH oxidase function and aggressive multisystemic infections. We present the case of a 9-year-old child with a rare CYBB mutation that preserves some NADPH oxidase activity, resulting in an atypical mild form of X-linked CGD with isolated lung involvement. Although the clinical picture and partially preserved oxidase function suggested an autosomal recessive form of CGD, genetic testing demonstrated a mutation in the exon 3 of CYBB gene (c.252 G>A, p.Ala84Ala), an uncommon Xlinked CGD variant that affects splicing. Atypical presentation and diagnostic difficulties are discussed. This case highlights that the diagnosis of mild forms of X-linked CGD caused by rare CYBB mutations and partially preserved NADPH function should be considered early in the evaluation of atypical and recurrent lung infections. [ABSTRACT FROM AUTHOR]

Background. Obese adolescents with Obstructive Sleep Apnea (OSA) have a unique pathophysiology that combines adenotonsillar hypertrophy and increased visceral fat distribution. We hypothesized that in this population waist circumference (WC), as a clinical marker of abdominal fat distribution, correlates with the likelihood of response to AT. Methods. We conducted a retrospective cohort study of obese adolescents (BMI = 97th percentile) that underwent AT for therapy of severe OSA (n = 21). We contrasted WC and covariates in a group of subjects that had complete resolution of severe OSA after AT (n = 7) with those obtained in subjects with residual OSA after AT (n = 14). Multivariate linear and logistic models were built to control possible confounders. Results. WC correlated negatively with a positive AT response in young adolescents and the percentage of improvement in obstructive apnea-hypopnea index (OAHI) after AT (P = 0.01). Extended multivariate analysis demonstrated that the link between WC and AT response was independent of demographic variables, OSA severity, clinical upper airway assessment, obesity severity (BMI), and neck circumference (NC). Conclusion. The results suggest that in obese adolescents, abdominal fat distribution determined by WC may be a useful clinical predictor for residual OSA after AT. [ABSTRACT FROM AUTHOR]

This study's aims were to evaluate the effects of Sorensen's Therapy of Instability in Mood (Sorensen, 2005; Sorensen, Done & Rhodes, 2007), an intervention based on a short relapse-prevention program for clients suffering from Bipolar Disorder (BD), delivered within a clinical setting, by an assistant psychologist with limited training in CBT. The experimental treatment consisted of four individual sessions in addition to treatment as usual. Twelve clients with diagnoses of BD participated. Outcomes were measured across four domains: symptom severity, perceived hopelessness, perceived control over symptoms and level of insight. Measures of client satisfaction were also collected. Statistical analysis of the data revealed significant improvements to depression and perceived control levels at both one and three month follow-ups. In addition, clients reported significantly lower levels of hopelessness at three months follow-up. The study also considered the clinical significance of the research findings with the Jacobson-Truax (Jacobson & Truax, 1991) method. A substantial number of clients attained clinically significant changes with regards to depression, hopelessness and perceived control at one and three months follow-ups. Recovery rates at three months were 50%, 41.6% and 25% respectively. Neither statistically nor clinically significant changes were found with regards to mania or insight at either one or three month follow-ups. All clients reported high levels of satisfaction. [ABSTRACT FROM AUTHOR]

Purpose. The most common pharmacological therapies used in the treatment of stridor in children are glucocorticosteroids (GC) and alpha-adrenergic (αAR) agonists. Despite the long-standing reported efficacy of these medications, there is a paucity of data relating to their actualmechanisms of action in the upper airway. Summary. There is compelling scientific evidence supporting the use of αAR-agonists and GCs in pediatric stridor. αAR signaling and GCs regulate the vasomotor tone in the upper airwaymucosa. The latter translates into better airflow dynamics, as delineated by human and nonhuman upper airway physiological models. In turn, clinical trials have demonstrated that GCs and the nonselective αAR agonist, epinephrine, improve respiratory distress scores and reduce the need for further medical care in children with stridor. Future research is needed to investigate the role of selective αAR agonists and the potential synergism of GCs and αAR-signaling in the treatment of upper airway obstruction and stridor. [ABSTRACT FROM AUTHOR]

To characterize the pharmacokinetic, pharmacodynamic and safety profiles of donepezil in subjects with moderate renal impairment and matched healthy controls during single-dose and multiple-dose phases.This open-label study enrolled subjects with moderate renal impairment (creatinine clearance[CLCr] 17–33 ml min−1 1.73 m−2 body surface area) and age, weight and sex-matched healthy controls. A single-dose (5 mg donepezil) phase was followed by a 23-day multiple dose (5 mg day−1 donepezil) steady-state phase. The pharmacokinetic and pharmacodynamic parameters of donepezil were determined for up to 144 h after the first dose and 168 h after the last dose.Thirty-six subjects were enrolled, 19 renally impaired and 17 healthy controls. All pharmacokinetic and pharmacodynamic parameters were similar between groups after a single dose of donepezil (Cmax 5.17 ± 0.36 and 6.07 ± 0.49 ng ml−1; AUC0−24 76.05 ± 5.54 and 77.45 ± 4.49 ng·h ml−1; mean maximum percentage inhibition[ Imax] red blood cell (RBC) AChE activity 32.07 ± 2.00 and 31.69 ± 2.45%; for subjects with renal impairment and healthy subjects, respectively). Pharmacokinetic parameters under steady-state conditions did not differ between renally impaired and healthy subjects (CSS 20.83 ± 1.78 and 18.38 ± 1.52 ng ml−1; AUC0−24 500.0 ± 42.8 and 441.1 ± 36.4 ng·h ml−1; degree of accumulation[ RA] 6.98 ± 0.59 and 5.94 ± 0.53; for subjects with renal impairment and healthy subjects, respectively). Main pharmacodynamic parameters were also similar in renally impaired and healthy subjects at steady state (average percentage inhibition[ ISS] RBC AChE activity 65.11 ± 2.52 and 60.62 ± 2.95, respectively). Protein binding was also similar between groups (% free donepezil 23.54 ± 1.96 and 20.23 ± 0.64, respectively). Donepezil was well tolerated by both groups.These results indicate that the pharmacokinetics of donepezil are not altered after dosing to steady state, and that donepezil can be administered safely to subjects with moderate renal impairment. [ABSTRACT FROM AUTHOR]

Purpose of Review: Pulmonary cytomegalovirus (CMV) infection is a potential lethal disease in children, but it remains a diagnostic challenge. The differentiation between latent CMV infections with viral shedding and active infections is difficult and may lead to false positives in bronchoalvolar lavage (BAL) PCR detection. This review summarizes current diagnostic approaches for CMV lung infection in children including progress in the identification of underlying immune defects linked to this condition. Recent Findings: There is increasing literature supporting that the combined assessment of host risk factors and lung disease pattern is essential for the diagnosis of pulmonary CMV infection in children. The most important host risk factor is an immunecompromised state that has expanded from primary or acquired immunodeficiency (e.g., HIV) to include a myriad of immune-dysregulation syndromes (e.g., CTLA4, PIK3 defects). Newborns, paricularly those born premature, are also a high-risk group. At the pulmonary level, active CMV infection is typically characterized by alveolar compromise leading to hypoxemia, ground-glass opacities, and intra-alveolar infiltrates with CMV inclusions in lung biopsy. The identification of active CMV lung infection should trigger additional evaluation of immune defects (primary or secondary) impairing T and NK cell function or innate antiviral responses as well as other immune dysregulation disorders. Summary: Lung CMV infections in children are more prevalent in immunocompromised hosts and premature newborns. Lung CMV infections should prompt further investigation into conditions altering immune mechanisms usually in place to contain CMV infections. Common clinical and radiological patterns such as hypoxemia and ground-glass pulmonary opacities may allow early identification and treatment of CMV lung infection and underlying causes in the pediatric population. [ABSTRACT FROM AUTHOR]

Thymic stromal lymphopoietin (TSLP) is a primarily epithelial‐derived cytokine that drives type 2 allergic immune responses. Early life viral respiratory infections elicit high TSLP production, which leads to the development of type 2 inflammation and airway hyperreactivity. The goal of this study was to examine in vivo and in vitro the human airway epithelial responses leading to high TSLP production during viral respiratory infections in early infancy. A total of 129 infants (<1–24 m, median age 10 m) with severe viral respiratory infections were enrolled for in vivo (n = 113), and in vitro studies (n = 16). Infants were classified as ‘high TSLP’ or ‘low TSLP’ for values above or below the 50th percentile. High versus low TSLP groups were compared in terms of type I–III IFN responses and production of chemokines promoting antiviral (CXCL10), neutrophilic (CXCL1, CXCL5, CXCL8), and type 2 responses (CCL11, CCL17, CCL22). Human infant airway epithelial cell (AEC) cultures were used to define the transcriptomic (RNAseq) profile leading to high versus low TSLP responses in vitro in the absence (baseline) or presence (stimulated) of a viral mimic (poly I:C). Infants in the high TSLP group had greater in vivo type III IFN airway production (median type III IFN in high TSLP 183.2 pg/mL vs. 63.4 pg/mL in low TSLP group, p = 0.007) and increased in vitro type I–III IFN AEC responses after stimulation with a viral mimic (poly I:C). At baseline, our RNAseq data showed that infants in the high TSLP group had significant upregulation of IFN signature genes (e.g., IFIT2, IFI6, MX1) and pro‐inflammatory chemokine genes before stimulation. Infants in the high TSLP group also showed a baseline AEC pro‐inflammatory state characterized by increased production of all the chemokines assayed (e.g., CXCL10, CXCL8). High TSLP responses in the human infant airways are associated with pre‐activated airway epithelial IFN antiviral immunity and increased baseline AEC production of pro‐inflammatory chemokines. These findings present a new paradigm underlying the production of TSLP in the human infant airway epithelium following early life viral exposure and shed light on the long‐term impact of viral respiratory illnesses during early infancy and beyond childhood. [ABSTRACT FROM AUTHOR]

Contains correspondence over proposed psychiatric training for family doctors. Structure of 8-week block rotation for the first and second years; Evidence of improvement of recognition skills by residents; Favorable treatment response of patients.