Donor KIR2DL1 Allelic Polymorphism Influences Posthematopoietic Progenitor Cell Transplantation Outcomes in the T Cell Depleted and Reduced Intensity Conditioning Setting.

The majority of established KIR clinical assessment algorithms used for donor selection for hematopoietic progenitor cell transplantation (HPCT) evaluate gene content (presence/absence) of the KIR gene complex. In comparison, relatively little is known about the impact of KIR allelic polymorphism. By analyzing donors of T cell depleted (TcD) reduced intensity conditioning (RIC) HPCT, this study investigated the influence on post-transplant outcome of 2 polymorphic residues of the inhibitory KIR2DL1. The aim of this study was to expand upon existing research into the influence of KIR2DL1 allelic polymorphism upon post-transplant outcome. The effects of allele groups upon transplant outcomes were investigated within a patient cohort using a defined treatment protocol of RIC with TcD. Using phylogenetic data, KIR2DL1 allelic polymorphism was categorized into groups on the basis of variation within codons 114 and 245 (positive or negative for the following groups: KIR2DL1*002/001g, KIR2DL1*003, KIR2DL1*004g) and the identification of null alleles. The influence of these KIR2DL1 allele groups in hematopoietic progenitor cell transplantation (HPCT) donors was assessed in the post-transplant data of 86 acute myelogenous leukemia patients receiving RIC TcD HPCT at a single center. KIR2DL1 allele groups in the donor significantly impacted upon 5-year post-transplant outcomes in RIC TcD HPCT. Donor KIR2DL1*003 presented the greatest influence upon post-transplant outcomes, with KIR2DL1*003 positive donors severely reducing 5-year post-transplant overall survival (OS) compared to those receiving a transplant from a KIR2DL1*003 negative donor (KIR2DL1*003 pos versus neg: 27.0% versus 60.0%, P = .008, pc = 0.024) and disease-free survival (DFS) (KIR2DL1*003 pos versus neg: 23.5% versus 60.0%, P = .004, pc = 0.012), and increasing 5-year relapse incidence (KIR2DL1*003 pos versus neg: 63.9% versus 27.2%, P = .009, pc = 0.027). KIR2DL1*003 homozygous and KIR2DL1*003 heterozygous grafts did not present significantly different post-transplant outcomes. Donors possessing the KIR2DL1*002/001 allele group were found to significantly improve post-transplant outcomes, with donors positive for the KIR2DL1*004 allele group presenting a trend towards improvement. KIR2DL1*002/001 allele group (KIR2DL1*002/001g) positive donors improved 5-year OS (KIR2DL1*002/001g pos versus neg: 56.4% versus 27.2%, P = .009, pc = 0.024) and DFS (KIR2DL1*002/001g pos versus neg: 53.8% versus 25.5%, P = .018, pc = 0.036). KIR2DL1*004 allele group (KIR2DL1*004g) positive donors trended towards improving 5-year OS (KIR2DL1*004g pos versus neg: 53.3% versus 35.5%, P = .097, pc = 0.097) and DFS (KIR2DL1*004g pos versus neg: 50.0% versus 33.9%, P = .121, pc = 0.121), and reducing relapse incidence (KIR2DL1*004g pos versus neg: 33.1% versus 54.0%, P = .079, pc = 0.152). The presented findings suggest donor selection algorithms for TcD RIC HPCT should consider avoiding KIR2DL1*003 positive donors, where possible, and contributes to the mounting evidence that KIR assessment in donor selection algorithms should reflect the conditioning regime protocol used.

Assessment and Management of Sleep Disturbances in Atopic Dermatitis: A Review.

Atopic dermatitis (AD) is a chronic burdensome inflammatory skin disease with well-established cutaneous and systemic comorbidities and disease burden. AD particularly has profound impacts on sleep in individuals of all ages. Sleep disturbances (SDs) affect 6.2% of school-age children and 33-87.1% of adults with AD. This narrative review addresses the burden of SD in AD patients, as well as biological mechanisms of SD in AD, including biological clocks influencing sleep, inflammation, and behavior. Approaches for early detection, diagnosis, objective quantification, patient education, and management are reviewed. It is imperative to break the itch-scratch cycle to reduce SDs and improve quality of life in individuals with AD.

Timing of scratch and limb movements during sleep in children with atopic dermatitis.

In this retrospective analysis of children with atopic dermatitis (n = 6) who coincidentally had a video polysomnography, we found that most nocturnal limb movements in children with atopic dermatitis are non-scratch versus scratch, 109.0 ± 67.9 vs. 15.3 ± 5.4 (p = 0.01). Average scratch duration was 8.4 ± 2.7 s, which was not different by sleep stage. Scratch movements are distinct in timing, occurring most often during N2 sleep, in the first third of sleep, and peaking at 90 minutes after sleep onset, corresponding with completion of the first sleep cycle.

An early evaluation of the HISTO SPOT® AB ID Class I & II test in cardiothoracic transplant patients.

The HISTO SPOT® AB ID assay (BAG Diagnostics GmbH) is a novel single antigen HLA Class I & II antibody definition test used with the MR.SPOT® processor. We compared this assay with Luminex® -based assays to assess its potential application in defining unacceptable antigens for transplantation in patients awaiting transplants with cardiothoracic organs. A cohort of 40 sensitized cardiothoracic patients were identified, and one sample was selected from each patient. The required screening was based on the patients' antibody profiles (Class I, n = 17, Class II, n = 11, Class I & II, n = 12). Samples were screened with LABScreen™ Single Antigen (SAg), LIFECODES® LSA™, HISTO SPOT® AB ID, and an acid modified LABScreen™ SAg test for detecting antibodies against denatured HLA. Results indicated that HISTO SPOT® AB ID had reduced sensitivity (68% for Class I; 69% for Class II). When compared to LABScreen™ and LIFECODES® , HISTO SPOT® AB ID failed to detect Luminex® -defined antibodies with median fluorescence intensity (MFI) ranging from 1114 to 24,489. The HISTO SPOT® AB ID panel used in the study had reduced antigen representation compared with Luminex® -based assays which further compromised its capacity for antibody detection and definition. Further work is needed to evaluate the clinical relevance of these differences between the performance of HISTO SPOT® and Luminex® -based methods.

Association of obstructive sleep apnea and total sleep time with health-related quality of life in children undergoing a routine polysomnography: a PROMIS approach.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) negatively impacts health-related quality of life (HR-QoL) in adults, but few pediatric studies have explored this relationship or the relationships between HR-QoL domains. METHODS: Patients aged 8-17 years visiting the sleep laboratory from July 2019 to January 2020 for overnight polysomnography participated in the study. Controls seen for problems other than sleep disturbance were recruited from Department of Pediatrics outpatient clinics. HR-QoL was assessed by Patient-Reported Outcome Measure Information System (PROMIS) profile questionnaires, version 2.0. Statistical analysis was conducted using R 3.6.0 (R Foundation for Statistical Computing, Vienna, Austria). RESULTS: One hundred twenty-two patients were included in the final analysis. Sixty-four patients were males (52.4%). Twenty-nine (23.8%) had mild OSA, 8 (6.6%) had moderate OSA, 17 (13.9%) had severe OSA, 46 (37.7%) were without OSA, and 22 (18.0%) were controls. Patients referred for polysomnography had lower physical function mobility compared with controls (P = .03). Increased OSA severity was linearly associated with a decrease in physical function mobility (P = .008). Correlation analysis revealed that physical function mobility was positively associated with total sleep time (P = .02) and negatively associated with apnea-hypopnea index (P = .01). Age was positively associated with fatigue (P = .02) and negatively associated with deep sleep (P < .001). Regression analysis revealed that physical function mobility was positively associated with total sleep time (P = .02) and negatively associated with apnea-hypopnea index (P = .04) after controlling for age, sex, and number of arousals. CONCLUSIONS: OSA and total sleep time were associated with problems with physical function mobility after adjusting for age, sex, and number of arousals. CITATION: Xu S, Turakhia S, Miller M, et al. Association of obstructive sleep apnea and total sleep time with health-related quality of life in children undergoing a routine polysomnography: a PROMIS approach. J Clin Sleep Med. 2022;18(3):801-808.

Sleep and Limb Movement Characteristics of Children With Atopic Dermatitis Coincidentally Undergoing Clinical Polysomnography.

STUDY OBJECTIVES: Atopic dermatitis (AD) is a prevalent, chronic, itchy skin condition. Children undergoing polysomnography (PSG) may coincidentally have AD. Many children with AD have sleep disturbances. Our study aimed to characterize limb movements in children with AD and their effect on sleep. METHODS: A retrospective chart review was conducted for children who underwent comprehensive attended PSG and had AD. PSG sleep parameters were compared to published normative data. A subset of patients with markedly elevated total limb movements was further compared to a matched group of patients with a diagnosis of periodic limb movement disorder (PLMD) and no history of AD. RESULTS: There were 34 children with AD 6.36 ± 3.21 years (mean ± standard deviation), 50% female and with mild to moderate AD. There was increased wake after sleep onset (WASO = 46.0 ± 37.8 minutes), sleep onset latency (46.5 ± 53.0 minutes) and total limb movement index (13.9 ± 7.5 events/h) compared to normative values. Although our cohort was mostly mild AD, 7 of the 34 children with AD (20%) had a total limb movement index during sleep > 15 events/h. Increased total limb movements in PLMD versus patients with AD was most notable during stage N2 sleep (38 ± 17 versus 22 ± 7, P = .01, respectively). CONCLUSIONS: We found altered PSG parameters in children with AD, suggesting that clinicians should consider the diagnosis when affected children undergo PSG. Although our AD cohort was mild, we still determined a need to consider AD when diagnosing PLMD given the presence of elevated total limb movements in children with AD. CITATION: Treister AD, Stefek H, Grimaldi D, Rupani N, Zee P, Yob J, Sheldon S, Fishbein AB. Sleep and limb movement characteristics of children with atopic dermatitis coincidentally undergoing clinical polysomnography. J Clin Sleep Med. 2019;15(8):1107-1113.

Cervical spinal cord compression in infants with achondroplasia: should neuroimaging be routine?

PURPOSE: To examine results of magnetic resonance imaging (MRI), polysomnograms (PSG), and patient outcomes in patients with achondroplasia in light of recent screening recommendations for infants with achondroplasia. METHODS: We reviewed medical records of 49 patients with achondroplasia followed at our institution between September 1997 and January 2017, including physical exams, MRIs, PSGs (when available), and surgical histories. Appropriate PSG data were available for 39 of these patients. RESULTS: Twenty-seven of 49 patients had cervical cord compression on MRI, and 20 of those patients required surgery. Central apnea was detected in 2/23 patients with cervical cord compression in whom PSG data was available. Physical exam revealed depressed deep-tendon reflexes in two patients with cord compression and one patient without cord compression. Besides hypotonia in some, the neurological exams of these patients were unremarkable. CONCLUSIONS: Cervical cord compression is a common occurrence in infants with achondroplasia and necessitates surgical intervention in some patients. Physical exam and PSG are poor predictors of the presence of cord compression or the need for surgery. All infants with achondroplasia should have MRIs of the craniocervical junction in the first 6 months of life.

Sleep disturbance in children with moderate/severe atopic dermatitis: A case-control study.

BACKGROUND: Sleep is disturbed in 60% of children with atopic dermatitis (AD). OBJECTIVE: To characterize sleep in a cohort of children with moderate-to-severe AD and determine methods for assessment of sleep disturbance. METHODS: A case-control study compared children age 6 to 17 years who have moderate-to-severe AD with age- and sex-matched healthy controls. Participants wore actigraphy watches and completed sleep- and disease-specific questionnaires. RESULTS: Nineteen patients with AD and 19 controls completed the study. The patients with AD experienced wake after sleep onset (WASO) for 103 plus or minus 55 minutes as compared with 50 plus or minus 27 minutes in the controls (P < .01). They had a higher frequency of restless sleep, daytime sleepiness, difficulty falling back to sleep at night, and teacher-reported daytime sleepiness. Disease severity correlated well with WASO (total SCORing Atopic Dermatitis score: r = 0.61, P < .01; objective SCORing Atopic Dermatitis score: r = 0.58, P = .01; and Eczema Area and Severity Index: r = 0.68, P < .01). The Children's Dermatology Life Quality Index sleep question correlated with WASO (r = 0.52, P = .03), but self-reported itch severity did not (r = 0.28, P = .30). LIMITATIONS: The study cohort was small. CONCLUSION: Children with moderate-to-severe AD experience more WASO and lower sleep efficiency than healthy controls but similar bedtime and wake time, sleep duration, and sleep onset latency.

Validation of Polyvinylidene Fluoride Impedance Sensor for Respiratory Event Classification during Polysomnography in Children.

STUDY OBJECTIVES: Polysomnography is the gold standard for diagnosis and characterization of severity of sleep-disordered breathing. Accuracy and reliability of the technology used are critical to the integrity of the study's interpretation. Strict criteria for obstructive sleep apnea in children are lacking and diagnosis often requires consideration of frequency of respiratory events in addition to other measures. Current American Academy of Sleep Medicine recommendations for pediatric patients includes use of respiratory inductance plethysmography (RIP) belts, whereas polyvinylidene fluoride (PVDF) belts are currently only acceptable for use in adults. We hypothesized that PVDF belts would be equally effective as RIP belts for detection of respiratory effort and events in children. METHODS: Children ages 2-17 y were recruited from a large pediatric tertiary referral center after obtaining consent for participation. Fifty subjects were recruited (average age, 7.8 y). Clinically relevant limits of agreement were predetermined to be a difference in total count of obstructive or central apneas or hypopneas of ± 5 events. RESULTS: Scoring of respiratory events was not significantly different by belt type based on Bland-Altman plots of total apnea-hypopnea index and obstructive apneas. Obstructive hypopneas scoring ranged beyond our clinical limit of agreement. Findings in obese subjects were consistent with the larger sample with the exception of an increase in outliers. Artifact amount was comparable (RIP 10.9% ± 22.5% and PVDF 10.5% ± 19.5%). CONCLUSIONS: Based on these findings, PVDF belts appear to be as effective as RIP belts in detection of respiratory effort and events in children. COMMENTARY: A commentary on this article appears in this issue on page 159.

Nocturnal eczema: Review of sleep and circadian rhythms in children with atopic dermatitis and future research directions.

Children with atopic dermatitis (AD) experience significant sleep disruption, and clinically, the disease is noted to worsen in a circadian manner at night. Epidemiologic findings highlight many negative consequences of AD, such as impaired linear growth, which is uniquely related to disturbed sleep. Clinical guidelines currently recommend assessing sleep in patients with AD as a crucial parameter of disease control with appropriate treatment. In this review we describe our current understanding of the roles of sleep cycles and circadian rhythms in the nighttime exacerbation of AD (nocturnal eczema). We present a schematic to explain the mechanism of nocturnal eczema. Treatment options for sleep disturbance and future directions for research are discussed in the context of AD.

Mallampati score and pediatric obstructive sleep apnea.

RATIONALE: Pediatric obstructive sleep apnea (OSA) is common, and a delay in diagnosis can lead to significant morbidity. Polysomnography (PSG) is the gold standard for the diagnosis of OSA. However, difficulty accessing PSG due to the relative shortage of sleep centers with pediatric expertise can lead to a delay in the diagnosis and management of OSA. OBJECTIVES: To assess the utility of Mallampati score (sitting and supine) in predicting the presence and severity of OSA in children. METHODS: A retrospective study of 158 children from a single pediatric sleep center. All patients had a PSG and a physical examination documenting Mallampati score. The Mallampati score, tonsillar size, age, sex, and apnea hypopnea index (AHI) were analyzed. Odds ratio of having pediatric OSA (AHI > 1) with increase in Mallampati score and tonsillar size were calculated. MEASUREMENTS AND MAIN RESULTS: A significant correlation was found between Mallampati score, tonsillar size, and AHI. For every point increase in the Mallampati score, the odds ratio of having OSA increased by more than 6-fold. For every point increase in tonsillar size, the odds ratio of having OSA increased by more than 2-fold. CONCLUSIONS: Mallampati score and tonsillar size are independent predictors of OSA. Oral examination including Mallampati score and tonsillar size should be considered when evaluating a patient for OSA. They can be used to prioritize children who may need PSG.

Clinical indicators that predict the presence of moderate to severe obstructive sleep apnea after adenotonsillectomy in children.

OBJECTIVE: To determine if clinical indicators can predict the presence of moderate to severe Obstructive Sleep Apnea (OSA) after Adenotonsillectomy (T&A) in children. STUDY DESIGN: Retrospective study. SETTING: Urban Tertiary Care Pediatric Hospital. METHODS: Parents of children (<18 yrs.) with OSA completed a 55-item questionnaire based on their child's symptoms at the time of preoperative polysomnography and then again at the follow up polysomnography completed 3 to 6 months after T&A. MAIN OUTCOME MEASURES: 55 item questionnaire, polysomnography variables. RESULTS: 97 children were included (59 Male and 38 Female). The mean preoperative apnea hypopnea index (AHI) was 30.5±31.6/h and the mean postoperative AHI was 4.4±6.0/h. After T&A, all 97 children had reduction in AHI, and 35 (36.1%) no longer had OSA (AHI<1/h). The total symptom scores decreased from 15.8±9.4 to 11.3±8.7 after T&A (p<.0001). Fourteen symptoms highly predictive of moderate to severe OSA were identified in the univariate analysis (p<0.1). Using a cut-point of 4, this 14-item subscale illustrated an overall predictability of 72.2% (73.7% sensitivity and 70.0% specificity) for identifying children with moderate to severe OSA. CONCLUSION: A cluster of 14 clinical sleep symptoms are highly predictive of moderate to severe OSA and can serve as clinical predictor for the presence of moderate to severe OSA after T&A.

Metabolic alterations in children with obstructive sleep apnea.

IMPORTANCE: The incidence of obesity is rising in the United States and has been linked to Obstructive Sleep Apnea (OSA) even in young children. Understanding the role that obesity and OSA play in alterations in metabolic variables that can lead to serious health issues is essential to the care and counseling of affected children. OBJECTIVES: To evaluate the association of alterations in metabolic variables, including insulin resistance, to OSA in young, obese children. DESIGN: Retrospective, case-control series. SETTING: Tertiary care children's hospital. PARTICIPANTS: Obese children aged 2-12 years who had undergone overnight polysomography and routine laboratory testing for lipid levels, fasting glucose, and insulin from January 1, 2006 to December 31, 2012 were identified from a TransMed Bio-Integration Suite and Epic's clarity database search. RESULTS: A total of 76 patients were included for analysis. Forty-three (56.6%) were male, and the mean age was 8.3±2.5 years (range, 2.4-11.9 years). The mean body mass index (BMI) z score was 2.8±0.75 (range, 1.7-6.3), and all patients were obese (BMI z score>95th percentile). Twenty two patients (28.9%) had an apnea-hypopnea index (AHI) <1/h (no OSA), 27 (35.5%) an AHI≥1<5/h, 12 (15.8%) had an AHI ≥5<9.99/h, and 15 (19.7%) had an AHI≥10/h. There was no significant difference in total cholesterol, triglycerides, high and low density lipoprotein levels, systolic and diastolic blood pressure in those patients with or without OSA. Fasting insulin, blood glucose, and homeostasis model assessment (HOMA) were significantly higher in patients with OSA compared to those with no OSA (p<0.01). AHI correlated to alterations in insulin as well as glucose homeostasis on multivariate analysis. Results from logistic regression analysis showed that fasting insulin (p<0.01), and HOMA (p<0.01) predicted severe OSA independent of age, gender, and BMI z score in these patients. CONCLUSION: Metabolic alterations in glucose and insulin levels, known to be associated with obesity and increased risk for cardiovascular disease, appear to relate to the severity of OSA in young children.

Just a scary dream? A brief review of sleep terrors, nightmares, and rapid eye movement sleep behavior disorder.

The clinical spectrum of sleep disorders in children is broad, ranging from primary snoring and obstructive sleep apnea (OSA) syndrome to complex sleep-related behaviors and movement disorders. Although snoring and OSA typically receive significant attention and discussion, other biologically based sleep disorders are as common, if not more common, in children. A general pediatrician is frequently presented with the complaint of sleep talking, sleep walking, or abnormal movements during sleep. Even more alarming is the presentation of the child suddenly and explosively screaming during sleep. Such complaints fall under the category of parasomnias. Exclusive to sleep and wake-to-sleep transitions, these parasomnias include arousals with abnormal motor, behavioral, autonomic, or sensory symptoms. Parasomnias can be noticeably dissimilar in clinical manifestations, but most share biologic characteristics. Three parasomnias associated with loud vocalizations associated with sleep that can present to general practitioners include sleep terrors, nightmares, and rapid eye movement sleep behavior disorder (RBD). Although usually benign, these sleep disorders can be disruptive and even potentially dangerous to the patient and can often be threatening to quality of life. In this article, we describe the clinical features of some of these disorders and how to differentiate between their alarming presentations.