[New Swedish National care process for pediatric obstructive sleep disordered breathing]. / Nytt vårdförlopp för barn med OSDB är godkänt att tas i bruk.

Obstructive sleep disordered breathing (OSDB) is a spectrum from habitual snoring and labored breathing to obstructive sleep apnea (OSA), which is common and potentially serious in children. The process contains a new question at child care centers, directed at caretakers with children at age 18 months and 3 years, concerning habitual snoring (3 times a week or more). A primary care doctor verifies the suspicion of OSDB in case of a positive answer to one of 7 additional questions or 4 status findings (e.g. tonsil hypertrophy). The process starts with the suspicion of OSDB, from the age of 18 months to 18 years, and ends when symptoms are improved after watchful waiting or upper airway surgery. National equality is a goal, with increased access to nocturnal respiratory recordings of children with comorbidities or doubtful cases. Also, with short waiting time to first visit at ORL department, and to surgery. Children with comorbidities or severe symptoms get postoperative follow-ups with a nurse after 6 months. The new ICD code for OSDB is R06.8A.

National Knowledge-Driven Management of Obstructive Sleep Apnea-The Swedish Approach.

INTRODUCTION: This paper describes the development of "Swedish Guidelines for OSA treatment" and the underlying managed care process. The Apnea Hypopnea Index (AHI) is traditionally used as a single parameter for obstructive sleep apnea (OSA) severity classification, although poorly associated with symptomatology and outcome. We instead implement a novel matrix for shared treatment decisions based on available evidence. METHODS: A national expert group including medical and dental specialists, nurses, and patient representatives developed the knowledge-driven management model. A Delphi round was performed amongst experts from all Swedish regions (N = 24). Evidence reflecting treatment effects was extracted from systematic reviews, meta-analyses, and randomized clinical trials. RESULTS: The treatment decision in the process includes a matrix with five categories from a "very weak"" to "very strong" indication to treat, and it includes factors with potential influence on outcome, including (A) OSA-related symptoms, (B) cardiometabolic comorbidities, (C) frequency of respiratory events, and (D) age. OSA-related symptoms indicate a strong incitement to treat, whereas the absence of symptoms, age above 65 years, and no or well-controlled comorbidities indicate a weak treatment indication, irrespective of AHI. CONCLUSIONS: The novel treatment matrix is based on the effects of treatments rather than the actual frequency of respiratory events during sleep. A nationwide implementation of this matrix is ongoing, and the outcome is monitored in a prospective evaluation by means of the Swedish Sleep Apnea Registry (SESAR).

Correlations between objective and subjective outcomes after adenotonsillar surgery in children with OSA.

Objectives: To investigate whether the OSA-18 questionnaire and a postoperative patient-reported outcome measure (PROM) question correlated with polysomnography (PSG) data. Methods: A prospective study of otherwise healthy young children with moderate to severe obstructive sleep apnea (OSA) to investigate if the obstructive apnea-hypopnea index (OAHI) before and 6-12 months after adenotonsil surgery correlated with the OSA-18 total symptom score (TSS) and the sleep disturbance subscale (SDS), as well as a PROM question on symptom improvement with responses on a 4-grade Likert scale. Results: Of 201 children, 173 (86%) had complete data of OAHI and OSA-18 pre- and postoperatively. The mean age was 3.2 years (SD 1.0) and the mean OAHI was 15.9 (11.3). Significant correlations between changes in the OAHI and OSA-18 were found, both TSS (r = 0.29, p < .001) and SDS (r = 0.53, p < .001). A total of 136 (68%) patients responded to the PROM question, the majority of whose symptoms had disappeared (n = 102) or almost disappeared (n = 30). Four patients had unchanged symptoms, and none had worsening symptoms. A correlation was found between the PROM question and a change in the OAHI (r = 0.36, p < .001), as well as a change in the OSA-18 TSS (r = 0.24, p = .006) and the SDS (r = 0.34, p < .001). The specificity of the PROM question for prediction of a postoperative OAHI < 2 was 82%, and the sensitivity was 38%. Conclusion: Changes in the OAHI significantly correlated with changes in the OSA-18, especially with the sleep disturbance scale, which could be an alternative for evaluation at follow-ups. Level of Evidence: 3.

Effectiveness of Tonsillectomy vs Modified Uvulopalatopharyngoplasty in Patients With Tonsillar Hypertrophy and Obstructive Sleep Apnea: The TEAMUP Randomized Clinical Trial.

Importance: Modified uvulopalatopharyngoplasty (mUPPP) is a surgical treatment for selected adults with obstructive sleep apnea (OSA). Tonsillectomy (TE) alone is a less extensive alternative treatment. Objective: To investigate whether mUPPP is more effective than TE alone in treating adult patients with tonsillar hypertrophy and moderate to severe OSA. Design, Setting, and Participants: This blinded randomized clinical trial compared the effectiveness of mUPPP with TE alone before surgery and 6 months postsurgery in adults with tonsillar hypertrophy (sizes 2, 3, or 4 according to the Friedman staging) and moderate to severe OSA in a university hospital in Stockholm, Sweden. Participants underwent surgery from January 2016 to February 2021; the last postsurgery follow-up was completed in September 2021. Data analyses were performed from January to September 2022. Interventions: mUPPP vs TE alone. Main Outcomes and Measures: Between-group differences on the apnea-hypopnea index (AHI) and Epworth sleepiness scale (ESS). Results: The study cohort comprised 93 patients (mean [SD] age, 41.6 [9.4] years; 80 [86%] men; race/ethnicity were not considered) with a mean (SD) body mass index of 29.0 (2.8), calculated as weight in kg divided by height in m2. Of these, 90 participants (97%) completed the protocol (mUPPP, n = 45; TE, n = 45). The mean (SD) AHI score (number of events per hour [events/h]) for the mUPPP group decreased by 43%, from 51.0 (22.6) to 28.0 (20.0) events/h; and for the TE group, 56%, from 56.9 (25.1) to 24.7 (22.6) events/h. The mean between-group difference in AHI score was 9.2 events/h (95% CI, 0.5 to 17.9), with a small effect size (Cohen d = 0.44) in favor of TE. For ESS scores, the between-group difference was also small, only 1.1 (95% CI, -1.3 to 3.4; Cohen d = 0.21). Neither difference was considered to be clinically relevant. Conclusions and Relevance: This randomized clinical trial demonstrated that mUPPP was not more effective than TE alone in treating patients with tonsillar hypertrophy and moderate to severe OSA. However, there was a small difference in favor of TE. Because TE alone is less extensive, it could be considered as an alternative to mUPPP in this selected group of patients with OSA. Trial Registration: ClinicalTrials.gov Identifier: NCT02523248.

Adenotonsillotomy versus adenotonsillectomy in pediatric obstructive sleep apnea: A 5-year RCT.

Objectives: Adenotonsillectomy (ATE) is a common treatment for pediatric obstructive sleep apnea (OSA). Intracapsular adenotonsillotomy (ATT) is associated with less postoperative morbidity. Our previous randomized controlled trial (RCT) compared ATE and ATT in otherwise healthy children with moderate to severe OSA. No differences in polysomnographic (PSG) and OSA-18 were found between the groups at one-year follow-up. This study presents the long-term results of the RCT. Methods: Non-obese children (n = 79, 2-6 years) who had undergone either ATE (n = 40) or ATT (n = 39) were offered PSG and OSA-18 questionnaire five-years after surgery. Primary outcome was the group difference in postoperative Obstructive Apnea/Hypopnea Index (OAHI). ATE was recommended to the ATT group if they had a relapse of OSA. Results: The follow-up was completed by 45 of 79 (57%) children; 28 (35%) drop-outs, and six of 39(15%) in the ATT group were excluded after ATE. After ATE(n = 17), OAHI decreased from mean 12.3(SD 8.0) to 0.6(0.7), and after ATT(n = 28) from 12.6(7.4) to 0.5(0.6), a mean difference in postoperative OAHI of 0.1(95% CI -0.3 - 0.5). Sensitivity analyses did not change the results. The median OSA-18 decreased in the ATE group from 57(interquartile range 47-79) to 27(22-36), and in the ATT group from 67(53-79) to 32(25-44), without group differences for postoperative values. Conclusion: The results of this five-year follow-up of otherwise healthy OSA-children showed a high drop-out rate, but indicates that ATT could be an effective treatment for pediatric OSA. However, ATT warrants follow-up due to the risk of recurrence, and further studies are needed.

CD45RA+CD62L- ILCs in human tissues represent a quiescent local reservoir for the generation of differentiated ILCs.

Innate lymphoid cells (ILCs) are highly plastic and predominantly mucosal tissue-resident cells that contribute to both homeostasis and inflammation depending on the microenvironment. The discovery of naïve-like ILCs suggests an ILC differentiation process that is akin to naïve T cell differentiation. Delineating the mechanisms that underlie ILC differentiation in tissues is crucial for understanding ILC biology in health and disease. Here, we showed that tonsillar ILCs expressing CD45RA lacked proliferative activity, indicative of cellular quiescence. CD62L distinguished two subsets of CD45RA+ ILCs. CD45RA+CD62L+ ILCs (CD62L+ ILCs) resembled circulating naïve ILCs because they lacked the transcriptional, metabolic, epigenetic, and cytokine production signatures of differentiated ILCs. CD45RA+CD62L- ILCs (CD62L- ILCs) were epigenetically similar to CD62L+ ILCs but showed a transcriptional, metabolic, and cytokine production signature that was more akin to differentiated ILCs. CD62L+ and CD62L- ILCs contained uni- and multipotent precursors of ILC1s/NK cells and ILC3s. Differentiation of CD62L+ and CD62L- ILCs led to metabolic reprogramming including up-regulation of genes associated with glycolysis, which was needed for their effector functions after differentiation. CD62L- ILCs with preferential differentiation capacity toward IL-22-producing ILC3s accumulated in the inflamed mucosa of patients with inflammatory bowel disease. These data suggested distinct differentiation potential of CD62L+ and CD62L- ILCs between tissue microenvironments and identified that manipulation of these cells is a possible approach to restore tissue-immune homeostasis.

The Tonsil Lymphocyte Landscape in Pediatric Tonsil Hyperplasia and Obstructive Sleep Apnea.

Tonsil hyperplasia is the most common cause of pediatric obstructive sleep apnea (OSA). Despite the growing knowledge in tissue immunology of tonsils, the immunopathology driving tonsil hyperplasia and OSA remains unknown. Here we used multi-parametric flow cytometry to analyze the composition and phenotype of tonsillar innate lymphoid cells (ILCs), T cells, and B cells from pediatric patients with OSA, who had previous polysomnography. Unbiased clustering analysis was used to delineate and compare lymphocyte heterogeneity between two patient groups: children with small tonsils and moderate OSA (n = 6) or large tonsils and very severe OSA (n = 13). We detected disturbed ILC and B cell proportions in patients with large tonsils, characterized by an increase in the frequency of naïve CD27-CD21hi B cells and a relative reduction of ILCs. The enrichment of naïve B cells was not commensurate with elevated Ki67 expression, suggesting defective differentiation and/or migration rather than cellular proliferation to be the causative mechanism. Finally, yet importantly, we provide the flow cytometry data to be used as a resource for additional translational studies aimed at investigating the immunological mechanisms of pediatric tonsil hyperplasia and OSA.

Identification of resident memory CD8+ T cells with functional specificity for SARS-CoV-2 in unexposed oropharyngeal lymphoid tissue.

Cross-reactive CD4+ T cells that recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more commonly detected in the peripheral blood of unexposed individuals compared with SARS-CoV-2­reactive CD8+ T cells. However, large numbers of memory CD8+ T cells reside in tissues, feasibly harboring localized SARS-CoV-2­specific immune responses. To test this idea, we performed a comprehensive functional and phenotypic analysis of virus-specific T cells in tonsils, a major lymphoid tissue site in the upper respiratory tract, and matched peripheral blood samples obtained from children and adults before the emergence of COVID-19 (coronavirus disease 2019). We found that SARS-CoV-2­specific memory CD4+ T cells could be found at similar frequencies in the tonsils and peripheral blood in unexposed individuals, whereas functional SARS-CoV-2­specific memory CD8+ T cells were almost only detectable in the tonsils. Tonsillar SARS-CoV-2­specific memory CD8+ T cells displayed a follicular homing and tissue-resident memory phenotype, similar to tonsillar Epstein-Barr virus­specific memory CD8+ T cells, but were functionally less potent than other virus-specific memory CD8+ T cell responses. The presence of preexisting tissue-resident memory CD8+ T cells in unexposed individuals could potentially enable rapid sentinel immune responses against SARS-CoV-2.

Eight-Year Follow-up of Modified Uvulopalatopharyngoplasty in Patients With Obstructive Sleep Apnea.

OBJECTIVE: To investigate whether modified uvulopalatopharyngoplasty (UPPP) for treatment of obstructive sleep apnea (OSA) remained effective after 8 years. METHODS: Prospective intervention study. Sixty-five patients with OSA were offered re-evaluation with polysomnography and the Epworth Sleepiness Scale (ESS) 8 years after UPPP. Results were compared with baseline and with a previous 2-year follow-up. Baseline predictors were analyzed with regression analyses. RESULTS: The dropout rate at the 8-year follow-up was 28%. The mean decrease in apnea-hypopnea index (AHI) between baseline and the 8-year follow-up was significant, 14.0 events/hour (from 52.9 to 38.9), 27% (P < .001). The mean increase in AHI between the 2-year and the 8-year follow-up was significant, 14.7 events/hour (from 24.2 to 38.9), 61% (P < .0001). Overweight at baseline predicted an AHI at the 8-year follow-up that was 22.9 events higher compared to patients with normal weight (P = .015). An increase in body mass index (BMI) of 1 kg/m2 between baseline and the 8-year follow-up predicted a mean AHI increase of 3.8 events/hour (P = .015). The median decrease in ESS between baseline and the 8-year follow-up was significant, 7 (from 13.0 to 6.0), 54% (P < .0001). The median increase in ESS between the 2-year and the 8-year follow-up was not significant, 1.0 (from 5.0 to 6.0), 20%. CONCLUSION: Modified UPPP was effective as a long-term treatment for OSA in selected patients, although the effect on AHI decreased over time. Daytime sleepiness remained improved even in the long term. High BMI at baseline and an increase in BMI predicted a reduced long-term respiratory outcome. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E307-E313, 2021.

Effectiveness of Adenotonsillectomy vs Watchful Waiting in Young Children With Mild to Moderate Obstructive Sleep Apnea: A Randomized Clinical Trial.

Importance: Adenotonsillectomy (ATE) is one of the most common surgical procedures to treat children with obstructive sleep apnea (OSA), but to our knowledge there are no randomized clinical trials confirming the benefit of surgery compared with watchful waiting in children between 2 and 4 years of age. Objective: To determine whether ATE is more effective than watchful waiting for treating otherwise healthy children with mild to moderate OSA. Design, Setting, and Participants: This randomized clinical trial was conducted from December 2014 to December 2017 at the Otorhinolaryngology Department of the Karolinska University Hospital, Stockholm, Sweden. A total of 60 children, 2 to 4 years of age, with an obstructive apnea-hypopnea index (OAHI) score of 2 or greater and less than 10, were randomized to ATE (n = 29) or watchful waiting (n = 31). A total of 53 participants (88%; ATE, n = 25; watchful waiting, n = 28) completed the study. Data were analyzed from August 2018 to December 2018. Interventions: Adenotonsillectomy. Main Outcomes and Measures: The primary outcome was the difference between the groups in mean OAHI score change. Secondary outcomes were other polysomnography parameters, score on the Obstructive Sleep Apnea-18 (OSA-18) questionnaire, and subgroup analyses. Polysomnography and the OSA-18 questionnaire were completed at baseline and after 6 months. Results: Of the 60 included children, 34 (57%) were boys and the mean (SD) age at first polysomnography was 38 (9) months. Both groups had a decrease in mean OAHI score, and the difference in mean OAHI score change between the groups was small (-1.0; 95% CI, -2.4 to 0.5), in favor of ATE. However, there were large differences between the groups in favor of ATE regarding the OSA-18 questionnaire (eg, total OSA-18 score: -17; 95% CI, -24 to -10). Also, a subgroup analysis of 24 children with moderate OSA (OAHI ≥5 and <10) showed a meaningful difference in mean OAHI score change between the groups in favor of ATE (-3.1; 95% CI, -5.7 to -0.5). Of 28 children, 10 (36%) in the watchful waiting group received ATE after the follow-up, and 7 of these had moderate OSA at baseline. Conclusions and Relevance: This randomized clinical trial found only small differences between the groups regarding changes in OAHI, but further studies are needed. However, there were large improvements in quality of life after ATE. These results suggest that otherwise healthy children with mild OSA and mild effect on quality of life may benefit from watchful waiting, while children with moderate OSA should be considered for ATE. Trial Registration: ClinicalTrials.gov Identifier: NCT02315911.

Postoperative morbidity after adenotonsillectomy versus adenopharyngoplasty in young children with obstructive sleep apnea: an RCT.

PURPOSE: In our previous randomized controlled trial (RCT), comparing adenotonsillectomy (ATE) with adenopharyngoplasty (APP) in children with severe obstructive sleep apnea (OSA), there were no differences in respiratory sleep parameters or quality of life. The purpose of the present report was to evaluate postoperative morbidity from this RCT. METHODS: The study was a blinded RCT in 83 children (ATE = 47; APP = 36), 2-4 years of age, with an obstructive apnea-hypopnea index of ≥ 10. Pain was assessed from the first until the tenth day after surgery with a logbook that reported pain by child (FPS-R, Faces Pain Scale-Revised) and caregiver (visual analogue scale), analgesic use, return to normal diet, and weight change. Bleeding, infection, satisfaction with treatment, speech, and swallowing were assessed with a questionnaire and medical records 6 months after surgery. RESULTS: Sixty-four children (77%) returned the logbook and 65 (78%) answered the questionnaire. The median (interquartile range) day the children graded themselves as pain free (FPS-R = 0) was 7 (6-10) after ATE, compared with 9 (7 to > 10) after APP (p = 0.018). There were no other significant differences between the groups regarding any other pain-related outcomes, bleeding, infection, satisfaction, swallowing, or speech, but three children (11%) reported impaired speech after APP compared to none after ATE (p = 0.067). CONCLUSION: The results regarding postoperative morbidity were in favor of ATE and the results from our previous report showed no advantages of APP. Therefore, APP should not be recommended in young, otherwise healthy children with OSA.

Emotional Awareness Correlated With Number of Awakenings From Polysomnography in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-A Pilot Study.

INTRODUCTION: Unrefreshing sleep is one of the diagnostic criteria in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which could be explained by sleep disorders, for example obstructive sleep apnea, reported in our previous study with polysomnography. Our previous findings also indicate difficulties in emotional regulation when measuring alexithymia by TAS-20 (Toronto Alexithymia Scale) and level of emotional awareness by LEAS (Level of Emotional Awareness Scale) in ME/CFS patients. However, the reasons for this are unknown. The purpose of this study was to investigate correlations between data from subjective emotional regulation and polysomnography. METHODS: Twenty-three ME/CFS patients (5 men and 18 women) of mean age 43, and 30 matched healthy controls (9 males and 21 women) of mean age 45, filled in TAS-20, LEAS, and Hospital Depression and Anxiety Scale (HADS). A polysomnography was performed on patients but not on healthy controls. Thus, values of normal population were used for sleep evaluation in ME/CFS patients. RESULT: There were significant differences between patients and controls in several aspects of emotional regulation, for example LEAS-self and LEAS-total. Seventy percent of the patients had increased numbers of awakenings (shifts from any sleep stage to awake), 22% had obstructive sleep apneas, and 27% had periodic limb movements. Correlation analysis showed that number of awakenings significantly correlated with LEAS-self and LEAS-total, p < 0.01, respectively. There were no other significant correlations. CONCLUSION: This pilot study demonstrated significant correlations between reduced emotional awareness and number of awakenings in polysomnography. Future studies with larger cohorts need to be conducted.

Randomised trial showed no difference in behavioural symptoms between surgical methods treating paediatric obstructive sleep apnoea.

AIM: Our previous randomised controlled trial of children with obstructive sleep apnoea (OSA) showed no significant differences between adenotonsillectomy (ATE) and adenotonsillotomy (ATT) in improving nocturnal respiration and quality of life after 1 year. The aim of this report was to evaluate the effects on behavioural symptoms using the Strengths and Difficulties Questionnaire (SDQ). METHODS: Children between 2 and 6 years with OSA were randomised to ATT or ATE. Parents, blinded to method, answered the SDQ while their child underwent polysomnography before and 1 year after surgery. Differences between the total SDQ scores were analysed between the treatment groups. RESULTS: The SDQ was filled out in 87% of the cases preoperatively, and in 86% postoperatively. At follow-up, the mean total SDQ score was 9.6 SD ± 5.1 in the ATE group (n = 31), and 8.2 ± 6.7 in the ATT group (n = 37), P = .09. The mean total SDQ score for all was preoperatively 10.6 ± 5.0, and postoperatively 8.8 ± 6.0, P = .0002. CONCLUSION: There were no significant differences in SDQ scores between the groups at follow-up, indicating that the more conservative ATT is a treatment option in paediatric OSA. The whole group of patients showed a significant improvement after surgery.

Long-term evaluation of satisfaction and side effects after modified uvulopalatopharyngoplasty.

OBJECTIVES/HYPOTHESIS: We have previously shown that modified uvulopalatopharyngoplasty (UPPP) is effective to treat obstructive sleep apnea (OSA) and that the effect is stable after 24 months. This continuous report includes questionnaires and phone interviews. STUDY DESIGN: Prospective intervention study. METHODS: Sixty-five patients with apnea-hypopnea index (AHI) score ≥ 15, body mass index <36 kg/m2 , and Epworth Sleepiness Scale (ESS) score ≥ 8 underwent modified UPPP after failing nonsurgical treatment. The results from a patient questionnaire at 6 and 24 months after surgery were correlated with age, body mass index, and ESS and AHI scores. Patients reporting side effects and/or regretting the surgery after 24 months were selected for phone interviews 9 years after surgery. RESULTS: The response rate was 80% and 74% at the 6- and 24-month follow-ups, respectively. Of those who responded to the questionnaire, 96% and 83% were satisfied after 6 and 24 months, respectively; 98% and 92% recommended the surgery. Side effects (globus, mucus, and voice and swallowing disorders) occurred in 38% and 31%, respectively. Dissatisfaction correlated significantly with high postoperative AHI and ESS scores, but not with occurrence of side effects. Younger subjects had a higher rate of recommendation and lower rate of side effects than did older subjects. Phone interviews after 9 years were responded to by 14 of 16 selected patients, and the responders reported minor or no side effects. CONCLUSIONS: The vast majority of the OSA patients were satisfied 24 months after surgery, even though a third of them were experiencing side effects. Younger patients had fewer side effects than did older patients. Patients with better OSA outcomes were also more satisfied. After 9 years the side effects were no longer problematic. LEVEL OF EVIDENCE: 2b Laryngoscope, 130:263-268, 2020.

29-Color Flow Cytometry: Unraveling Human Liver NK Cell Repertoire Diversity.

Recent studies have demonstrated extraordinary diversity in peripheral blood human natural killer (NK) cells and have suggested environmental control of receptor expression patterns on distinct subsets of NK cells. However, tissue localization may influence NK cell differentiation to an even higher extent and less is known about the receptor repertoire of human tissue-resident NK cells. Advances in single-cell technologies have allowed higher resolution studies of these cells. Here, the power of high-dimensional flow cytometry was harnessed to unravel the complexity of NK cell repertoire diversity in liver since recent studies had indicated high heterogeneity within liver NK cells. A 29-color flow cytometry panel allowing simultaneous measurement of surface tissue-residency markers, activating and inhibitory receptors, differentiation markers, chemokine receptors, and transcription factors was established. This panel was applied to lymphocytes across three tissues (liver, peripheral blood, and tonsil) with different distribution of distinct NK cell subsets. Dimensionality reduction of this data ordered events according to their lineage, rather than tissue of origin. Notably, narrowing the scope of the analysis to the NK cell lineage in liver and peripheral blood separated subsets according to tissue, enabling phenotypic characterization of NK cell subpopulations in individual tissues. Such dimensionality reduction, coupled with a clustering algorithm, identified CD49e as the preferred marker for future studies of liver-resident NK cell subsets. We present a robust approach for diversity profiling of tissue-resident NK cells that can be applied in various homeostatic and pathological conditions such as reproduction, infection, and cancer.

Systemic and Intra-Nodal Activation of NK Cells After Rituximab Monotherapy for Follicular Lymphoma.

Monotherapy with the anti-CD20 monoclonal antibody rituximab can induce complete responses (CR) in patients with follicular lymphoma (FL). Resting FcRγIII+ (CD16+) natural killer (NK) cells respond strongly to rituximab-coated target cells in vitro. Yet, the contribution of NK cells in the therapeutic effect in vivo remains unknown. Here, we followed the NK cell repertoire dynamics in the lymph node and systemically during rituximab monotherapy in patients with FL. At baseline, NK cells in the tumor lymph node had a naïve phenotype albeit they were more differentiated than NK cells derived from control tonsils as determined by the frequency of CD56dim NK cells and the expression of killer cell immunoglobulin-like receptors (KIR), CD57 and CD16. Rituximab therapy induced a rapid drop in NK cell numbers coinciding with a relative increase in the frequency of Ki67+ NK cells both in the lymph node and peripheral blood. The Ki67+ NK cells had slightly increased expression of CD16, CD57 and higher levels of granzyme A and perforin. The in vivo activation of NK cells was paralleled by a temporary loss of in vitro functionality, primarily manifested as decreased IFNγ production in response to rituximab-coated targets. However, patients with pre-existing NKG2C+ adaptive NK cell subsets showed less Ki67 upregulation and were refractory to the loss of functionality. These data reveal variable imprints of rituximab monotherapy on the NK cell repertoire, which may depend on pre-existing repertoire diversity.

Postoperative pain and bleeding after adenotonsillectomy versus adenotonsillotomy in pediatric obstructive sleep apnea: an RCT.

PURPOSE: Our previous randomized controlled trial (RCT) of children with obstructive sleep apnea (OSA) showed no significant differences between adenotonsillectomy (ATE) and adenotonsillomy (ATE) in improving nocturnal respiration and symptoms after one year. This is the continuous report with the evaluation of postoperative morbidity concerning bleeding and pain. METHODS: A double-blinded RCT including 79 children, aged 2-6 years, with moderate to severe OSA, randomized to either ATE (n = 40) or ATT (n = 39). From one to ten days postoperatively, parents filled in a logbook with six pain-related outcomes (parent and child grading pain at different levels, days of analgesic use and return to normal diet). Peri- and postoperative bleeding were also registered. RESULTS: 63 patients (80%) returned the logbook. There were significant differences between groups in only two of the six pain-related outcomes in favor of the ATT group; first day when the children graded themselves as pain free (p = 0.021, Log Rank Test), and first day the caregiver estimated pain VAS ≤ 5 (p = 0.007, Log Rank Test). Two (5%) cases of postoperative bleeding occurred in the ATE group, one of which needed a return to theatre. No case of postoperative bleeding was seen in the ATT group. CONCLUSIONS: The results from this RCT are in line with previous comparative studies between ATT and ATE. Children operated with ATT had significantly less postoperative pain in one-third of the outcomes, and less bleeding than ATE. However, as the differences in morbidity between the surgical methods were minor the clinical significance is uncertain. TRIAL REGISTRATION: This study was approved by the Swedish Regional Ethics Board in Stockholm, Sweden (Dnr 2011/925-32 and 2013/2274-32) and registered at ClinicalTrials.gov (Trial registration number NCT01676181).

Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3-ILC1/NK cell transdifferentiation.

The Ikaros family of transcription factors (TFs) are important regulators of lymphocyte function. However, their roles in human innate lymphoid cell (ILC) function remain unclear. Here, we found that Ikaros (IKZF1) is expressed by all ILC subsets, including NK cells, in blood, tonsil, and gut, while Helios (IKZF2) is preferentially expressed by ILC3 in tonsil and gut. Aiolos (IKZF3) followed the expression pattern of T-bet and Eomes, being predominantly expressed by ILC1 and NK cells. Differentiation of IFN-γ-producing ILC1 and NK cells from ILC3 by IL-1ß plus IL-12-stimulation was associated with upregulation of T-bet and Aiolos. Selective degradation of Aiolos and Ikaros by lenalidomide suppressed ILC1 and NK cell differentiation and expression of ILC1 and NK cell-related transcripts (LEF1, PRF1, GRZB, CD244, NCR3, and IRF8). In line with reduced ILC1/NK cell differentiation, we observed an increase in the expression of the ILC3-related TF Helios, as well as ILC3 transcripts (TNFSF13B, IL22, NRP1, and RORC) and in the frequency of IL-22 producing ILC3 in cultures with IL-1ß and IL-23. These data suggest that suppression of Aiolos and Ikaros expression inhibits ILC1 and NK cell differentiation while ILC3 function is maintained. Hence, our results open up for new possibilities in targeting Ikaros family TFs for modulation of type 1/3 immunity in inflammation and cancer.

Preterm birth and risk of sleep-disordered breathing from childhood into mid-adulthood.

BACKGROUND: Preterm birth (gestational age <37 weeks) has previously been associated with cardiometabolic and neuropsychiatric disorders into adulthood, but has seldom been examined in relation to sleep disorders. We conducted the first population-based study of preterm birth in relation to sleep-disordered breathing (SDB) from childhood into mid-adulthood. METHODS: A national cohort study was conducted of all 4 186 615 singleton live births in Sweden during 1973-2014, who were followed for SDB ascertained from nationwide inpatient and outpatient diagnoses through 2015 (maximum age 43 years). Cox regression was used to examine gestational age at birth in relation to SDB while adjusting for other perinatal and maternal factors, and co-sibling analyses assessed for potential confounding by unmeasured shared familial factors. RESULTS: There were 171 100 (4.1%) persons diagnosed with SDB in 86.0 million person-years of follow-up. Preterm birth was associated with increased risk of SDB from childhood into mid-adulthood, relative to full-term birth (39-41 weeks) [adjusted hazard ratio (aHR), ages 0-43 years: 1.43; 95% confidence interval (CI), 1.40, 1.46; P <0.001; ages 30-43 years: 1.40; 95% CI, 1.34, 1.47; P <0.001]. Persons born extremely preterm (<28 weeks) had more than 2-fold risks (aHR, ages 0-43 years: 2.63; 95% CI, 2.41, 2.87; P <0.001; ages 30-43 years: 2.22; 95% CI, 1.64, 3.01; P <0.001). These associations affected both males and females, but accounted for more SDB cases among males (additive interaction, P = 0.003). Co-sibling analyses suggested that these findings were only partly due to shared genetic or environmental factors in families. CONCLUSIONS: Preterm-born children and adults need long-term follow-up for anticipatory screening and potential treatment of SDB.