Danielle Friberg

Abnormal afferent nerve endings in the soft palatal mucosa of sleep apnoics and habitual snorers

Habitual snoring precedes obstructive sleep apnea (OSA), but the pathophysiological mechanisms behind progression are still unclear. The patency of upper airways depends on a reflexogen mechanism reacting on negative intrapharyngeal pressure at inspiration, probably mediated by mucosal receptors, i.e., via afferent nerve endings. Such nerves contain a specific nerve protein, protein-gene product 9.5 (PGP 9.5) and in some cases substance P (SP) and calcitonin gene-related (CGRP). Biopsies of the soft palatial mucosa were obtained from non-smoking men ten OSA patients, 11 habitual snorers and 11 non-snoring controls. The specimens were immunohistochemically analyzed for PGP 9.5, SP and CGRP. As compared to controls, an increased number of PGP-, SP- and CGRP-immunoreactive nerves were demonstrated in the mucosa in 9/10 OSA patients and 4/11 snorers, in addition to varicose nerve endings in the papillae and epithelium. Using double staining methodology, it could be shown that SP- and CGRP-like immunoreactivities (LIs) often coexisted in these fibres, as did CGRP- and PGP 9.5-LIs. The increased density in sensory nerve terminals are interpreted to indicate an afferent nerve lesion. Our results support the hypothesis of a progressive neurogenic lesion as a contributory factor to the collapse of upper airways during sleep in OSA patients.

The heterogeneity of human CD127+ innate lymphoid cells revealed by single-cell RNA sequencing

Innate lymphoid cells (ILCs) are increasingly appreciated as important participants in homeostasis and inflammation. Substantial plasticity and heterogeneity among ILC populations have been reported. Here we have delineated the heterogeneity of human ILCs through single-cell RNA sequencing of several hundreds of individual tonsil CD127+ ILCs and natural killer (NK) cells. Unbiased transcriptional clustering revealed four distinct populations, corresponding to ILC1 cells, ILC2 cells, ILC3 cells and NK cells, with their respective transcriptomes recapitulating known as well as unknown transcriptional profiles. The single-cell resolution additionally divulged three transcriptionally and functionally diverse subpopulations of ILC3 cells. Our systematic comparison of single-cell transcriptional variation within and between ILC populations provides new insight into ILC biology during homeostasis, with additional implications for dysregulation of the immune system.

Heavy Snorer's Disease: A Progressive Local Neuropathy

?Heavy snorers disease? is defined as progression from heavy snoring to obstructive sleep apnoea syndrome (OSAS). Apart from significant weight gain, the aetiology underlying progression to a collapse of the upper airways during inspiration and sleep remains unclear. Previous studies have shown that nocturnal respiratory disturbances became worse, even in some OSAS patients who did not gain weight. The patency of the upper airways depends on the balance between the negative intrapharyngeal pressure developed during inspiration and its counteraction by dilating muscles. The reflexogenic dilation is probably mediated by afferent nerve endings in the pharyngeal mucosa. Chronic vibration of a tissue may cause neuronal damage. Therefore, the hypothesis that snoring per se might cause progressive pharyngeal nerve lesion has been tested in a series of studies from the Karolinska Institute, Stockholm, which, along with other studies, will be reviewed here. In these studies it was found that a majority of patient...

Habitual Snorers and Sleep Apnoics Have Abnormal Vascular Reactions of the Soft Palatal Mucosa on Afferent Nerve Stimulation

A local disturbance in the afferent nerves involved in the reflexogenic dilation of the upper airways (UAs) could contribute to the increased collapsibility seen in patients with obstructive sleep apnea (OSA). Laser Doppler perfusion monitoring, combined with electrical stimulation, is a method for investigating the afferent nerve regulation of the microcirculation. It was used in the mucosa of the soft palate in 35 patients with various degrees of UA obstruction and in 13 control subjects, all nonsmoking men. In a majority of snorers and patients with mild OSA, stimulation induced an exaggerated vasodilation, compared with controls. In contrast, in patients with severe OSA, the vasodilation was significantly reduced, compared with controls. These signs of disturbances in the microcirculation support the hypothesis of a local progressive afferent nerve lesion in heavy snorers with or without OSA.

SKUP3 randomised controlled trial: polysomnographic results after uvulopalatopharyngoplasty in selected patients with obstructive sleep apnoea

Objective To assess the 6-month efficacy of uvulopalatopharyngoplasty (UPPP) compared with expectancy in selected patients with obstructive sleep apnoea syndrome (OSAS). Design A prospective single-centre randomised controlled trial with two parallel arms stratified by Friedman stage and body mass index (BMI). Participants 65 consecutive patients with moderate to severe OSAS (apnoea-hypopnoea index (AHI) ≥15 events/h sleep), BMI <36 kg/m2, Epworth sleepiness scale ≥8, Friedman stage I or II. Intervention Surgical treatment with UPPP. The control group underwent UPPP after a delay of 6 months. Outcomes Changes in AHI and other polysomnography parameters at baseline compared with the 6-month follow-up. Results All patients (32 in the intervention group and 33 in the control group) completed the trial. The mean (SD) AHI in the intervention group decreased significantly (p<0.001) by 60% from 53.3 (19.7) events/h to 21.1 (16.7) events/h . In the control group the mean AHI decreased by 11% from 52.6 (21.7) events/h to 46.8 (22.8) events/h, with a significant difference between the groups (p<0.001). The mean time in the supine position and the BMI were unchanged in both groups. Subgroup analyses for Friedman stage, BMI group and tonsil size all showed significant reductions in AHI in the intervention group compared with controls. There were no severe complications after surgery. Conclusions This trial demonstrates the efficacy of UPPP in treating selected patients with OSAS with a mean reduction in AHI of 60% compared with 11% in controls, a highly significant and clinically relevant difference between the groups. Trial registration number NCT01659671.

UPPP for habitual snoring: A 5‐year follow‐up with respiratory sleep recordings

Fifty‐six men who underwent uvulopalatopha‐ryngoplasty (UPPP) because of habitual snoring without preoperative obstructive sleep apnea (OSA), according to respiratory sleep recordings, were interviewed concerning persistent snoring and excessive daytime sleepiness (EDS). Renewed recordings were made in 53 of them at a median time of 63 months postoperatively. Median preoperative oxygen desaturation index (ODI) was 0; the median postoperative index was 1. Median duration of the preoperative obstructive respiratory pattern was 8% of total sleeping time, and the median duration postoperatively was 17%. (Significant individual increases were P=.0005 and P=.004, respectively.) Six patients answered to OSA criteria postoperatively. Weight increases were significantly correlated to increases in both ODI and obstructive respiratory pattern and to persistent snoring. Preoperatively 51 of 56 patients reported EDS, and 73% of the patients were improved or cured. From snoring, 87% reported improvement or cure. No patient had any serious sequelae of UPPP. Uvulopalatopharyngoplasty is a safe and effective treatment for habitual snoring, but it does not give absolute protection from development of OSA.

Questionnaire OSA-18 has poor validity compared to polysomnography in pediatric obstructive sleep apnea

OBJECTIVE To evaluate the diagnostic value of the quality-of-life instrument OSA-18 by comparing it with objective data from polysomnography in children with sleep-disordered breathing. STUDY DESIGN Cross-sectional. PATIENTS AND METHODS Full-night polysomnographic data were obtained from 225 subjects, 139 boys and 86 girls, median age 4.5 years (1-12) in our sleep laboratory. Their caregivers answered the OSA-18 quality-of-life instrument (range 18-126). The polysomnographic parameter, the apnea-hypopnea index (AHI) was compared with the total symptom score (TSS) and with the subscale of sleep disturbance (SD) from the OSA-18 questionnaire. Receiver operating characteristic (ROC) curves were created to test the predictive value of OSA-18. RESULTS With the TSS of the OSA-18 at ≥60, compared with AHI levels of >1 and ≥5, the sensitivity was 55.2% and 59.3% respectively, and the specificity 40.9% and 48.4%, respectively. With the TSS>80 and AHI levels of ≥5 and ≥10, the sensitivity was 24.6% and 32.1%, respectively. For the subscale of SD, the majority of the subjects showed poor correlation with the AHI values. The ROC area under the curve for different levels of the AHI (>1, ≥5, and ≥10) was 0.49, 0.57, and 0.56, respectively. CONCLUSIONS The OSA-18 questionnaire showed poor validity in detecting and predicting pediatric OSA. The majority of the children with severe OSA would not be correctly diagnosed if the OSA-18 were used as a dominant diagnostic tool.

Uvulopalatopharyngoplasty in 158 OSAS patients failing non-surgical treatment

Conclusions: Uvulopalatopharyngoplasty (UPPP) in patients with obstructive sleep apnoea syndrome (OSAS) who had failed treatment with continuous positive airway pressure (CPAP) and mandibular retaining device (MRD) was effective and safe. The satisfaction rate was high. We recommend UPPP in selected OSAS patients, especially younger patients. Objectives: To evaluate the efficacy and complication rate of UPPP. Patients and methods: This was a non-randomized prospective study of 139 men and 19 women, median age 45 years (range 20–75), median body mass index (BMI) 29 (range 20–48), who underwent UPPP. One year follow-up comprised ambulant sleep apnoea recordings and questionnaires with the Epworth Sleepiness Scale (ESS). Results: In all, 76% of the patients underwent sleep recordings preoperatively and postoperatively. The oxygen desaturation index (ODI4) decreased from median 23 (range 6–100) to 8 (range 0–60), p<0.001. Criteria of success (>50% reduction and ODI<20), was 64%. The ESS value decreased from median 12 (range 0–21) to 6 (0–22), p<0.001. In all, 88% of the patients were satisfied. Four of 158 patients (2.5%) had serious postoperative complications. There was neither sequel of complications nor mortality.

Prostaglandin E2 suppresses human group 2 innate lymphoid cell function

Background Group 2 innate lymphoid cells (ILC2s) are involved in the initial phase of type 2 inflammation and can amplify allergic immune responses by orchestrating other type 2 immune cells. Prostaglandin (PG) E2 is a bioactive lipid that plays protective roles in the lung, particularly during allergic inflammation. Objective We set out to investigate how PGE2 regulates human ILC2 function. Methods The effects of PGE2 on human ILC2 proliferation and intracellular cytokine and transcription factor expression were assessed by means of flow cytometry. Cytokine production was measured by using ELISA, and real‐time quantitative PCR was performed to detect PGE2 receptor expression. Results PGE2 inhibited GATA‐3 expression, as well as production of the type 2 cytokines IL‐5 and IL‐13, from human tonsillar and blood ILC2s in response to stimulation with a combination of IL‐25, IL‐33, thymic stromal lymphopoietin, and IL‐2. Furthermore, PGE2 downregulated the expression of IL‐2 receptor &agr; (CD25). In line with this observation, PGE2 decreased ILC2 proliferation. These effects were mediated by the combined action of E‐type prostanoid receptor (EP) 2 and EP4 receptors, which were specifically expressed on ILC2s. Conclusion Our findings reveal that PGE2 limits ILC2 activation and propose that selective EP2 and EP4 receptor agonists might serve as a promising therapeutic approach in treating allergic diseases by suppressing ILC2 function. Graphical abstract Figure. No Caption available.

Familial risk of sleep-disordered breathing

OBJECTIVE To estimate the incidence of hospitalization for paediatric obstructive sleep apnoea syndrome (OSAS) or sleep-disordered breathing (SDB) caused by adenotonsillar or tonsillar hypertrophy without infection in children with a parent affected by OSAS. PATIENTS AND METHODS Using the MigMed database at Lund University, hospital data on all children aged 0-18 years in Sweden between 1997 and 2007 (total of 3 million individuals) were used to identify all first hospital admissions for OSAS or either adenotonsillar or tonsillar hypertrophy. Next, individuals were categorized as either having or not having a parent affected by OSAS. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were estimated for boys and girls with a parent affected by OSAS. Children with OSAS or adenotonsillar or tonsillar hypertrophy without a parent affected by OSAS acted as the reference group (SIR=1). RESULTS After accounting for socio-economic status, age, and geographic region, the SIRs of OSAS in boys and girls with a parent affected by OSAS were 3.09 (95% CI 1.83-4.90) and 4.46 (95% CI 2.68-6.98), respectively. The SIRs of adenotonsillar or tonsillar hypertrophy in boys and girls with a parent affected by OSAS were 1.82 (95% CI 1.54-2.14) and 1.56 (95% CI 1.30-1.87), respectively. CONCLUSION This study indicates familial clustering of sleep-disordered breathing, which is important information for clinicians.