Association between upper and lower respiratory disease among patients with primary ciliary dyskinesia: an international study.

Introduction: Nearly all patients with primary ciliary dyskinesia (PCD) report ear-nose-throat (ENT) symptoms. However, scarce evidence exists about how ENT symptoms relate to pulmonary disease in PCD. We explored possible associations between upper and lower respiratory disease among patients with PCD in a multicentre study. Methods: We included patients from the ENT Prospective International Cohort (EPIC-PCD). We studied associations of several reported ENT symptoms and chronic rhinosinusitis (defined using patient-reported information and examination findings) with reported sputum production and shortness of breath, using ordinal logistic regression. In a subgroup with available lung function results, we used linear regression to study associations of chronic rhinosinusitis and forced expiratory volume in 1 s (FEV1) accounting for relevant factors. Results: We included 457 patients (median age 15 years, interquartile range 10-24 years; 54% males). Shortness of breath associated with reported nasal symptoms and ear pain of any frequency, often or daily hearing problems, headache when bending down (OR 2.1, 95% CI 1.29-3.54) and chronic rhinosinusitis (OR 2.3, 95% CI 1.57-3.38) regardless of polyp presence. Sputum production associated with daily reported nasal (OR 2.2, 95% CI 1.20-4.09) and hearing (OR 2.0, 95% CI 1.10-3.64) problems and chronic rhinosinusitis (OR 2.1, 95% CI 1.48-3.07). We did not find any association between chronic rhinosinusitis and FEV1. Conclusion: Reported upper airway symptoms and signs of chronic rhinosinusitis associated with reported pulmonary symptoms, but not with lung function. Our results emphasise the assessment and management of upper and lower respiratory disease as a common, interdependent entity among patients with PCD.

Elevated FVIII levels in hereditary hemorrhagic telangiectasia: Implications for clinical management.

Objectives: The objective of this study was twofold: to determine the prevalence of arterial and venous thromboembolic events in the Norwegian Hereditary Hemorrhagic Telangiectasia (HHT) population, and to explore potential factors linked to such events, with particular emphasis on FVIII. Methods: Patients with an HHT diagnosis attending the Otorhinolaryngology Department at Oslo University Hospital-Rikshospitalet were included consecutively between April 2021 and November 2022. We recorded the participants' medical history with an emphasis on thromboembolic events. Measurements of blood constituents, including FVIII, FIX, vWF, hemoglobin, iron, ferritin, and CRP were performed. Results: One hundred and thirty-four patients were included in the study. The total prevalence of thromboembolic events among the participants was 23.1%. FVIII levels were high (>150 IU/dL) in the majority of HHT patients (n = 84) (68.3%) and were significantly associated with thromboembolic events (p < .001), as was age. Of the patients with high FVIII levels, 28 (33%) had experienced a thromboembolic event. Furthermore, FVIII levels were measured consecutively in 51 patients and were found to fluctuate above or below 150 IU/dL in 25% of these cases. Conclusion: Thromboembolic events are highly prevalent in the Norwegian HHT population and are significantly associated with FVIII levels. FVIII levels can fluctuate, and measurements should be repeated in HHT patients to assess the risk of thromboembolic events. Level of Evidence: 4.

Endoscopic four-hands technique for pituitary tumours. / Endoskopisk firehåndsteknikk ved hypofysesvulster.

Tumours in the pituitary fossa region can be resected by endoscopic transnasal surgery using a four-hands technique. The technique, which is atraumatic, safe and minimally invasive, should be the first-line treatment for pituitary tumours and certain skull-base tumours.

Sinonasal disease among patients with primary ciliary dyskinesia: an international study.

Background: Sinonasal symptoms are a common feature of primary ciliary dyskinesia (PCD); however, literature about their severity and frequency, particularly during the life course, is scarce. Using baseline data from the Ear, nose and throat (ENT) Prospective International Cohort of PCD patients, we describe sinonasal disease in PCD. Methods: We included participants who had a routine sinonasal examination during which they completed a symptoms questionnaire. We compared frequency of reported symptoms and examination findings among children and adults, and identified characteristics potentially associated with higher risk of sinonasal disease using ordinal regression. Results: 12 centres contributed 384 participants; median age was 16 years (IQR 9-22), and 54% were male. Chronic nasal problems were the most common feature, reported by 341 (89%). More adults (33; 24%) than children (10; 4%) described hyposmia. Quality of life was moderately affected by rhinosinusitis among 136 participants with completed SNOT-22 questionnaires (median score 31; IQR 23-45). Examinations revealed nasal polyps among 51 of 345 participants (15%) and hypertrophic inferior nasal turbinates among 127 of 341 participants (37%). Facial pain was detected in 50 of 342 participants (15%). Nasal polyps, hypertrophic turbinates, deviated septum and facial pain were found more commonly in adults than children. The only characteristic associated with higher risk of sinonasal disease was age 10 years and older. Conclusions: Based on our findings, regular sinonasal examinations are relevant for patients with PCD of all ages. There is a need for improved management of sinonasal disease supported by evidence-based guidelines.

Characteristics of Otologic Disease Among Patients With Primary Ciliary Dyskinesia.

Importance: Otologic disease is common among people with primary ciliary dyskinesia (PCD), yet little is known about its spectrum and severity. Objective: To characterize otologic disease among participants with PCD using data from the Ear-Nose-Throat Prospective International Cohort. Design, Setting, and Participants: This cross-sectional analysis of baseline cohort data from February 2020 through July 2022 included participants from 12 specialized centers in 10 countries. Children and adults with PCD diagnoses; routine ear, nose, and throat examinations; and completed symptom questionnaires at the same visit or within 2 weeks were prospectively included. Exposures: Potential risk factors associated with increased risk of ear disease. Main Outcomes and Measures: The prevalence and characteristics of patient-reported otologic symptoms and findings from otologic examinations, including potential factors associated with increased risk of ear inflammation and hearing impairment. Results: A total of 397 individuals were eligible to participate in this study (median [range] age, 15.2 [0.2-72.4] years; 186 (47%) female). Of the included participants, 204 (51%) reported ear pain, 110 (28%) reported ear discharge, and 183 (46%) reported hearing problems. Adults reported ear pain and hearing problems more frequently when compared with children. Otitis media with effusion-usually bilateral-was the most common otoscopic finding among 121 of 384 (32%) participants. Retracted tympanic membrane and tympanic sclerosis were more commonly seen among adults. Tympanometry was performed for 216 participants and showed pathologic type B results for 114 (53%). Audiometry was performed for 273 participants and showed hearing impairment in at least 1 ear, most commonly mild. Season of visit was the strongest risk factor for problems associated with ear inflammation (autumn vs spring: odds ratio, 2.40; 95% CI, 1.51-3.81) and age 30 years and older for hearing impairment (41-50 years vs ≤10 years: odds ratio, 3.33; 95% CI, 1.12-9.91). Conclusion and Relevance: In this cross-sectional study, many people with PCD experienced ear problems, yet frequency varied, highlighting disease expression differences and possible clinical phenotypes. Understanding differences in otologic disease expression and progression during lifetime may inform clinical decisions about follow-up and medical care. Multidisciplinary PCD management should be recommended, including regular otologic assessments for all ages, even without specific complaints.

Intranasal bevacizumab injections improve quality of life in HHT patients.

BACKGROUND: Epistaxis is the most common symptom in patients with hereditary hemorrhagic telangiectasia (HHT), with the greatest negative impact on quality of life (QoL). Repeated intranasal submucosal bevacizumab injections (RISBI) is a relatively new treatment option for moderate or severe grades of epistaxis in HHT. However, the effect of RISBI on QoL is not fully evaluated. STUDY DESIGN: Prospective, non-comparative study. MATERIALS AND METHODS: Patients treated by RISBI for HHT-associated epistaxis between June 2011 and August 2013 were prospectively invited to the present study. The end of follow-up was October 2013. The patients were requested to answer QoL questionnaires before the first treatment, and 6-8 weeks after the last treatment. Three levels of QoL were assessed: Overall QoL using Cantril's Self-Anchoring Ladder; Health-related QoL using Short Form 36 (SF-36), and Disease-specific QoL. Psychological distress was measured with the Hospital Anxiety and Depression scale (HADS). RESULTS: Thirty-three patients were treated with RISBI during the period referred to above. Twenty-three patients completed the QoL questionnaires. The average number of treatments per patient was 2.15 ± 1.3 (Range: 1-5). The mean overall QoL improved from 6.47 ± 1.9 to 7.26 ± 1.6 (P < .05). Several dimensions measured by SF-36 were significantly improved with a medium to strong effect size. HADS demonstrated a significant decrease in psychological distress after the last treatment. CONCLUSION: HHT patients treated by RISBI improved in several aspects of quality of life, and psychological distress decreased. RISBI was an effective treatment option for moderate and severe grades of HHT-associated epistaxis. LEVEL OF EVIDENCE: 4 (case series). Laryngoscope, 130:E284-E288, 2020.

Pentraxin 3 level is elevated in hereditary hemorrhagic telangiectasia and reflects the severity of disease-associated epistaxis.

OBJECTIVES/HYPOTHESIS: We aimed to investigate if vascular endothelial growth factor (VEGF) and other angiogenic and inflammatory factors correlated with the clinical presentation in hereditary hemorrhagic telangiectasia (HHT) patients, particularly in regard to the severity of epistaxis. STUDY DESIGN: Prospective, comparative, single-center study. METHODS: One hundred nine samples were collected from 75 HHT patients attending the ear, nose, and throat department at Oslo University Hospital from February 2012 to August 2013. For comparison, samples were collected from 16 healthy controls. Angiogenic and inflammatory factors related to endothelial cell activation were analyzed by enzyme immunoassays. The grade of epistaxis was evaluated using the Epistaxis Severity Score and epistaxis Intensity, Frequency, and Need for Blood Transfusion score at the day of blood sampling. The presence of internal organ manifestations in the HHT group was recorded. RESULTS: Pentraxin 3 (PTX3) was the only factor that was significantly higher in the HHT patients than the controls and showed significant correlation to the epistaxis severity grade and the hemoglobin level. The VEGF level was higher in the HHT patients compared to controls but not to a significant degree. In addition, a significant correlation of the level of VEGF and the grade of epistaxis could not be observed. Also, no significant correlations were observed between the presence of internal organ manifestations and the level of angiogenic factors. CONCLUSIONS: PTX3, at least partly reflecting vascular inflammation, can be a potential biomarker for the severity of HHT associated epistaxis. The serum level of VEGF was not correlated with the severity of epistaxis in the HHT patients. LEVEL OF EVIDENCE: 2 Laryngoscope, 129:E44-E49, 2019.

Monocytes accumulate in the airways of children with fatal asthma.

BACKGROUND: Activated T helper type 2 (Th2) cells are believed to play a pivotal role in allergic airway inflammation, but which cells attract and activate Th2 cells locally have not been fully determined. Recently, it was shown in an experimental human model of allergic rhinitis (AR) that activated monocytes rapidly accumulate in the nasal mucosa after local allergen challenge, where they promote recruitment of Th2 cells and eosinophils. OBJECTIVE: To investigate whether monocytes are recruited to the lungs in paediatric asthma. METHODS: Tissue samples obtained from children and adolescents with fatal asthma attack (n = 12), age-matched non-atopic controls (n = 9) and allergen-challenged AR patients (n = 8) were subjected to in situ immunostaining. RESULTS: Monocytes, identified as CD68+S100A8/A9+ cells, were significantly increased in the lower airway mucosa and in the alveoli of fatal asthma patients compared with control individuals. Interestingly, cellular aggregates containing CD68+S100A8/A9+ monocytes obstructing the lumen of bronchioles were found in asthmatics (8 out of 12) but not in controls. Analysing tissue specimens from challenged AR patients, we confirmed that co-staining with CD68 and S100A8/A9 was a valid method to identify recently recruited monocytes. We also showed that the vast majority of accumulating monocytes both in the lungs and in the nasal mucosa expressed matrix metalloproteinase 10, suggesting that this protein may be involved in their migration within the tissue. CONCLUSIONS AND CLINICAL RELEVANCE: Monocytes accumulated in the lungs of children and adolescents with fatal asthma attack. This finding strongly suggests that monocytes are directly involved in the immunopathology of asthma and that these pro-inflammatory cells are potential targets for therapy.

Long-term experience with intranasal bevacizumab therapy.

OBJECTIVES/HYPOTHESIS: Long-term follow-up of intranasal bevacizumab therapy in hereditary hemorrhagic telangiectasia (HHT). STUDY DESIGN: Prospective, noncomparative study. METHODS: Patients treated for HHT-associated epistaxis by intranasal submucosal bevacizumab injections between June 2011 and August 2013 were included and followed prospectively. The effectiveness of the treatment was evaluated by the epistaxis severity score (ESS); the epistaxis intensity, frequency, and the need of blood transfusion (IFT) score; and hemoglobin levels. RESULTS: Thirty-three patients were included. The total number of treatments with intranasal bevacizumab injection was 210. The mean number of treatments per patient was 6.2 ± 4.6 (range, 1-16), and the mean treatment and observation period was 38.8 ± 21.8 months (range, 2-66 months). Four patients showed no improvement after treatment. Eleven patients (33.3%) showed initial improvement in both ESS and IFT, but the treatment was discontinued before the end of the study because the effect became gradually shorter lasting despite repeated injections. Twelve patients (36.3%) continued to have a positive response to the treatment at the end of the study. No local adverse effects were observed, but one patient developed osteonecrosis in both knees during the treatment period. CONCLUSIONS: Intranasal bevacizumab injection is an effective treatment for most of the moderate and severe grades of HHT-associated epistaxis. The duration of the effect of the treatment was variable. Primary and late resistance phenomena to the treatment were quite common. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2237-2244, 2018.

Osteonecrosis after intranasal injection with bevacizumab in treating hereditary hemorrhagic telangiectasia: A case report.

Intranasal bevacizumab injections have been used in treating hereditary hemorrhagic telangiectasia (HHT)-related epistaxis since 2009. It is believed to be a safe and effective treatment for a selected group of HHT patients in reducing frequency and intensity of epistaxis, with few or none adverse effects. In this case report, however, we will describe a patient who developed bilateral osteonecrosis in the knees while undergoing regular intranasal submucosal bevacizumab injections. Although osteonecrosis previously has been documented in patients receiving bevacizumab intravenously in oncologic doses, thus far it has not been reported in patients treated with intranasal submucosal injections. Laryngoscope, 128:593-596, 2018.

A multicenter, prospective, noninterventional study in a Norwegian cohort of patients with moderate-to-severe allergic rhinitis treated with MP-AzeFlu.

BACKGROUND: Allergic Rhinitis and its Impact on Asthma guidelines recently recommended a treatment strategy for allergic rhinitis (AR) based on disease control rather than symptom severity by using a visual analog scale (VAS) to categorize control. OBJECTIVES: To evaluate the effectiveness of MP-AzeFlu (Dymista®) by using this VAS in routine clinical practice in Norway. MP-AzeFlu comprises a novel formulation that contains azelastine hydrochloride, fluticasone propionate and excipients delivered in a single spray. METHODS: This multicenter, prospective, noninterventional study enrolled patients (n = 160) with moderate-to-severe AR and acute symptoms who were eligible to receive treatment with MP-AzeFlu according to its summary of product characteristics. Patients assessed symptom severity by using a VAS from 0 (not at all bothersome) to 100 mm (very bothersome) in the morning before MP-AzeFlu use on days 0, 1, 3, 7, and after ∼14 days. On day 3, the patients assessed their level of disease control as well controlled, partly controlled, or uncontrolled. The proportion of Norwegian patients who achieved defined VAS score cutoffs for "well-controlled" and "partly controlled" AR were also calculated. RESULTS: MP-AzeFlu reduced the mean ± standard deviation VAS score from 68.1 ± 16.4 mm at baseline to 37.4 ± 25.9 mm on the last day, a reduction of 30.8 ± 27.2 mm. The results were consistent, irrespective of disease severity, phenotype (i.e., seasonal AR [SAR], perennial AR [PAR], SAR plus PAR, unknown) or age (i.e., 12-17, 18-65, and >65 years). Of the patients (with recorded data), 88.1% considered their symptoms to be partly or well controlled at day 3; and 19.5, 32.0, 50.0, and 61.0% of the patients achieved a ≤38 mm well-controlled VAS score cutoff on days 1, 3, 7, and the last day, respectively. CONCLUSIONS: MP-AzeFlu provided rapid sustained symptom control in a routine clinical practice in Norway, which provided support for its effectiveness for the treatment of AR in real life.

Rapid recruitment of CD14(+) monocytes in experimentally induced allergic rhinitis in human subjects.

BACKGROUND: Activated TH2 cells and eosinophils are hallmarks of the allergic inflammation seen in patients with allergic rhinitis (AR). However, which cells activate and attract T cells and eosinophils to the inflammatory lesion has not been determined. OBJECTIVE: We wanted to assess the role of mucosal mononuclear phagocytes, consisting of monocytes, macrophages, and dendritic cells, in the local allergic inflammatory reaction. METHODS: Patients with AR and nonatopic control subjects were challenged with pollen extract, and nasal symptoms were recorded. Mucosal biopsy specimens obtained at different time points before and after challenge were used for immunostaining in situ and flow cytometric cell sorting. Sorted mononuclear phagocytes were subjected to RNA extraction and gene expression profiling. RESULTS: In an in vivo model of AR, we found that CD14(+) monocytes were recruited to the nasal mucosa within hours after local allergen challenge, whereas conventional dendritic cells accumulated after several days of continued provocation. Transcriptomic profiling of mucosal mononuclear phagocytes sorted after 1 week of continued allergen challenge showed an activated phenotype at least partially driven by IL-4 signaling, IL-13 signaling, or both. Importantly, gene expression of several TH2-related chemokines was significantly upregulated by the mononuclear phagocyte population concomitant with an increased recruitment of CD4(+) T cells and eosinophils. CONCLUSION: Our findings suggest that the mononuclear phagocyte population is directly involved in the production of proinflammatory chemokines that attract other immune cells. Rapid recruitment of CD14(+) monocytes to the challenged site indicates that these proinflammatory mononuclear phagocytes have a central role in orchestrating local allergic inflammation.

Living with hereditary haemorrhagic telangiectasia: coping and psychological distress - a cross-sectional study.

PURPOSE: The purpose of this study was to examine the relationship between coping strategies measured by Coping Orientation to Problems Experienced Scale (COPE) and psychological distress measured by Hospital Anxiety and Depression Scale (HADS) and Becks Hopelessness Scale (BHS) in individuals living with Hereditary hemorrhagic telangiectasia (HHT) and to examine if coping strategies might have a mediating role between experienced illness and psychological distress. HHT is mainly caused by mutations in the ENG- or ALK1-genes and associated with a shorter life span. 90% of patients have recurrent nosebleeds. METHOD: 66 individuals affected of HHT participated in this cross-sectional study, completing questions due to demographic variables, Experience of illness, COPE, BHS and HADS. X(2) test, bivariate correlations with Pearson r and hierarchical multiple regression were used using PASW 18. RESULTS: Experience of illness made the highest variance in anxiety, depression and hopelessness and the coping strategy "behavioral disengagement" seems to have a mediating role between nose bleedings, being afraid of complications, satisfied with life and psychological distress. CONCLUSIONS: Experience of illness is of big importance in psychological distress in individuals affected of HHT, and behavioral disengagement explained the actual relationship between experience of illness and psychological distress.

Bevacizumab in hereditary hemorrhagic telangiectasia-associated epistaxis: effectiveness of an injection protocol based on the vascular anatomy of the nose.

OBJECTIVE/HYPOTHESIS: To evaluate the effectiveness of a standardized intranasal bevacizumab injection in treating hereditary hemorrhagic telangiectasia (HHT)-associated epistaxis. STUDY DESIGN: Prospective pilot study. METHODS: A total dose of 100 mg bevacizumab (25 mg/mL Avastin) was injected submucosally, 50 mg on each side. A total of 0.5 mL was injected in the sphenopalatine area, upper part of bony septum, upper part of the later nasal wall, and the anterior part of nasal floor. No cauterizations or laser therapy were done during or after the procedure. The hemoglobin level and grades of epistaxis were recorded before and monthly after the procedure. The IFT grading system (intensity [I], frequency [F] of epistaxis, and the amount of blood transfusion [T]) and epistaxis severity score (ESS) for hereditary hemorrhagic telangiectasia system were used. Quality of life (QoL) was evaluated before and 4 weeks after the procedure using the Short Form-36 Health Survey questionnaire, Cantril's Self-Anchoring Ladder questionnaire, and Slotosch disease-specific QoL questionnaire. RESULTS: A significant improvement was found in IFT grading (P = .007), ESS grading (P = .001), and hemoglobin level (P = .01). The QoL differences were statistically not significant. CONCLUSIONS: The four-injection site technique of intranasal administration of bevacizumab is an effective treatment option in HHT-associated epistaxis, at least on the short-term effect. Long-term and comparative studies are needed to further evaluate the significance of this treatment modality.

Quality of life in patients with hereditary hemorrhagic telangiectasia in Norway: a population based study.

Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant disease characterized by the presence of recurrent epistaxis and small characteristic malformations of the peripheral blood vessels near the surface of the skin or mucosal linings. Arteriovenous malformations (AVM) of the lung, liver, and CNS are also known clinical findings. The purpose of this study was to examine quality of life (QoL) in patients with HHT in Norway. Sixty-six affected patients (39 women and 27 men) were included. QoL on overall-, health-related (HR-QoL), and disease-specific levels were measured with Cantril's Ladder (CL), Short Form 36 (SF-36), and a Symptom-specific QoL question in HHT patients (SFB-HHT-Q), respectively. Comparisons were made between patients and an age and gender adjusted normative sample from the Norwegian population (N = 990). Overall, the results reflected that several HHT disease-related variables were associated with reduced QoL on all three levels; overall QoL (CL), HR-QoL (SF36) as well as disease-specific QoL (SFB-HHT-Q), while demographic variables impacted HR-QoL in HHT patients. Compared to the normative sample, all subscales of SF36, but bodily pain, were significantly poorer in the HHT patients. HHT disease variables had the strongest association with QoL compared to demographic variables. The results substantiate that disease severity is associated with poorer QoL in this patients. Pain contributed independently to all levels of QoL.

The natural history of epistaxis in patients with hereditary hemorrhagic telangiectasia in the Norwegian population: a cross-sectional study.

BACKGROUND: Epistaxis is usually the first and most common symptom in hereditary hemorrhagic telangiectasia (HHT), which is known also as Rendu-Osler-Weber syndrome. The severity of HHT-associated epistaxis is highly variable and can affect the patient's quality of life. In the literature, the natural history of epistaxis in HHT patients has been described in a few countries but not from the Norwegian population. OBJECTIVE: This work focused on the natural history of epistaxis in the Norwegian population in a cross-sectional study. MATERIAL AND METHODS: Ninety-eight patients with three or four Curaçao criteria were included. The severity of epistaxis was graded depending on epistaxis intensity, frequency, and the amount of blood transfusion during a period of 4 weeks. The epistaxis grades were studied in association with age, gender, gene mutation, age of onset, and whether the patient had or had not been treated for epistaxis during the last 2 years. RESULTS: Most of the HHT patients (90%) complained of mild-to-moderate epistaxis. Seventy-seven percent of the patients started epistaxis by or before the age of 20 years. The progression of HHT-associated epistaxis with age could not be proved statistically in this study. There was no statistically significant difference in the grades of epistaxis between HHT1 and HHT2 type, neither between female and male patients. Most of the patients started epistaxis by or before the age of 20 years. There was a significant difference in the grade of epistaxis between non-ENG, non-ALK1 carrier patients, and ENG or ALK1 carrier patients. CONCLUSION: Compared with other populations, the grading of epistaxis in Norwegian patients with HHT gave generally similar results. A multicenter epidemiological study is required to get a larger study population. A common internationally accepted grading or classification system for epistaxis in HHT is highly recommended.