Internet-delivered cognitive-behaviour therapy for anxiety related to asthma: study protocol for a randomised controlled trial.

INTRODUCTION: There is an established association between asthma and anxiety. The overlap between asthma symptoms and symptoms of anxiety may cause individuals to overestimate their asthma severity and restrict their daily activities leading to a low quality of life. There is currently weak evidence for treatments targeting anxiety related to asthma, but cognitive-behavioural therapy (CBT) has shown some promising but mixed results. The current randomised controlled trial will investigate if exposure-based internet-delivered CBT (Internet-CBT) is more effective than treatment as usual+medical education (TAU+ME) to relieve symptoms of anxiety and asthma control. METHODS AND ANALYSIS: 90 participants will be randomised 1:1 to 8 weeks of Internet-CBT or TAU+ME. The primary outcome, the patient-reported Catastrophising Asthma Scale, will be analysed from baseline to the primary endpoint at 16 weeks using hierarchical linear mixed model of the slope over time. Secondary outcomes, such as asthma control, quality of life and forced expiratory volume in 1 s, will be analysed correspondingly. ETHICS AND DISSEMINATION: All participants will be informed about the study and leave their consent before study entry. All results will be analysed at group level and reported through publication in a peer-reviewed scientific journal within the field. The study received ethical approval by the Swedish Ethical Review Authority in January 2020 (ID: 2019-05985; 2022-01117-02). TRIAL REGISTRATION NUMBER: Registered at ClinicalTrials.gov (ID: NCT04230369).

The Fear of Asthma Symptoms Scale and the Asthma Behavior Checklist: preliminary validity of two novel patient reported outcome measures.

Objective: The aim of this study was to investigate the preliminary validity of two novel scales, the Fear of Asthma Symptoms scale (FAS) and the Asthma Behavior Checklist (ABC). Methods: Using cross-sectional design, data was collected online from 188 adult participants (Age 18-71 years) with a diagnosis of asthma and self-reported anxiety related to asthma, recruited through social media. Confirmatory factor analysis, internal consistency and test-retest reliability were ascertained to address validity.Results: The confirmatory factor analysis demonstrated convergent validity for both the FAS (average variance extracted; AVE=.57) and the item-reduced ABC-8 (AVE=.61) as well as divergent validity for both scales. Both scales demonstrated high internal consistency (FAS: α = 0.94; ABC-8: α = 0.92). Test-retest reliability assessed after 1 week was good (FAS: r=.85; ABC-8: r=.88).Conclusions: We observed promising psychometric properties of the FAS and the ABC-8. The two novel scales could be useful to identify excessive fear and avoidance in patients with asthma and to investigate putative mechanisms in clinical research on anxiety related to asthma. Further evaluation of psychometric properties in independent samples are needed.

Targeting excessive avoidance behavior to reduce anxiety related to asthma: A feasibility study of an exposure-based treatment delivered online.

There is an established relationship between anxiety and asthma, which is associated with poor health outcomes. Most previous cognitive behavior therapies (CBT) have focused on comorbid panic disorder whereas anxiety related to asthma may rather be illness-specific. The feasibility of an online CBT targeting avoidance behavior in anxiety related to asthma was evaluated, using a pretest-posttest design. Thirty participants with self-reported anxiety related to asthma were offered an eight-week treatment with therapist support. Mean adherence was good (80% of content), and most participants (89%) reported adequate relief after treatment. Catastrophizing about asthma (CAS), assessed at 2 months after treatment, improved significantly with a large effect size (Cohen's d = 1.52). All secondary outcomes, including asthma control, avoidance behavior, fear of asthma symptoms and quality of life, improved significantly with moderate to large effect sizes (d: 0.40-1.44). All improvements were stable at 4 months follow up. Weekly ratings showed that a decrease in avoidance behavior predicted a decrease in CAS the following week throughout the treatment period. We conclude that CBT targeting avoidance behavior is a feasible treatment for anxiety related to asthma. The results justify investigation of efficacy and mechanisms of change in a randomized controlled trial. ClinicalTrials.gov, ID: NCT03486756.

Exposure-based cognitive behavior therapy for anxiety related to asthma: A feasibility study with multivariate baseline design.

In the presence of asthma, the risk of having an anxiety disorder is increased twofold. The few trials conducted on cognitive behavior therapy (CBT) for anxiety and asthma have mainly targeted panic disorder, and with mixed results. Experimental laboratory research indicates that increased anxiety may lead to hypervigilance toward asthma. Hence, fear and avoidance associated with increased anxiety due to asthma may be an important treatment target. A treatment that learn participants to differentiate between anxiety and asthma through gradual exposure to situations that risk triggering anxiety for asthma may be a possible avenue. As a first step to investigate this issue further, we developed a 10-week exposure-based CBT protocol for anxiety related to asthma and tested it in six participants using multivariate baseline design with repeated assessments throughout treatment. All participants reported satisfaction with treatment, as well as subjective overall improvement after treatment. Visual analysis, using graphs over each individual's trajectory, as well as potential efficacy on group level analyzing standardized mean change, indicated improvements in important outcomes. We conclude that exposure-based CBT is feasible and may improve anxiety related to asthma. Further investigation under randomized controlled trial conditions is warranted.

Antigen-induced regulation of T-cell motility, interaction with antigen-presenting cells and activation through endogenous thrombospondin-1 and its receptors.

Antigen recognition reduces T-cell motility, and induces prolonged contact with antigen-presenting cells and activation through mechanisms that remain unclear. Here we show that the T-cell receptor (TCR) and CD28 regulate T-cell motility, contact with antigen-presenting cells and activation through endogenous thrombospondin-1 (TSP-1) and its receptors low-density lipoprotein receptor-related protein 1 (LRP1), calreticulin and CD47. Antigen stimulation induced a prominent up-regulation of TSP-1 expression, and transiently increased and subsequently decreased LRP1 expression whereas calreticulin was unaffected. This antigen-induced TSP-1/LRP1 response down-regulated a motogenic mechanism directed by LRP1-mediated processing of TSP-1 in cis within the same plasma membrane while promoting contact with antigen-presenting cells and activation through cis interaction of the C-terminal domain of TSP-1 with CD47 in response to N-terminal TSP-1 triggering by calreticulin. The antigen-induced TSP-1/LRP1 response maintained a reduced but significant motility level in activated cells. Blocking CD28 co-stimulation abrogated LRP1 and TSP-1 expression and motility. TCR/CD3 ligation alone enhanced TSP-1 expression whereas CD28 ligation alone enhanced LRP1 expression. Silencing of TSP-1 inhibited T-cell conjugation to antigen-presenting cells and T helper type 1 (Th1) and Th2 cytokine responses. The Th1 response enhanced motility and increased TSP-1 expression through interleukin-2, whereas the Th2 response weakened motility and reduced LRP1 expression through interleukin-4. Ligation of the TCR and CD28 therefore elicits a TSP-1/LRP1 response that stimulates prolonged contact with antigen-presenting cells and, although down-regulating motility, maintains a significant motility level to allow serial contacts and activation. Th1 and Th2 cytokine responses differentially regulate T-cell expression of TSP-1 and LRP1 and motility.

A cytokine-controlled mechanism for integrated regulation of T-lymphocyte motility, adhesion and activation.

The co-ordination of T-cell motility, adhesion and activation remains poorly understood. It is also unclear how these functions are co-ordinated with external stimuli. Here we unveil a series of molecular interactions in cis at the surface of T lymphocytes with potent effects on motility and adhesion in these cells, and communicating with proliferative responses. These interactions were controlled by the signature cytokines of T helper subsets interleukin-2 (IL-2) and IL-4. Low-density lipoprotein receptor-related protein 1 (LRP1) was found to play a key role for T-cell motility by promoting development of polarized cell shape and cell movement. Endogenous thrombospondin-1 (TSP-1) enhanced cell surface expression of LRP1 through CD47. Cell surface expressed LRP1 induced motility and processing of TSP-1 while inhibiting adhesion to intercellular adhesion molecule 1 and fibronectin. Interleukin-2, but not IL-4, stimulated synthesis of TSP-1 and motility through TSP-1 and LRP1. Stimulation of the T-cell receptor (TCR)/CD3 complex inhibited TSP-1 expression. Inhibitor studies indicated that LRP1 regulated TSP-1 expression and promoted motility through JAK signalling. This LRP1-mediated motogenic signalling was connected to CD47/Gi protein signalling and IL-2-induced signalling through TSP-1. The motogenic TSP-1/LRP1 mechanism antagonized TCR/CD3-induced T-cell proliferation. These results indicate that LRP1 in collaboration with TSP-1 directs a counter-adhesive and counter-proliferative motogenic cascade. T cells seem programmed to prioritize movement before adhesion through this cascade. In conclusion, vital decision-making in T lymphocytes regulating motility, adhesive interactions and proliferation, are integrated through a molecular mechanism connecting different cell surface receptors and their signalling pathways.

Postoperative regional distribution of pulmonary ventilation and perfusion in infants with congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Advances in management of patients with congenital diaphragmatic hernia (CDH) have improved mortality rates but with a risk of increased pulmonary morbidity. The prognosis for CDH survivors remains difficult to predict owing to the lack of adequate methods. We used single photon emission computed tomography (SPECT) to measure the regional distribution of ventilation and perfusion in CDH infants to quantify the degree of lung function impairment and relate it to neonatal clinical disease severity. METHODS: Single photon emission computed tomography was performed in 12 CDH infants at the mean age of six months. Ventilation and perfusion were traced with 5 MBq Technegas and technetium-labelled albumin macro-aggregates, respectively. Neonatal clinical data collected during the patient's stay in the pediatric intensive care unit was correlated with the SPECT data. RESULTS: Single photon emission computed tomography revealed varying degrees of ventilation-perfusion abnormalities which correlated with the presence of pulmonary artery hypertension, days on ventilator and days on extracorporeal membrane oxygenation. CONCLUSIONS: The grade of clinical disease severity in infants following CDH repair is closely related to the ventilation-perfusion abnormality as seen using SPECT. The persistence of pulmonary artery hypertension into the postoperative neonatal period appears to be an important pathophysiological factor related to ventilation-perfusion abnormalities. Single photon emission computed tomography provides valuable clinical information for patient follow-up.

Quality of life in adolescents with asthma, during the transition period from child to adult.

AIM: The present investigation was designed to evaluate the health-related quality of life (HRQOL) of adolescents with asthma between the age of 16 and 21, when they are transferred from paediatric to adult care. METHODS: In this prospective study, 156 teenagers (69 females) with asthma were screened employing spirometry, a histamine challenge, skin prick test for allergy and filled out the 'Living with Asthma Questionnaire' both at the time of entry into the study and after 2 and 5 years of follow-up. An exercise test and questions concerning regular performed exercise were carried out at baseline and 5 years later. RESULTS: At all three time-points, the HRQOL of the men was generally better than that of the women. At the same time, the HRQOL of both genders was significantly better, both in terms of the overall scores (P < 0.001) as well as the scores for most of the individual domains, in connection with the 5-year follow-up. The young women who exercised regularly at the time of their entry exhibited better HRQOL at this time than those who did not (P < 0.001), whereas regular exercise had no impact on the HRQOL of the young men. The women with severe asthma demonstrated a poorer HRQOL than those suffering from mild-to-moderate asthma. CONCLUSION: The HRQOL of adolescents with asthma improves with age. The pronounced positive correlation between regular exercise and HRQOL in female adolescents with asthma revealed here deserves special attention in the care of young women and deserves further exploration.

Adolescents with asthma: consequences of transition from paediatric to adult healthcare.

PURPOSE: A prospective follow-up of adolescents with asthma designed to identify risk factors for deterioration during and after transfer from paediatric to adult healthcare. METHODS: Adolescents (n=150) with asthma being transferred from paediatric to adult healthcare were recruited consecutively and those with mild/moderate asthma assigned randomly to primary care or specialized care at an adult asthma clinic. Tests of pulmonary function, bronchial responsiveness and working capacity and skin prick tests were performed at the time of entry into the study and two and/or five years later. RESULTS: Initially, 88.7% of the subjects demonstrated at least one positive skin prick test. During the five-year follow-up, FEV(1) improved, while FEV(1)/FVC remained unchanged. Bronchial hyperresponsiveness was present in 71% of the subjects at the time of inclusion and 59% five years later, while 20 developed hyperresponsiveness during this period. Poor adherence to treatment, female gender and inhalation of steroids exerted negative impacts on logPD(20). The risk for persistence of bronchial hyperresponsiveness was elevated by poor adherence and attenuated by regular exercise. The decline observed in working capacity demonstrated no correlation to the risk factors examined. Subjects with mild/moderate asthma who received primary or specialized care exhibited similar pulmonary function, responses to a histamine challenge and working capacities. CONCLUSIONS: During a five-year follow-up of asthmatic adolescents leaving paediatric care, pulmonary function rarely deteriorated, but bronchial hyperresponsiveness persisted. Female gender and poor adherence to treatment exerted negative impact on bronchial hyperresponsiveness. Mild/moderate asthma was managed equally effectively with primary or specialized care.

Primary tuberculosis infection in 35 children at a Swedish day care center.

BACKGROUND AND METHOD: The decline of tuberculosis (TB) in the Swedish population since the middle of the 20th century resulted in decreased awareness of the disease. Increased migration from TB-endemic countries has resulted in new cases and risk of transmission. A day care provider was diagnosed with cavitary TB after being symptomatic for 5 months. We describe the contact tracing at the day care center, the clinical and radiographic findings, and treatment of the infected children. RESULTS: We stratified the children by contact with the source case and examined the most exposed first. Thirty-two of 53 attending and 3 of 84 visiting preschool children were infected. All of them had spent at least 3 days at the center. Symptoms were usually mild and nonspecific. Seventeen children had pulmonary radiographic changes compatible with primary TB, and one had miliary TB. The radiographic resolution was slow, with normalization in 50% after 12 months. Eighteen months after termination of treatment, there have been no relapses. The children with latent infection were treated with rifampin for 4 months and none has developed TB. CONCLUSIONS: The manifestations of primary TB in children today are similar to those described 50-70 years ago. The tuberculin skin test is an effective tool for contact tracing in an unvaccinated, previously nonexposed childhood population. Rapid detection of contagious patients and thorough contact investigation remain our most important means to reduce transmission.

Asthma mortality among Swedish children and young adults, a 10-year study.

BACKGROUND: Previous reports indicate that morbidity and mortality from asthma have increased during the past decades. Here, the mortality rate associated with asthma and possible risk factors in children and young adults in Sweden during the period 1994-2003 were evaluated. METHODS: The medical profession was asked to report suspected cases of death from asthma in individuals 1-34 years of age. All death certificates containing relevant ICD codes were reviewed. Medical records and autopsy reports were assessed and telephone interviews with next-of-kin performed. RESULTS: During the 10-year period 37 deaths due to asthma were identified. The median age at the time of death was 27 years and 6 of the deceased were younger than 15. The overall incidence of death from asthma decreased from 1.54 deaths per million in 1994 to 0.53 per million in 2003. Common risk factors were under-treatment (23/37), poor adherence to prescribed treatment (17/37) and adverse psychosocial situation (19/37). An alarming finding was that 11 of the 37 deaths were probably caused by food allergy and for 8 subjects death was associated with exposure to pet dander. The death certificates were found to contain inaccuracies with 30% of those for whom asthma was reported as the underlying cause having died from other causes. CONCLUSION: Asthma mortality in children and young adults in Sweden decreased between 1994 and 2003. Food allergy and inadequate treatment were the major risk factors for such a death. Recognition and special care of patients with asthma who have shown signs of non-compliance, denial or severe food allergy must be encouraged.

A technique for lung ventilation-perfusion SPECT in neonates and infants.

BACKGROUND: Single photon emission tomography (SPECT) of the lung is a well-established non-invasive technique for quantitative assessment of regional lung ventilation and perfusion distribution in children and in adults. However, its application in neonates as well as infants has been scarce because of several practical limitations, such as the trade off between image quality and restricted effective radiation doses and the lack of suitable inhalations agents and administration techniques. METHODS: In this paper, a new technique for quantitative regional lung SPECT based on a passive Technegas administration procedure is described and clinically applied. The first clinical findings in neonates are reported. RESULTS: This technique overcomes some of the limitations of commercial ventilation systems by making patient compliance unnecessary, avoiding difficult breathing manoeuvres and by minimizing both facemask dead space and inspiratory-expiratory resistance. CONCLUSION: This technique satisfies requirements for routine applications in neonates, infants and even older patients and has a potential use also for mechanically ventilated patients. It has the potential to allow a more precise functionally oriented diagnosis, which is of importance for treatment and follow-up in patients with severe lung diseases.

Tidal volume forced expiration in asthmatic infants: reproducibility and reversibility tests.

BACKGROUND: The tidal volume forced expiration technique used in infants is considered as the first practical noninvasive method of assessing airway physiology in infants. However, its role has been discussed mainly due to the high variability of the derived parameters. OBJECTIVES: The aim of the study was to assess the reproducibility of a complete measurement with the tidal volume forced expiration technique in infants as measured by the maximal flow at FRC (V(max)FRC). A second aim was to evaluate the bronchial reversibility test in infant asthma. METHODS: Thirty infants with asthma were investigated with the tidal volume forced expiration technique twice with 10 min in between and a third time 10 min after inhalation of terbutalin 0.5 mg. RESULTS: The mean V(max)FRC in the first investigation was 285 ml.s(-1) (coefficient of variation 57%), unchanged in the second investigation and significantly lower than the mean predicted value of 404 ml.s(-1). The relative difference between the 2 investigations of V(max)FRC was mean 10.5% (SD 8.4) of the absolute V(max)FRC value and independent of the size of this V(max)FRC value. The 95% confidence interval for individual changes would then be up to 27% (mean + 2 SD). The infants with the lowest V(max)FRC percent predicted decreased further in V(max)FRC after inhalation of the bronchodilator (p < 0.05). CONCLUSIONS: The tidal volume forced expiration technique was able to measure flow at late expiration with the same reproducibility as seen with spirometry in adults, even if the flow was low. We found the technique acceptable for clinical practice and research, but the results from reversibility tests are difficult to interpret. A significant change of V(max)FRC would, however, be 27% or more.

T lymphocyte expression of thrombospondin-1 and adhesion to extracellular matrix components.

The mechanisms controlling the formation of pseudopodia and other active cell edges in T lymphocytes are not understood. We show here that T lymphocytes express thrombospondin-1 (TSP-1). TSP-1 in T lymphocytes has a high turnover as shown by the fact that brefeldin and monensin rapidly increase while cycloheximide tend to decrease the cellular TSP-1 content. T cell TSP-1 is preferentially stored intracellularly and shows variable cell surface expression. T lymphocyte adhesion to fibronectin and collagen type IV induces TSP-1 expression on the cell surface via a brefeldin sensitive mechanism. A monoclonal antibody to TSP-1 inhibits the flattening and pseudopodia formation of the adherent T cells. Furthermore, the same antibody to TSP-1 also exerts an inhibitory effect on T cell migration in the absence of exogenous TSP-1. These results indicate that endogenous TSP-1 is part of an adhesion-dependent mechanism controlling cytoplasmic spreading and migration in T lymphocytes.