Comparison of the symptom networks of long-COVID and chronic fatigue syndrome: From modularity to connectionism.

The objective was to compare the symptom networks of long-COVID and chronic fatigue syndrome (CFS) in conjunction with other theoretically relevant diagnoses in order to provide insight into the etiology of medically unexplained symptoms (MUS). This was a cross-sectional comparison of questionnaire items between six groups identified by clinical diagnosis. All participants completed a 65-item psychological and somatic symptom questionnaire (GSQ065). Diagnostically labelled groups were long-COVID (N = 107), CFS (N = 254), irritable bowel syndrome (IBS, N = 369), fibromyalgia (N = 1,127), severe asthma (N = 100) and healthy group (N = 207). The 22 symptoms that best discriminated between the six groups were selected for network analysis. Connectivity, fragmentation and number of symptom clusters (statistically related symptoms) were assessed. Compared to long-COVID, the symptom networks of CFS, IBS and fibromyalgia had significantly lower connectivity, greater fragmentation and more symptom clusters. The number of clusters varied between 9 for CFS and 3 for severe asthma, and the content of clusters varied across all groups. Of the 33 symptom clusters identified over the six groups 30 clusters were unique. Although the symptom networks of long-COVID and CFS differ, the variation of cluster content across the six groups is inconsistent with a modular causal structure but consistent with a connectionist (network, parallel distributed processing) biological basis of MUS. A connectionist structure would explain why symptoms overlap and merge between different functional somatic syndromes, the failure to discover a biological diagnostic test and how psychological and behavioral interventions are therapeutic.

"Life-changing": the experience of super-responders to biologics in severe asthma.

BACKGROUND: There is limited information on the patient's perspective of how biologic treatments impact their lives. We conducted a qualitative study to explore the patient's experience of being considered a super-responder from a quality of life perspective. METHODS: Patients with severe asthma identified as super-responders were invited to semi-structured interviews conducted online. Participants could bring a family member/friend to the interview. The interviews explored experiences of biologic treatment, were transcribed and underwent thematic analysis. RESULTS: Twenty-five participants took part in this study. Themes emerged on the impact of biologic treatment for participants and for their friends/family: (i) Words used to describe their often life-changing experiences and (ii) the positive changes noted. Biologic treatment stopped the disruption of family life and social life caused by exacerbations. Improvements in mental health were also noted. Marked individual variations in the way it affected their lives were noted. Most participants noticed improvements 2-3 months after starting their biologic, but some noticed improvement within a few days and others after 6 months. CONCLUSIONS: Super-responders reported profound but heterogeneous improvements following biologic treatment beyond asthma symptoms and exacerbations including important benefits to social and family life. Improvements may be underestimated as social and family benefits are not reliably measured in current studies with implications for health economic evaluations. Not all patients are super-responders, and excellent responses may be lost in group mean data in trials. Individual time course and response patterns need further elucidation to identify who will respond best to biologics.

Preliminary development of a questionnaire to measure the extra-pulmonary symptoms of severe asthma.

BACKGROUND: Research into the effects of asthma treatments on the extra-pulmonary symptoms of severe asthma is limited by the absence of a suitable questionnaire. The aim was to create a questionnaire suitable for intervention studies by selecting symptoms that are statistically associated with asthma pathology and therefore may improve when pathology is reduced. METHODS: Patients attending a specialist asthma clinic completed the 65-item General Symptom Questionnaire (GSQ-65), a questionnaire validated for assessing symptoms of people with multiple medically unexplained symptoms. Lung function (FEV1%) and cumulative oral corticosteroids (OCS) calculated from maintenance dose plus exacerbations were obtained from clinic records. Pathology was represented by the two components of a principal component analysis (PCA) of FEV1% and OCS. LASSO regression was used to select symptoms that had high coefficients with these two principal components and occurred frequently in severe asthma. RESULTS: 100 patients provided data. PCA revealed two components, one where FEV1% and OCS were inversely related and another where they were directly related. LASSO regression revealed 39 symptoms with non-zero coefficients on one or more of the two principal components from which 16 symptoms were selected for the GSQ-A on the basis of magnitude of coefficient and frequency. Asthma symptoms measured by asthma control questionnaires were excluded. The GSQ-A correlated 0.33 and - 0.34 (p = 0.001) with the two principal components. CONCLUSION: The GSQ-A assesses the frequency of 16 heterogenous non-respiratory symptoms that are associated with asthma severity using the statistical combination of FEV1% and OCS.

Comparison of the sensitivity of patient-reported outcomes for detecting the benefit of biologics in severe asthma.

BackgroundThe sensitivity of patient-reported outcomes (PROs) to detect the effects of treatment change depends on the match between the change in items of the PRO and the change that takes place in a sample of people. The aim of this study is to compare the sensitivity of different PROs in detecting changes following the initiation of biologic treatment in asthma. Methods: Patients starting a biologic treatment as part of clinical care completed the Asthma Control Questionnaire (ACQ-6), the Severe Asthma Questionnaire (SAQ and SAQ-global scores) and the EQ5D (EQ-5D-5L and EQ5D-VAS) at baseline. They completed the ACQ-6, SAQ, SAQ-global and a retrospective global rating of change (GRoC) scale at weeks 4, 8 and 16 and completed the EQ-5D-5L and EQ5D-VAS at week 16. The SAQ-global and EQ5D-VAS differ but both are single item 100-point questions. Sensitivity was measured by Cohen's D effect size at each of the three time points. Results: 110 patients were recruited. Depending on the time of assessment, effect size varied between 0.45 and 0.64 for the SAQ, between 0.50 and 0.77 for the SAQ-global; between 0.45 and 0.69 for ACQ-6; between 0.91 and 1.22 for GRoC; 0.32 for EQ-5D-5L and 0.49 for EQ5D-VAS. Conclusion: The sensitivity to change of a questionnaire varies with the time of measurement. The three asthma-specific prospective measures (SAQ, SAQ-global and ACQ-6) have similar sensitivity to change. The single-item EQ5D-VAS was less sensitive than the asthma specific measures and less sensitive than the single-item SAQ-global. The EQ-5D-5L was least sensitive.

Validation of subscales of the Severe Asthma Questionnaire (SAQ) using exploratory factor analysis (EFA).

BACKGROUND: The Severe Asthma Questionnaire (SAQ) is a health related quality of life (HRQoL) questionnaire validated for use in severe asthma. It is scored using the mean value of 16 items (SAQ score) in addition to a single item global rating of HRQoL (SAQ-global). The aim was to validate clinically relevant subscales using exploratory factor analysis (EFA). METHODS: The SAQ was completed, along with measures of asthma control and EQ5D-5L by patients attending six UK severe asthma centres. Clinical data were included in the analysis. EFA using principal axis factoring and oblimin rotation was used to achieve simple structure of data. RESULTS: 460 patients with severe asthma participated, 65% women, mean age 51 (16-83) years. A three factor solution achieved best fit and showed that the SAQ items formed three distinct but inter-correlated groups of items where items were grouped in a way that was consistent with item content. The three subscales were differentially associated with clinically relevant variables (lung function and mood). Males and females interpreted the question of night disturbance in different ways. CONCLUSIONS: This paper provides a template for best practice in the use of EFA when validating HRQoL subscales. The SAQ can be scored as three subscales with content reflecting three different constructs people with severe asthma use when making judgements about their lives. The subscale 'My Life' assesses the impact of severe asthma on different life activities, 'My Mind' assesses the perceived emotional impact and 'My Body' the impact of extra-pulmonary symptoms and side effects.

Functional disorders can also be explained through a non-reductionist application of network theory.

A network structure explains why reductionism is not possible for mental illness, but the same argument applies for the somatic symptoms of functional disorders. Because the covariation of symptoms of functional disorders cannot be explained in terms of symptom-to-symptom causality, explanation requires a network of biological mechanisms having emergent properties that cannot be reduced to biology.

The construction and validation of the Severe Asthma Questionnaire.

The US Food and Drug Administration's procedure for scale validation requires a documented stepwise process of qualitative and quantitative data. The aim of this paper is to provide final quantitative validating data for the Severe Asthma Questionnaire (SAQ).The SAQ, Asthma Control Test, Mini Asthma Quality of Life Questionnaire and EQ-5D-5L were completed by 160 patients attending a severe asthma clinic; 51 patients completed the SAQ on two occasions for test-retest reliability analysis. The SAQ produces two scores, a SAQ score based on the average of 16 items and a SAQ-global score from a single 100-point global quality of life scale.Construct validity was demonstrated by factor analysis of the 16 items, convergent validity by correlations of >0.6 between the SAQ, SAQ-global and other questionnaires, and discriminant validity by the ability of the SAQ and SAQ-global to distinguish between different treatment levels. Test-retest reliability (intra-class correlation) was 0.93 for the SAQ and 0.93 for the SAQ-global, and the alpha coefficient for the SAQ was 0.93.The SAQ was developed using recommended qualitative and quantitative procedures for scale development, and can be used to gain insight into patients' perceptions of how severe asthma and its treatment affects their lives.

How patient participation was used to develop a questionnaire that is fit for purpose for assessing quality of life in severe asthma.

BACKGROUND: Previous research shows that existing asthma quality of life questionnaires fail to measure the burden of oral corticosteroids that can be used to treat severe asthma, and are therefore not fit for purpose for severe asthma according to the USA's Federal Drug Authority's (FDA) criteria for content validity. Patient input and documentation of that input is key to achieving content validity according to FDA guidelines. This paper describes the process of constructing a new questionnaire to measure the burden of asthma symptoms and burden of treatment in severe asthma, using criteria specified by the FDA. METHODS: A draft severe asthma questionnaire (SAQ) was constructed using qualitative input from severe asthma patients who took part in an earlier study. The aim of this study was to improve that draft questionnaire using a further group of patients. In four iterative focus groups, 16 people with severe asthma completed the draft questionnaire, discussed the wording and structure and suggested changes that were incorporated into the final version. RESULTS: The original intention to ask patients to identify whether problems were caused by asthma symptoms or side effects of medication was abandoned as the attribution of cause was found to be difficult and inconsistent. The recall period of 2 weeks was acceptable but fails to reflect the patients' desire to express the variability of severe asthma. Patients suggested improvements to the wording of the draft questionnaire, including splitting some items in two, combining two items in one, and changes to some of the words in individual items and the response scale. CONCLUSIONS: The final version of the questionnaire was substantially different from one constructed using only qualitative reports from patients about the quality of life deficits of severe asthma. Patients make a valuable contribution to the questionnaire if they are asked to comment and improve an initial draft and where patients are treated as partners in the process of questionnaire construction, rather than only as a source of information to experts who construct the questionnaire.

A qualitative study of the impact of severe asthma and its treatment showing that treatment burden is neglected in existing asthma assessment scales.

BACKGROUND: People with severe asthma experience significant respiratory symptoms and suffer adverse effects of oral corticosteroids (OCS), including disturbed mood and physical symptoms. OCS impacts on health-related quality of life (HRQoL) have not been quantified. Asthma HRQoL scales are valid as outcome measures for patients requiring OCS only if they assess the deficits imposed by OCS. AIMS: The aim of this study was to compare the burden of disease and treatment in patients with severe asthma with items in eight asthma-specific HRQoL scales. METHODS: Twenty-three patients with severe asthma recruited from a severe asthma clinic were interviewed about the impact of their respiratory symptoms and the burden of their treatment. The domains from a thematic analysis of these interviews were compared with the items of eight asthma-specific HRQoL scales. RESULTS: In addition to the burden caused by symptoms, ten domains of OCS impact on HRQoL were identified: depression, irritability, sleep, hunger, weight, skin, gastric, pain, disease anxiety, and medication anxiety. Some patients experienced substantial HRQoL deficits attributed to OCS. Although all HRQoL scales include some OCS-relevant items, all eight scales fail to adequately assess the several types of burden experienced by some patients while on OCS. CONCLUSION: The burden of OCS in severe asthma is neglected in policy and practice because it is not assessed in outcome studies. Existing asthma HRQoL scales provide an overly positive estimation of HRQoL in patients with frequent exposure to OCS and underestimate the benefit of interventions that reduce OCS exposure. Changes to existing measurement procedures are needed.

Common Factor Mechanisms in Clinical Practice and Their Relationship with Outcome.

UNLABELLED: This study investigates three common factor mechanisms that could affect outcome in clinical practice: response expectancy, the affective expectation model and motivational concordance. Clients attending a gestalt therapy clinic (30 clients), a sophrology (therapeutic technique) clinic (33 clients) and a homeopathy clinic (31 clients) completed measures of expectancy and the Positive Affect and Negative Affect Schedule (PANAS) before their first session. After 1 month, they completed PANAS and measures of intrinsic motivation, perceived effort and empowerment. Expectancy was not associated with better outcome and was no different between treatments. Although some of the 54 clients who endorsed highest expectations showed substantial improvement, others did not: 19 had no change or deteriorated in positive affect, and 18 had the same result for negative affect. Intrinsic motivation independently predicted changes in negative affect (ß = -0.23). Intrinsic motivation (ß = 0.24), effort (ß = 0.23) and empowerment (ß = 0.20) independently predicted positive affect change. Expectancy (ß = -0.17) negatively affected changes in positive affect. Clients found gestalt and sophrology to be more intrinsically motivating, empowering and effortful compared with homeopathy. Greater improvement in mood was found for sophrology and gestalt than for homeopathy clients. These findings are inconsistent with response expectancy as a common factor mechanism in clinical practice. The results support motivational concordance (outcome influenced by the intrinsic enjoyment of the therapy) and the affective expectation model (high expectations can lead for some clients to worse outcome). When expectancy correlates with outcome in some other studies, this may be due to confound between expectancy and intrinsic enjoyment. KEY PRACTITIONER MESSAGE: Common factors play an important role in outcome. Intrinsic enjoyment of a therapeutic treatment is associated with better outcome. Active engagement with a therapeutic treatment improves outcome. Unrealistic expectations about a therapeutic treatment can have a negative impact on outcome.

A biological, latent variable model of health (EarlyBird 68).

OBJECTIVE: To determine whether factor analysis of a set of health-related biomarkers provides evidence of an underlying common dimension of variation, and to explore the relationship between this dimension of variation with positive and negative affect. METHOD: Twelve health-related metabolic, immune and body-composition biomarkers at ages 5, 7, 9, 11, 14 and 16years were obtained from the EarlyBird longitudinal cohort of 347 children and supplemented by positive affect (PA) and negative affect (NA) measured at age 16years. RESULTS: At each age, principal factor analysis revealed that nine of the 12 biomarkers consistently loaded on the first extracted factor, accounting for 25% of the variance at age 5, and 37-44% of the variance at 7-16years. High loading biomarkers included physical indicators of adiposity, insulin resistance, C-reactive protein, triglycerides, and cholesterol. Factor scores at different ages correlated between .48 and .85. Correlations between the first factor scores and mood measured at age 16 were r=-.17 (p=.02) for PA and r=.13 (p=.07) for NA. CONCLUSIONS: There is a latent variable, h, that accounts for about a third of the variance of a set of health related physical and biochemical biomarkers. h is comparatively stable during childhood and is a weak predictor of mood. These data provide a rationale for aggregating biomarkers in psychoneuroimmunological research. The concept of h provides a possible biological rationale for the role of common factors in disease onset and progression, mental illness, and functional disorders.

Mood and its association with metabolic health in adolescents: a longitudinal study, EarlyBird 65.

BACKGROUND: Mood comprises two main traits - positive and negative affect, both associated with depression and anxiety. Studies in children have linked depression with obesity, but the association with metabolic health is unclear. OBJECTIVE: To explore the relationship between mood and metabolic health in adolescents. METHODS: We studied 208 healthy children (115 boys) enrolled in the longitudinal EarlyBird Diabetes Study, and reviewed at 7 and 16 yr. Participants completed the Positive Affect and Negative Affect Schedule - Child Form (PANAS-C) at 16yr to assess positive and negative affect, together representing mood. Measures at 7 and 16 yr: body mass index (BMI), fat (%; dual energy X-ray absorptiometry), physical activity (accelerometer), metabolic risk z-score comprising homeostasis model assessment-insulin resistance (HOMA-IR), triglycerides, total cholesterol/high density lipoprotein (HDL) ratio and blood pressure. Pubertal development was determined by age at peak height velocity. RESULTS: Positive affect was higher in boys than girls, (50 vs. 46, p = 0.001), negative affect higher in girls than boys (26 vs. 22, p < 0.001). Those with lower mood were fatter (r = -0.24, p < 0.001), had higher HOMA-IR (r = -0.12, p = 0.05), higher cholesterol:HDL ratio (r = -0.14, p = 0.02), were less active (r = 0.20, p = 0.003) and had earlier pubertal development (r = 0.19, p = 0.004). Inverse associations between mood and metabolic risk z-score and change in metabolic risk z-score 7-16yr (ß = -0.26, p = 0.006, and -0.40, p = 0.004, respectively) were independent of adiposity, physical activity and puberty and sex. CONCLUSIONS: Low mood in healthy children is associated with poorer metabolic health independently of adiposity. These findings may have implications for the physical and mental health of contemporary youngsters, given their increasing obesity and cardiometabolic risk.

Placebo by proxy: the effect of parents' beliefs on therapy for children's temper tantrums.

A placebo by proxy effect occurs when a patient's response to therapy, assessed either objectively or subjectively, is affected by the behavior of other people who know that the patient is undergoing therapy. We recruited 58 children aged 2-5 years who reported frequent tantrums and examined the effect of a pharmacologically inert substance (flower essence) that is purported by the manufacturers to reduce temper tantrums. Tantrum frequency, tantrum severity, and parental mood were measured on 5 occasions over 8 days before treatment and on a further 5 occasions over 10 days after the start of treatment. Compared to the period before treatment, there was a continuing reduction in tantrum frequency (p = .002) and severity (p = .003) over the 8 days of placebo treatment. There were significant day-to-day correlations between parents' mood and tantrum frequency (r = .23) and severity (r = .19). Children's response to treatment for tantrums is associated with the beliefs and mood of the adult carer. We cannot say whether tantrum reduction was due to objective changes in child behavior, changes in parental perception, or both, but both are clinically important changes.

Beating and insulting children as a risk for adult cancer, cardiac disease and asthma.

The use of physical punishment for children is associated with poor psychological and behavioral outcomes, but the causal pathway is controversial, and the effects on later physical health unknown. We conducted a cross-sectional survey of asthma, cancer, and cardiac patients (150 in each category, 75 male) recruited from outpatient clinics and 250 healthy controls (125 male). All participants were 40-60 years old and citizens of Saudi Arabia, where the use of beating and insults is an acceptable parenting style. Demographic data and recalled frequency of beatings and insults as a child were assessed on an 8-point scale. Beating and insults were highly correlated (ρ = 0.846). Propensity score matching was used to control for demographic differences between the disease and healthy groups. After controlling for differences, more frequent beating (once or more per month) and insults were associated with a significantly increased risk for cancer (RR = 1.7), cardiac disease (RR = 1.3) and asthma (RR = 1.6), with evidence of increased risk for cancer and asthma with beating frequency of once every 6 months or more. Our results show that a threatening parenting style of beating and insults is associated with increased risk for somatic disease, possibly because this form of parenting induces stress. Our findings are consistent with previous research showing that child abuse and other early life stressors adversely affect adult somatic health, but provide evidence that the pathogenic effects occur also with chronic minor stress. A stress-inducing parenting style, even when normative, has long term adverse health consequences.

COVID-19 vaccination acceptance, safety and side-effects in European patients with severe asthma.

Background: Vaccination is vital for achieving population immunity to severe acute respiratory syndrome coronavirus 2, but vaccination hesitancy presents a threat to achieving widespread immunity. Vaccine acceptance in chronic potentially immunosuppressed patients is largely unclear, especially in patients with asthma. The aim of this study was to investigate the vaccination experience in people with severe asthma. Methods: Questionnaires about vaccination beliefs (including the Vaccination Attitudes Examination (VAX) scale, a measure of vaccination hesitancy-related beliefs), vaccination side-effects, asthma control and overall safety perceptions following coronavirus disease 2019 (COVID-19) vaccination were sent to patients with severe asthma in 12 European countries between May and June 2021. Results: 660 participants returned completed questionnaires (87.4% response rate). Of these, 88% stated that they had been, or intended to be, vaccinated, 9.5% were undecided/hesitant and 3% had refused vaccination. Patients who hesitated or refused vaccination had more negative beliefs towards vaccination. Most patients reported mild (48.2%) or no side-effects (43.8%). Patients reporting severe side-effects (5.7%) had more negative beliefs. Most patients (88.8%) reported no change in asthma symptoms after vaccination, while 2.4% reported an improvement, 5.3% a slight deterioration and 1.2% a considerable deterioration. Almost all vaccinated (98%) patients would recommend vaccination to other severe asthma patients. Conclusions: Uptake of vaccination in patients with severe asthma in Europe was high, with a small minority refusing vaccination. Beliefs predicted vaccination behaviour and side-effects. Vaccination had little impact on asthma control. Our findings in people with severe asthma support the broad message that COVID-19 vaccination is safe and well tolerated.

Is hospitalisation for COPD an opportunity for advance care planning? A qualitative study.

BACKGROUND: It is recognised that patients with chronic obstructive pulmonary disease (COPD) should have the chance to discuss end-of-life care and advance care planning (ACP). Admission to hospital with an exacerbation may be a possible opportunity. AIMS: To examine whether an admission to hospital for an exacerbation of COPD is an opportunity for ACP and to understand, from the patient perspective, the optimum circumstances for ACP. METHODS: Patients who had a recent admission for an exacerbation of COPD were identified. Sixteen patients and their carers were interviewed. The interviews were analysed using qualitative methodology. RESULTS: No patients recalled discussions about resuscitation or planning for the future. Hospital admission and discharge was seen as chaotic and lacking in continuity. Some patients welcomed the opportunity to discuss ACP and felt that their general practitioner (GP) would be the best person for this. Others wished to avoid end-of-life care discussions but there was evidence that, with empathetic and knowledgeable support, these discussions could be initiated. CONCLUSIONS: The period of hospitalisation may not be an appropriate time to initiate ACP but may be a milestone that can lead to discussions. GPs should be alert to that opportunity after discharge from hospital.

Frequency of non-asthma GP visits predicts asthma exacerbations: an observational study in general practice.

BACKGROUND: Being able to identify patients at risk of exacerbations is useful as it enables resources to be targeted at these patients. AIMS: To test the theoretically-derived prediction that the frequency of non-asthma related visits to the general practitioner (GP) predicts exacerbations. METHODS: Clinical and demographic data and both self-report and prescription-based adherence data were obtained from 166 patients diagnosed with asthma attending a GP clinic, all of whom were prescribed inhaled corticosteroids (ICS). Asthma exacerbations (treated by the GP or in hospital) and non-asthma visits and symptoms were assessed from notes for the subsequent 5 years. RESULTS: Exacerbations correlated with non-asthma visits (0.35), severity as measured by BTS step (0.28), and with prescription-based adherence (0.28). Asthma severity correlated with non-asthma visits (0.35). Receiver operating curves showed that ≥2 non-asthma visits per year provided 79% sensitivity and 58% specificity for detecting ≥3 exacerbations over 5 years. Poor adherence predicted outcomes only for patients with high levels of non-asthma visits (≥3) and only for those reporting regular-but-less ICS use but not symptom-directed ICS use. CONCLUSIONS: Non-asthma visits are a good predictor of asthma exacerbations, particular in non-adherent patients. These results are consistent with a mechanism where exacerbations result from a combination of random oscillating specific and non-specific inflammatory processes. It is important to consider the total patient rather than just the lung when managing patients with asthma.

Posttraumatic stress disorder and psychiatric co-morbidity following stroke: the role of alexithymia.

More research is needed to further our understanding of posttraumatic stress disorder symptoms (PTSD) and psychiatric co-morbidity following stroke, especially the trajectories of such symptoms over time. Previous studies suggest that exposure to a traumatic experience such as stroke is not sufficient to explain the etiology of PTSD. Alexithymia may be involved, but its relationships with PTSD and psychiatric co-morbidity following stroke remains unclear. This study aims to address these knowledge gaps. While in hospital, stroke patients (n=90) completed questionnaires assessing PTSD symptoms, psychiatric co-morbidity, alexithymia and physical disability. PTSD symptoms and psychiatric co-morbidity were re-assessed approximately 3 months post-stroke (n=78). The severity of post-stroke PTSD did not change significantly over time, while psychiatric co-morbidity reduced significantly. Alexithymia, in particular difficulty in identifying feelings, was associated with severity of post-stroke PTSD and psychiatric co-morbidity at baseline, but after adjusting for these, there was no significance 3 months post-stroke. We suggest that patients' difficulty in identifying feelings had a role to play in influencing relatively short-term rather than long-term PTSD and co-morbid psychiatric symptoms. Alternatively, PTSD could be interpreted as driving the alexithymic characteristics.