Low Prevalence of Idiopathic Mast Cell Activation Syndrome Among 703 Patients With Suspected Mast Cell Disorders.

BACKGROUND: Idiopathic mast cell activation syndrome (iMCAS) is characterized by severe, episodic systemic mast cell (MC) activation and mediator-related symptoms, an event-related increase in serum tryptase levels, and response to MC-targeted therapies in the absence of underlying IgE-mediated allergy or clonal MC disorder. Studies indicating its prevalence using evidence-based diagnostic criteria are lacking. OBJECTIVE: To assess the prevalence and clinical and laboratory features of patients with iMCAS. METHODS: We conducted a retrospective evaluation of data from 703 consecutive patients (aged ≥18 years) referred to our center based on suspicion of having MC disorders. Patients underwent a thorough clinical workup including patient history, allergy tests, KIT D816V mutation analysis, and/or bone marrow investigation. Disease activity was prospectively assessed during follow-up visits. RESULTS: We identified 31 patients with confirmed iMCAS. Furthermore, hereditary α-tryptasemia was detected in three patients with baseline tryptase levels greater than 8 ng/mL. The most common clinical presentation during MCAS episodes was mucocutaneous symptoms in patients with iMCAS, especially urticaria or angioedema. However, these symptoms were less prevalent in patients with clonal MCAS (P = .015). The duration of diagnostic delay was significantly longer in patients with iMCAS compared to those with clonal MCAS (P = .02). CONCLUSIONS: The overall prevalence of iMCAS was 4.4% in the entire cohort, which indicates that iMCAS is an uncommon condition. To accurately diagnose iMCAS, it is crucial to evaluate suspected patients using the three diagnostic MCAS criteria. This involves performing a comprehensive allergy work-up including laboratory tests and ultrasensitive mutation analysis of KIT D816V. Subsequently, recommended diagnostic algorithms should be applied.

The association between zero-crossing temperatures and accidents due to icy conditions.

AIMS: Rising temperatures lead to milder winters in Scandinavia. In certain regions, this could increase the number of winter days that fluctuate around 0°C (zero crossings). It has been frequently suggested that there is a higher risk of icy conditions during such days, which may lead to a predisposition to falls and road traffic accidents. Here, we examine the association between number of days with zero crossings and the number of hospitalisations and outpatient visits due to falls related to ice or snow or transport accidents. METHODS: We used Poisson regression to examine the association between the number of days with zero crossings and the incidence of inpatient and outpatient visits related to falls due to ice and snow and to transport accidents during 2001-2017 in the Swedish cities of Stockholm, Malmö and Umeå. RESULTS: We found a positive and significant association between the number of days of zero crossings and the number of in- and outpatient cases due to falls related to ice and snow. These associations were strongest in Umeå but less obvious in Stockholm and Malmö. In terms of injuries related to transport accidents, we saw a significant association between inpatient cases and number of zero crossings in Stockholm but not in Malmö or Umeå. CONCLUSIONS: An increased number of zero crossings may increase out- and inpatient visits related to falls due to ice and snow or transport accidents. This effect is more pronounced in the northern city of Umeå than in Malmö, a city in Sweden's southern-most region.

Non-steroidal anti-inflammatory drug-induced anaphylaxis infrequent in 388 patients with mastocytosis: A two-center retrospective cohort study.

Background: Anaphylaxis is a well-known feature of mastocytosis, particularly in relation to hymenoptera venom stings. It is therefore hypothesized that mastocytosis patients may also be predisposed to severe hypersensitivity reactions to certain medications including non-steroidal anti-inflammatory drugs (NSAIDs). For this reason, these patients are usually discouraged from using these drugs. The current study aimed to determine the prevalence and evaluate the severity of NSAID-related hypersensitivity reactions among patients with mastocytosis. Methods: A retrospective study was conducted among a total of 388 (≥18 years old) consecutive patients from two independent European mastocytosis centers, in Sweden and Italy. Patients underwent a thorough allergy work-up where self-reported NSAID-hypersensitivity reactions were re-evaluated by an allergist in the first cohort (202 patients) and results were validated in the second cohort (186 patients). Results: Overall frequency of NSAID-hypersensitivity was 11.3% in the total study cohort. Most patients reacted with cutaneous symptoms (89%), whereas severe hypersensitivity reactions were infrequent with only 11 patients (2.8%) experiencing anaphylaxis. All NSAID-related hypersensitivity reactions had occurred before mastocytosis was diagnosed. There was no difference between the groups regarding gender, baseline tryptase levels or presence of atopy, asthma/rhinitis. Conclusion: Our study indicates an approximate 4-fold increased prevalence of NSAID hypersensitivity among mastocytosis patients compared to the general population. However, most NSAID reactions were limited to the skin as the prevalence of overall anaphylaxis was infrequent. Our results support that mastocytosis patients with a known tolerance to NSAIDs can continue using these medications without special precautions, whereas those with a prior reaction to NSAIDs should undergo thorough allergy work-up, including drug challenges.

Combined Exposure to Birch Pollen and Thunderstorms Affects Respiratory Health in Stockholm, Sweden-A Time Series Analysis.

BACKGROUND: Thunderstorm asthma is a term used to describe surges in acute respiratory illnesses following a thunderstorm and is often attributed to an intense exposure to aeroallergens. Several episodes of thunderstorm asthma have been observed worldwide; however, no such cases have been described in Sweden. In Sweden, the most prominent exposure to air-borne pollen occurs during the blooming of the birch. We aimed to explore the associations between respiratory health and the combined exposure to thunderstorms and birch pollen. METHODS: We investigated the association between the daily numbers of outpatient visits due to respiratory cases and the combined exposure to thunderstorms and birch pollen during the period of 1 May-31 September in 2001-2017, in Stockholm County, Sweden, by using time series analysis with log linear models. RESULTS: We detected noticeable increases in the number of outpatient visits on both the same day (max 26%; 95% CI 1.16-1.37) and the day after (max 50%; 95% CI 1.32-1.70) the occurrence of a thunderstorm, when the concentrations of birch pollen and the number of lightning discharges were within the highest categories. CONCLUSIONS: It is possible that co-exposure to heavy thunderstorms and high concentrations of birch pollen affects the respiratory health of the Stockholm population. To the best of our knowledge, this is the first study addressing the thunderstorm-related respiratory illnesses in Sweden and the effects of birch pollen. Our study may be important for future public health advice related to thunderstorm asthma.

Tedizolid: a service evaluation in a large UK teaching hospital.

Tedizolid is a new oxazolidinone antibiotic with little real-life data on use outside of skin and soft tissue infections. There is a paucity of safety evidence in courses greater than 6 days. Our centre uses tedizolid predominantly when linezolid-associated adverse events have occurred. This service evaluation describes our experience to date. We performed a retrospective service evaluation by reviewing case notes, prescription charts, and laboratory system results for each patient prescribed tedizolid at our hospital and recording patient demographics, clinical details, and outcomes. Sixty patients received tedizolid between May 2016 and November 2018. Most were treated for bone or joint infections and had stopped linezolid prior to tedizolid prescription. Mean length of tedizolid therapy was 27 days. Haematological adverse effects were infrequent. Most patients (72%) finished the course and their clinical condition improved during treatment (72%). Adverse events were common, but often not thought to be tedizolid related. Tedizolid appears to be safe in prolonged courses within this context. It may be suitable for longer-term antibiotic therapy within a complex oral and parenteral outpatient antibiotic therapy (COPAT) service. Patients who do not tolerate linezolid can be safely switched to tedizolid if appropriate.

Impairments in cognitive performance in chronic fatigue syndrome are common, not related to co-morbid depression but do associate with autonomic dysfunction.

OBJECTIVES: To explore cognitive performance in chronic fatigue syndrome (CFS) examining two cohorts. To establish findings associated with CFS and those related to co-morbid depression or autonomic dysfunction. METHODS: Identification and recruitment of participants was identical in both phases, all CFS patients fulfilled Fukuda criteria. In Phase 1 (n = 48) we explored cognitive function in a heterogeneous cohort of CFS patients, investigating links with depressive symptoms (HADS). In phase 2 (n = 51 CFS & n = 20 controls) participants with co-morbid major depression were excluded (SCID). Furthermore, we investigated relationships between cognitive performance and heart rate variability (HRV). RESULTS: Cognitive performance in unselected CFS patients is in average range on most measures. However, 0-23% of the CFS sample fell below the 5th percentile. Negative correlations occurred between depressive symptoms (HAD-S) with Digit-Symbol-Coding (r = -.507, p = .006) and TMT-A (r = -.382, p = .049). In CFS without depression, impairments of cognitive performance remained with significant differences in indices of psychomotor speed (TMT-A: p = 0.027; digit-symbol substitution: p = 0.004; digit-symbol copy: p = 0.007; scanning: p = .034) Stroop test suggested differences due to processing speed rather than inhibition. Both cohorts confirmed relationships between cognitive performance and HRV (digit-symbol copy (r = .330, p = .018), digit-symbol substitution (r = .313, p = .025), colour-naming trials Stroop task (r = .279, p = .050). CONCLUSION: Cognitive difficulties in CFS may not be as broad as suggested and may be restricted to slowing in basic processing speed. While depressive symptoms can be associated with impairments, co-morbidity with major depression is not itself responsible for reductions in cognitive performance. Impaired autonomic control of heart-rate associates with reductions in basic processing speed.

Annoyance in Response to Vibrations from Railways.

Rail transport is a key stepping stone in the EU's transport policy and is pinpointed for investment and growth over the coming decades. This expanding infrastructure implies increased exposure to environmental stressors, such as noise and ground-borne vibrations. Little is known about the health impacts of exposure to these vibrations. The aim of this paper is to examine the association between annoyance from rail vibrations and the distance of residential dwelling from the railway. It reports the first results of a large epidemiological study, EpiVib, which was designed to investigate the long-term health effects of exposure to rail vibrations. The first part of this study examines a self-reported questionnaire. In total, 6894 individuals aged between 18 and 80 living within 1 km of a railway in west Sweden participated. Results presented here examine the association between distance to the railway and annoyance from vibrations and are stratified by train type. A positive association between closer distance and increased annoyance is seen. After adjustment for important modifiers, results showed that vibrations from freight trains and maintenance operations are reported to be moderately and highly annoying at distances of up to 400 m from the railway and diesel up to 300 m. Vibration from passenger and fast trains are significantly annoying up to 200 m from the track. Vibration from freight trains and maintenance operations were considered highly annoying up to 300 m from the track, diesel up to 400 m. Vibration from passenger and fast trains are not reported to be highly annoying after adjustment. Heavier, slower moving locomotives, in the form of diesel and freight trains, appear to be the source of annoyance at distances further from the railway compared to passenger and fast trains. This has implications in terms of property, transport, and infrastructure planning.

Reduction of Glucocorticoid Receptor Function in Chronic Fatigue Syndrome.

Glucocorticoid receptor (GR) function may have aetiopathogenic significance in chronic fatigue syndrome (CFS), via its essential role in mediating inflammatory responses as well as in hypothalamic-pituitary-adrenal axis regulation. GR function can be estimated ex vivo by measuring dexamethasone (dex) modulation of cytokine response to lipopolysaccharide (LPS), and in vivo using the impact of dex on cortisol levels. This study aimed to compare the GR function between CFS (n = 48), primary Sjögren's syndrome (a disease group control) (n = 27), and sedentary healthy controls (HCs) (n = 20), and to investigate its relationship with clinical measures. In the GR ex vivo response assay, whole blood was diluted and incubated with LPS (to stimulate cytokine production), with or without 10 or 100 nanomolar concentrations of dex. Cytometric bead array (CBA) and flow cytometry enabled quantification of cytokine levels (TNFα, interleukin- (IL-) 6, and IL-10) in the supernatants. In the in vivo response assay, five plasma samples were taken for determination of total cortisol concentration using ELISA at half-hourly intervals on two consecutive mornings separated by ingestion of 0.5 mg of dex at 11 pm. The association of the data from the in vivo and ex vivo analyses with reported childhood adversity was also examined. CFS patients had reduced LPS-induced IL-6 and TNFα production compared to both control groups and reduced suppression of TNFα by the higher dose of dex compared to HCs. Cortisol levels, before or after dex, did not differ between CFS and HCs. Cortisol levels were more variable in CFS than HCs. In the combined group (CFS plus HC), cortisol concentrations positively and ex vivo GR function (determined by dex-mediated suppression of IL-10) negatively correlated with childhood adversity score. The results do not support the hypothesis that GR dysregulation is aetiopathogenic in CFS and suggest that current and future endocrine cross-sectional studies in CFS may be vulnerable to the confounding influence of childhood trauma which is likely increased by comorbid depression.

Intracranial compliance is associated with symptoms of orthostatic intolerance in chronic fatigue syndrome.

Symptoms of orthostatic intolerance (OI) are common in Chronic Fatigue Syndrome (CFS) and similar disorders. These symptoms may relate to individual differences in intracranial compliance and cerebral blood perfusion. The present study used phase-contrast, quantitative flow magnetic resonance imaging (MRI) to determine intracranial compliance based on arterial inflow, venous outflow and cerebrospinal fluid flow along the spinal canal into and out of the cranial cavity. Flow-sensitive Alternating Inversion Recovery (FAIR) Arterial Spin Labelling was used to measure cerebral blood perfusion at rest. Forty patients with CFS and 10 age and gender matched controls were scanned. Severity of symptoms of OI was determined from self-report using the Autonomic Symptom Profile. CFS patients reported significantly higher levels of OI (p < .001). Within the patient group, higher severity of OI symptoms were associated with lower intracranial compliance (r = -.346, p = .033) and higher resting perfusion (r = .337, p = .038). In both groups intracranial compliance was negatively correlated with cerebral perfusion. There were no significant differences between the groups in intracranial compliance or perfusion. In patients with CFS, low intracranial compliance and high resting cerebral perfusion appear to be associated with an increased severity of symptoms of OI. This may signify alterations in the ability of the cerebral vasculature to cope with changes to systemic blood pressure due to orthostatic stress, but this may not be specific to CFS.

Rethinking childhood adversity in chronic fatigue syndrome.

Background: Previous studies have consistently shown increased rates of childhood adversity in chronic fatigue syndrome (CFS). However, such aetiopathogenic studies of CFS are potentially confounded by co-morbidity and misdiagnosis particularly with depression. Purpose: We examined the relationship between rates of childhood adversity using two complimentary approaches (1) a sample of CFS patients who had no lifetime history of depression and (2) a modelling approach. Methods: Childhood trauma questionnaire (CTQ) administered to a sample of 52 participants with chronic fatigue syndrome and 19 controls who did not meet criteria for a psychiatric disorder (confirmed using the Structured Clinical Interview for DSM-IV). Subsequently, Mediation Analysis (Baye's Rules) was used to establish the risk childhood adversity poses for CFS with and without depression. Results: In a cohort of CFS patients with depression comprehensively excluded, CTQ scores were markedly lower than in all previous studies and, in contrast to these previous studies, not increased compared with healthy controls. Post-hoc analysis showed that CTQ scores correlated with the number of depressive symptoms during the lifetime worst period of low mood. The probability of developing CFS given a history of childhood trauma is 4%, a two-fold increased risk compared to the general population. However, much of this risk is mediated by the concomitant development of major depression. Conclusions: The data suggests that previous studies showing a relationship between childhood adversity and CFS may be attributable to the confounding effects of co-morbid or misdiagnosed depressive disorder. Abbreviations: CFS: Chronic fatigue syndrome; CTQ: Childhood trauma questionnaire; MDD: Major depressive disorder; CA: Childhood adversity; P: Probability.

Grey and white matter differences in Chronic Fatigue Syndrome - A voxel-based morphometry study.

OBJECTIVE: Investigate global and regional grey and white matter volumes in patients with Chronic Fatigue Syndrome (CFS) using magnetic resonance imaging (MRI) and recent voxel-based morphometry (VBM) methods. METHODS: Forty-two patients with CFS and thirty healthy volunteers were scanned on a 3-Tesla MRI scanner. Anatomical MRI scans were segmented, normalized and submitted to a VBM analysis using randomisation methods. Group differences were identified in overall segment volumes and voxel-wise in spatially normalized grey matter (GM) and white matter (WM) segments. RESULTS: Accounting for total intracranial volume, patients had larger GM volume and lower WM volume. The voxel-wise analysis showed increased GM volume in several structures including the amygdala and insula in the patient group. Reductions in WM volume in the patient group were seen primarily in the midbrain, pons and right temporal lobe. CONCLUSION: Elevated GM volume in CFS is seen in areas related to processing of interoceptive signals and stress. Reduced WM volume in the patient group partially supports earlier findings of WM abnormalities in regions of the midbrain and brainstem.

Exploring Perception of Vibrations from Rail: An Interview Study.

Rail transport is an environmentally responsible approach and traffic is expected to increase in the coming decades. Little is known about the implications for quality of life of populations living close to railways. This study explores the way in which vibrations from rail are perceived and described by these populations. The study took place in the Västra Götaland and Värmland regions of Sweden. A qualitative study approach was undertaken using semi-structured interviews within a framework of predetermined questions in participants' homes. A 26.3% response rate was achieved and 17 participants were interviewed. The experience of vibrations was described in tangible terms through different senses. Important emerging themes included habituation to and acceptance of vibrations, worry about property damage, worry about family members and general safety. Participants did not reflect on health effects, however, chronic exposure to vibrations through multimodal senses in individual living environments may reduce the possibility for restoration in the home. Lack of empowerment to reduce exposure to vibrations was important. This may alter individual coping strategies, as taking actions to avoid the stressor is not possible. The adoption of other strategies, such as avoidance, may negatively affect an individual's ability to cope with the stressor and their health.

Are current chronic fatigue syndrome criteria diagnosing different disease phenotypes?

IMPORTANCE: Chronic fatigue syndrome (CFS) is characterised by a constellation of symptoms diagnosed with a number of different polythetic criteria. Heterogeneity across these diagnostic criteria is likely to be confounding research into the as-yet-unknown pathophysiology underlying this stigmatised and debilitating condition and may diagnose a disease spectrum with significant implications for clinical management. No studies to date have objectively investigated this possibility using a validated measure of CFS symptoms-the DePaul Symptom Questionnaire (DSQ). OBJECTIVE: To examine whether current CFS diagnostic criteria are identifying different disease phenotypes using the DSQ. DESIGN: Case control study. SETTING: Clinical Research Facility of the Royal Victoria Infirmary, Newcastle upon Tyne, UK. PARTICIPANTS: 49 CFS subjects and ten matched, sedentary community controls, excluded for co-morbid depression. MAIN OUTCOMES AND MEASURES: Self-reported autonomic and cognitive features were assessed with the Composite Autonomic Symptom Score (COMPASS) and Cognitive Failures Questionnaire (COGFAIL) respectively. Objective autonomic cardiovascular parameters were examined using the Task Force® Monitor and a battery of neuropsychological tests administered for objective cognitive assessment. RESULTS: Self-reported autonomic and cognitive symptoms were significantly greater in CFS subjects compared to controls. There were no statistically significant differences in objective autonomic measures between CFS and controls. There were clinically significant differences between DSQ subgroups on objective autonomic testing. Visuospatial memory, verbal memory and psychomotor speed were significantly different between DSQ subgroups. CONCLUSIONS AND RELEVANCE: The finding of no significant differences in objective autonomic testing between CFS and control subjects may reflect the inclusion of sedentary controls or exclusion for co-morbid depression. Consistent exclusion criteria would enable better delineation of these two conditions and their presenting symptoms. Findings across CFS subgroups suggest subjects have a different disease burden on subjective and objective measures of function, autonomic parameters and cognitive impairment when categorised using the DSQ. Different CFS criteria may at best be diagnosing a spectrum of disease severities and at worst different CFS phenotypes or even different diseases. This complicates research and disease management and may contribute to the significant stigma associated with the condition.

Elevated brain natriuretic peptide levels in chronic fatigue syndrome associate with cardiac dysfunction: a case control study.

Objectives: To explore levels of the brain natriuretic peptide (BNP) and how these associate with the cardiac abnormalities recently identified in chronic fatigue syndrome (CFS). Methods: Cardiac magnetic resonance examinations were performed using 3T Philips Intera Achieva scanner (Best, Netherlands) in CFS (Fukuda) participants and sedentary controls matched group wise for age and sex. BNP was also measured by using an enzyme immunoassay in plasma from 42 patients with CFS and 10 controls. Results: BNP levels were significantly higher in the CFS cohort compared with the matched controls (P=0.013). When we compared cardiac volumes (end-diastolic and end-systolic) between those with high BNP levels (BNP >400 pg/mL) and low BNP (<400 pg/mL), there were significantly lower cardiac volumes in those with the higher BNP levels in both end-systolic and end-diastolic volumes (P=0.05). There were no relationships between fatigue severity, length of disease and BNP levels (P=0.2) suggesting that our findings are unlikely to be related to deconditioning. Conclusion: This study confirms an association between reduced cardiac volumes and BNP in CFS. Lack of relationship between length of disease suggests that findings are not secondary to deconditioning. Further studies are needed to explore the utility of BNP to act as a stratification paradigm in CFS that directs targeted treatments. Trail registration number: Registered with NIHR Portfolio CLRN ID 97805.

Reduced cardiac volumes in chronic fatigue syndrome associate with plasma volume but not length of disease: a cohort study.

OBJECTIVES: To explore potential mechanisms that underpin the cardiac abnormalities seen in chronic fatigue syndrome (CFS) using non-invasive cardiac impedance, red cell mass and plasma volume measurements. METHODS: Cardiac MR (MR) examinations were performed using 3 T Philips Intera Achieva scanner (Best, NL) in participants with CFS (Fukuda; n=47) and matched case-by-case controls. Total volume (TV), red cell volume (RCV) and plasma volume (PV) measurements were performed (41 CFS and 10 controls) using the indicator dilution technique using simultaneous 51-chromium labelling of red blood cells and 125-iodine labelling of serum albumin. RESULTS: The CFS group length of history (mean±SD) was 14±10 years. Patients with CFS had significantly reduced end-systolic and end-diastolic volumes together with reduced end-diastolic wall masses (all p<0.0001). Mean±SD RCV was 1565±443 mL with 26/41 (63%) having values below 95% of expected. PV was 2659±529 mL with 13/41 (32%) <95% expected. There were strong positive correlations between TV, RCV and PV and cardiac end-diastolic wall mass (all p<0.0001; r(2)=0.5). Increasing fatigue severity correlated negatively with lower PV (p=0.04; r(2)=0.2). There were no relationships between any MR or volume measurements and length of history, suggesting that deconditioning was unlikely to be the cause of these abnormalities. CONCLUSIONS: This study confirms an association between reduced cardiac volumes and blood volume in CFS. Lack of relationship between length of disease, cardiac and plasma volumes suggests findings are not secondary to deconditioning. The relationship between plasma volume and severity of fatigue symptoms suggests a potential therapeutic target in CFS.