Thomas Meinertz Dantoft

An elevated pro-inflammatory cytokine profile in multiple chemical sensitivity

BACKGROUND Multiple chemical sensitivity (MCS) is a medically unexplained condition characterized by reports of recurrent unspecific symptoms attributed to exposure to low levels of common volatile chemicals. The etiology of MCS is poorly understood, but dysregulation of the immune system has been proposed as part of the pathophysiology. OBJECTIVE To compare plasma levels of cytokines in Danish MCS individuals with a healthy, sex- and age-matched control group. METHOD Blood samples were obtained from 150 un-exposed MCS individuals and from 148 age- and sex-matched healthy controls. Plasma concentrations of 14 cytokines, chemokines and growth and allergen-specific IgE were measured. All participants completed a questionnaire including questions on MCS, psychological distress, morbidities and medication use at the time of the study. RESULTS Plasma levels of interleukin-1β, -2, -4, and -6 were significantly (P<0.001) increased in the MCS group compared with controls, tumor necrosis factor-α was borderline significantly (P=0.05) increased and interleukin-13 was significantly decreased (P<0.001). CONCLUSION MCS individuals displayed a distinct systemic immune mediator profile with increased levels of pro-inflammatory cytokines and interleukin-2 and inverse regulation of Th2 associated cytokines interleukin-4 and interleukin-13 suggestive of low-grade systemic inflammation, along with a deviating Th2-associated cytokine response not involving IgE-mediated mechanisms.

Cohort description: The Danish study of Functional Disorders

The Danish study of Functional Disorders (DanFunD) cohort was initiated to outline the epidemiology of functional somatic syndromes (FSS) and is the first larger coordinated epidemiological study focusing exclusively on FSS. FSS are prevalent in all medical settings and can be defined as syndromes that, after appropriate medical assessment, cannot be explained in terms of a conventional medical or surgical disease. FSS are frequent and the clinical importance varies from vague symptoms to extreme disability. No well-described medical explanations exist for FSS, and how to delimit FSS remains a controversial topic. The specific aims with the cohort were to test delimitations of FSS, estimate prevalence and incidence rates, identify risk factors, delimitate the pathogenic pathways, and explore the consequences of FSS. The study population comprises a random sample of 9,656 men and women aged 18–76 years from the general population examined from 2011 to 2015. The survey comprises screening questionnaires for five types of FSS, ie, fibromyalgia, whiplash-associated disorder, multiple chemical sensitivity, irritable bowel syndrome, and chronic fatigue syndrome, and for the unifying diagnostic category of bodily distress syndrome. Additional data included a telephone-based diagnostic interview assessment for FSS, questionnaires on physical and mental health, personality traits, lifestyle, use of health care services and social factors, and a physical examination with measures of cardiorespiratory and morphological fitness, metabolic fitness, neck mobility, heart rate variability, and pain sensitivity. A biobank including serum, plasma, urine, DNA, and microbiome has been established, and central registry data from both responders and nonresponders are similarly available on morbidity, mortality, reimbursement of medicine, heath care use, and social factors. A complete 5-year follow-up is scheduled to take place from year 2017 to 2020, and further reexaminations will be planned. Several projects using the DanFunD data are ongoing, and findings will be published in the coming years.

Inflammatory Mediator Profiling of n-butanol Exposed Upper Airways in Individuals with Multiple Chemical Sensitivity

Background Multiple Chemical Sensitivity (MCS) is a chronic condition characterized by reports of recurrent symptoms in response to low level exposure to various chemical substances. Recent findings suggests that dysregulation of the immune system may play a role in MCS pathophysiology. Objectives The aim of this study was to examine baseline and low dose n-butanol-induced upper airway inflammatory response profiles in MCS subjects versus healthy controls. Method Eighteen participants with MCS and 18 age- and sex-matched healthy controls were enrolled in the study. Epithelial lining fluid was collected from the nasal cavity at three time points: baseline, within 15 minutes after being exposed to 3.7 ppm n-butanol in an exposure chamber and four hours after exposure termination. A total of 19 cytokines and chemokines were quantified. Furthermore, at baseline and during the exposure session, participants rated the perceived intensity, valence and levels of symptoms and autonomic recordings were obtained. Results The physiological and psychophysical measurements during the n-butanol exposure session verified a specific response in MCS individuals only. However, MCS subjects and healthy controls displayed similar upper airway inflammatory mediator profiles (P>0.05) at baseline. Likewise, direct comparison of mediator levels in the MCS group and controls after n-butanol exposure revealed no significant group differences. Conclusion We demonstrate no abnormal upper airway inflammatory mediator levels in MCS subjects before or after a symptom-eliciting exposure to low dose n-butanol, implying that upper airways of MCS subjects are functionally intact at the level of cytokine and chemokine production and secretory capacity. This suggests that previous findings of increased cytokine plasma levels in MCS are unlikely to be caused by systemic priming via excessive upper airway inflammatory processes.

Somatic symptom profiles in the general population: a latent class analysis in a Danish population-based health survey

Purpose The aim of this study was to identify and describe somatic symptom profiles in the general adult population in order to enable further epidemiological research within multiple somatic symptoms. Methods Information on 19 self-reported common somatic symptoms was achieved from a population-based questionnaire survey of 36,163 randomly selected adults in the Capital Region of Denmark (55.4% women). The participants stated whether they had been considerably bothered by each symptom within 14 days prior to answering the questionnaire. We used latent class analysis to identify the somatic symptom profiles. The profiles were further described by their association with age, sex, chronic disease, and self-perceived health. Results We identified 10 different somatic symptom profiles defined by number, type, and site of the symptoms. The majority of the population (74.0%) had a profile characterized by no considerable bothering symptoms, while a minor group of 3.9% had profiles defined by a high risk of multiple somatic symptoms. The remaining profiles were more likely to be characterized by a few specific symptoms. The profiles could further be described by their associations with age, sex, chronic disease, and self-perceived health. Conclusion The identified somatic symptom profiles could be distinguished by number, type, and site of the symptoms. The profiles have the potential to be used in further epidemiological studies on risk factors and prognosis of somatic symptoms but should be confirmed in other population-based studies with specific focus on symptom burden.

Irritable bowel symptoms and the development of common mental disorders and functional somatic syndromes identified in secondary care – a long-term, population-based study

Objective Irritable bowel syndrome (IBS) is associated with mental vulnerability, and half of patients report comorbid somatic and mental symptoms. We aimed to investigate the relationship between an IBS symptom continuum and the subsequent development of common mental disorders (CMDs) and functional somatic syndromes (FSSs). Methods and study design A longitudinal population-based study comprising two 5-year follow-up studies, Dan-MONICA 1 (1982–1987) and Inter99 (1999–2004), recruited from the western part of Copenhagen County. The total study population (n = 7,278) was divided into symptom groups according to the degree of IBS definition fulfillment at baseline and/or follow-up and was followed until December 2013 in Danish central registries. Cox regression was used for the analyses, adjusting for age, sex, length of education and cohort membership. In a subsequent analysis, we adjusted for mental vulnerability as a risk factor for both CMDs and FSSs, including IBS. Results Over a 5-year period, 51% patients had no IBS symptoms, 17% patients had IBS symptoms without abdominal pain, 22% patients had IBS symptoms including abdominal pain and 10% patients fulfilled the IBS definition. IBS and IBS symptoms including abdominal pain were significantly associated with the development of CMDs and other FSSs identified in secondary care. When adjusting for mental vulnerability, IBS and IBS symptoms including abdominal pain were no longer associated with CMDs, but the significant relationship to other FSSs remained. Conclusion In a clinical setting, the perspective should be broadened to individuals not fulfilling the symptom cluster of IBS but who report frequent abdominal pain. Additionally, it is important to combine symptom-based criteria of IBS with psychosocial markers such as mental vulnerability, because it could guide clinicians in decisions regarding prognosis and treatment.

Gene expression profiling in persons with multiple chemical sensitivity before and after a controlled n-butanol exposure session

Objectives To investigate the pathophysiological pathways leading to symptoms elicitation in multiple chemical sensitivity (MCS) by comparing gene expression in MCS participants and healthy controls before and after a chemical exposure optimised to cause symptoms among MCS participants. The first hypothesis was that unexposed and symptom-free MCS participants have similar gene expression patterns to controls and a second hypothesis that MCS participants can be separated from controls based on differential gene expression upon a controlled n-butanol exposure. Design Participants were exposed to 3.7 ppm n-butanol while seated in a windowed exposure chamber for 60 min. A total of 26 genes involved in biochemical pathways found in the literature have been proposed to play a role in the pathogenesis of MCS and other functional somatic syndromes were selected. Expression levels were compared between MCS and controls before, within 15 min after being exposed to and 4 hours after the exposure. Settings Participants suffering from MCS and healthy controls were recruited through advertisement at public places and in a local newspaper. Participants 36 participants who considered themselves sensitive were prescreened for eligibility. 18 sensitive persons fulfilling the criteria for MCS were enrolled together with 18 healthy controls. Outcome measures 17 genes showed sufficient transcriptional level for analysis. Group comparisons were conducted for each gene at the 3 times points and for the computed area under the curve (AUC) expression levels. Results MCS participants and controls displayed similar gene expression levels both at baseline and after the exposure and the computed AUC values were likewise comparable between the 2 groups. The intragroup variation in expression levels among MCS participants was noticeably greater than the controls. Conclusions MCS participants and controls have similar gene expression levels at baseline and it was not possible to separate MCS participants from controls based on gene expression measured after the exposure.

Irritable bowel symptoms, use of healthcare, costs, sickness and disability pension benefits: A long-term population-based study

Objectives: Irritable bowel syndrome (IBS) is associated with increased healthcare use and work absenteeism. We aimed to investigate long-term use of healthcare services and social benefits across IBS symptom groups. Additionally, we estimated excess healthcare costs. Methods: A longitudinal population-based study comprising two 5-year follow-up studies: The Danish part of the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (Dan-MONICA) 1 (1982–1987) and Inter99 (1999–2004) recruited from the western part of Copenhagen County. The total study population (n = 7278) was divided into symptom groups according to degree of IBS definition fulfillment at baseline and/or 5-year follow-up and was followed until 31 December 2013 in Danish central registries. Poisson regression was used for the analyses adjusting for age, sex, length of education, comorbidity, cohort membership and mental vulnerability. Results: IBS symptom groups compared to no IBS symptoms were associated with an increased number of contacts with primary and secondary healthcare, as well as weeks on sickness and disability benefits. Accounting for mental vulnerability decreased the estimates and all but two associations between IBS symptom groups and outcomes remained statistically significant. The two associations that became insignificant were contacts with psychiatric hospitals and weeks on disability pension. The excess unadjusted healthcare costs for IBS were 680 Euros per year and the overall association between symptom groups and total healthcare costs were statistically significant. Conclusions: IBS symptoms influence the long-term use and costs of healthcare, as well as the use of social benefits in the general population. Mental vulnerability explained some, but not all, of the use of healthcare and social benefits.

A step towards a new delimitation of functional somatic syndromes: A latent class analysis of symptoms in a population-based cohort study

OBJECTIVES The current delimitation of functional somatic syndromes (FSS) is inconsistent. We aimed to investigate somatic symptom profiles in the general adult population to contribute to a new, data-driven delimitation of FSS. METHODS Information on 31 self-reported somatic symptoms used in the delimitation of various FSS and bodily distress syndrome (BDS) was obtained from the DanFunD study-a population-based cohort study on 9656 adults (participation 33.6%) from Greater Copenhagen, Denmark. Latent class analysis was used to identify symptom profiles. The profiles were described by their relation with sex, age, chronic disease, self-perceived health, symptom impact, self-reported FSS, and BDS case-status. RESULTS Eight symptom profiles were identified. The largest profile had no symptoms (49% of the population). Three profiles were characterized by a few, specific symptoms: muscle and joint pain (17%), gastrointestinal symptoms (6%), and general symptoms (13%). Three profiles had multiple symptoms in specific combinations: musculoskeletal and general symptoms (7%); fatigue, musculoskeletal and gastrointestinal symptoms (3%); and cardiopulmonary, gastrointestinal and general symptoms (3%). Lastly, one profile (2%) had high probability of all symptoms. The last four profiles (15%) were strongly associated with BDS case-status, poor self-perceived health and high impact of symptoms. Analyses excluding persons with multi-symptomatic chronic disease showed similar results. CONCLUSIONS We identified eight symptom profiles characterized by specific combinations of symptoms. Four of these had multiple symptoms from several bodily systems showing large overlap with BDS, possibly indicating subtypes of FSS. The profiles contribute to a new delimitation of FSS by illustrating the importance of specific symptom combinations.