Long-term neurologic outcomes of COVID-19

Abstract:

The neurologic manifestations of acute COVID-19 are well characterized, but a comprehensive evaluation of postacute neurologic sequelae at 1 year has not been undertaken. Here we use the national healthcare databases of the US Department of Veterans Affairs to build a cohort of 154,068 individuals with COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls; we use inverse probability weighting to balance the cohorts, and estimate risks and burdens of incident neurologic disorders at 12 months following acute SARS-CoV-2 infection.

Our results show that in the postacute phase of COVID-19, there was increased risk of an array of incident neurologic sequelae including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (for example, migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain–Barré syndrome, and encephalitis or encephalopathy.

We estimated that the hazard ratio of any neurologic sequela was 1.42 (95% confidence intervals 1.38, 1.47) and burden 70.69 (95% confidence intervals 63.54, 78.01) per 1,000 persons at 12 months. The risks and burdens were elevated even in people who did not require hospitalization during acute COVID-19. Limitations include a cohort comprising mostly White males. Taken together, our results provide evidence of increased risk of long-term neurologic disorders in people who had COVID-19.

Source: Xu, E., Xie, Y. & Al-Aly, Z. Long-term neurologic outcomes of COVID-19. Nat Med (2022). https://doi.org/10.1038/s41591-022-02001-z https://www.nature.com/articles/s41591-022-02001-z (Full text)

Immunogenetic studies in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that affects about 0.1-0.2% of the general population. The core symptoms are persistent debilitating fatigue, post-exertional malaise (PEM) and cognitive dysfunction. Most symptoms of ME/CFS are not disease specific. Additionally, there is a lack of both biomarkers and diagnostic tests for the disease, which makes accurate diagnosis difficult.

More than 20 different patient classifications and diagnostic criteria have emerged over the last four decades. Due to this, the patient population can be quite heterogeneous in terms of clinical symptoms and the extent to which the disease impacts quality of life.

There are several different theories that aim to explain the disease development of ME/CFS. In this thesis, we have taken as our starting point the growing evidence for an immunological background for ME/CFS pathogenesis. Several studies have pointed to altered NK cells, autoantibodies and T cell abnormalities in ME/CFS patients.

In addition, several genetic studies reported significant associations in various immunologically relevant genes. Most of these previous studies have been suboptimal and included heterogeneous patient populations and/or few patients in total.

Therefore, we aimed to gain a better understanding of the role of immunologically relevant genes and disease development of ME/CFS.

To do this, we employed known strategies from genetic studies in autoimmune disease and applied them to ME/CFS. We used strict quality control and included, to the best of our knowledge, the largest cohort diagnosed with the Canadian consensus criteria.

In paper I, the main goal was to follow up previously performed work by our group that reported associations between ME/CFS and HLA-C: 07: 04 and HLA-DQB1: 03: 03 alleles. The HLA (human leukocyte antigen) region consists a multitude of immunologically relevant genes in addition to the HLA genes, and there is extensive and complex linkage disequilibrium (LD) in the region.

The previously observed association signals in the HLA region were fine-mapped by genotyping five additional classical HLA loci and 5,342 SNPs (single nucleotide variants) in 427 Norwegian ME/CFS patients, diagnosed according to the Canadian consensus criteria, and 480 healthy Norwegian controls. The analysis revealed two independent association signals (p ≤ 0.001) represented by the genetic variants rs4711249 in the HLA class I region and rs9275582 in the HLA class II region.

The primary association signal in the HLA class II region was located in the vicinity of the HLA-DQ genetic region, most likely due to the HLA-DQB1 gene. In particular, amino acid position 57 (aspartic acid / alanine) in the peptide binding pit of HLA-DQB1, or an SNP upstream of HLA-DQB1 seemed to explain the association signal we observed in the HLA class II region.

In the HLA class I region, the putative primary locus was not as clear and could possibly lie outside the classical HLA genes (the association signal spans several genes DDR1, GTF2H4, VARS2, SFTA2 and DPCR1) with expression levels influenced by the ME/CFS associated SNP genotypes.

Interestingly, we also observed that > 60% of the patients who responded to cyclophosphamide treatment for ME/CFS had either the rs4711249 risk allele and/or DQB1* 03:03 versus 12% of the patients who did not respond to the treatment. Our findings suggest the involvement of the HLA region, and in particular the HLA-DQB1 gene, in ME/CFS.

Although our study is the largest to date, it is still a relatively small study in the context of genetic studies. Our findings need to be replicated in much larger, statistically more representative, cohorts.

In particular, it is necessary to investigate the involvement of HLA- 12 DQB1, a gene that contains alleles that increase the risk of several established autoimmune diseases such as celiac disease.

In paper II, we aimed to investigate immunologically relevant genes using a genotyping array (iChip) targeting immunological gene regions previously associated with different autoimmune diseases.

In addition to the Norwegian cohort of 427 ME/CFS patients (the Canadian consensus criteria), we also analyzed data from two replication cohorts, a Danish one of 460 ME/CFS patients (Canadian consensus criteria) and a data set from the UK Biobank of 2105 self-reported CFS patients.

To the best of our knowledge, this is the first ME/CFS genetic association study of this magnitude and it included more than 2,900 patients in total (of whom 887 are diagnosed according to Canadian consensus criteria).

We found no ME/CFS risk variants with a genome wide significance level (p<5×10-8), but we identified six gene regions (TPPP, LINC00333, RIN3. IGFBP/IGFBP3, IZUMO1/MAMSTR and ZBTB46/STMN3) with possible association with ME/CFS which require further follow-up in future studies in order to assess whether they are real findings or not.

Interestingly, these genes are expressed in disease-relevant tissue, e.g. brain, nerve, skeletal muscle and blood, including immune cells (subgroups of T cells, B cells, NK cells and monocytes).

Furthermore, several of the ME/CFS associated SNP genotypes are associated with differential expression levels of these genes. Although we could not identify statistically convincing associations with genetic variants across the three cohorts, we believe that our data sets and analysis represent an important step in the ME/CFS research field.

Our study demonstrated that for the future understanding of the genetic architecture of ME/CFS much larger studies are required to established reliable associations.

In paper III, we wanted to investigate previous findings from a genome wide association study of 42 ME/CFS patients who reported significant association with two SNPs in the T cell receptor alpha (TRA) locus (P-value<5×10-8).

In order to replicate these previously reported findings, we used a large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK Biobank (2105 cases and 4786 controls). We examined a number of SNPs in the TRA locus, including the two previous ME/CFS-associated variants, rs11157573 and rs17255510. No statistically significant associations were observed in either the Norwegian cohort or UK biobank cohorts.

Nevertheless, other SNPs in the region showed weak signs of association (P-value <0.05) in the UK Biobank cohort and meta-analyzes of Norwegian and UK Biobank cohorts, but did not remain associated after applying correction for multiple testing. Thus, we could not confirm associations with genetic variants in the TRA locus in this study.

Source: Riad Hajdarevic. PhD thesis (University of Oslo) Electronic copies must be ordered. https://www.med.uio.no/klinmed/english/research/news-and-events/events/disputations/2022/hajdarevic-riad.html

General theory of inflammation: patient self-administration of hydrocortisone safely achieves superior control of hydrocortisone-responding disorders by matching dosage with symptom intensity

Abstract:

Objective: To determine if patient self-administration of hydrocortisone will safely achieve superior symptom control for all hydrocortisone-responding disorders as it does for Addison’s disease and rheumatoid arthritis.

Methods: Two thousand four hundred and twenty-eight participants with hydrocortisone-responding disorders were brought to a minimum symptom state using daily administered hydrocortisone tablets in a 24-week, open study. Thereafter, participants used 5-day, low-dose hydrocortisone regimens to quench subsequent disorder exacerbations (flares) to maintain the minimum symptom state. Stressors such as emotional traumas, infections, allergies, and injuries were minimized to reduce disorder intensity, hydrocortisone consumption, and participant discomfort.

Results: Two thousand fifteen participants, 601 with fibromyalgia, 579 with osteoarthritis, 246 with rheumatoid arthritis, 226 with undifferentiated arthritis, 75 with back pain, 51 with Parkinson’s disease, 44 with polymyalgia rheumatica, 25 with neuropathy, 25 with chronic fatigue syndrome, 25 with dementia, 21 with migraine headache, 19 with multiple sclerosis, and 78 with other disorders completed the 24-week study to achieve a composite average symptom improvement of 76% with equal response rates. The participants averaged ingesting 12 mg of hydrocortisone per day. No significant adverse reactions were observed.

Conclusions: Patient self-administration of hydrocortisone safely achieves superior symptom control for 38 hydrocortisone-responding disorders at equal rates and symptom improvements to confirm and amplify an earlier double-blind study finding on rheumatoid arthritis. These results are consistent with the body having an inflammation control system and chronic inflammation being a disorder unto itself with differing symptoms sets dependent on its location.

Clinical Trials Government Identifier: NCT03558971.

Source: Irwin JB, Baldwin AL, Stenberg VI. General theory of inflammation: patient self-administration of hydrocortisone safely achieves superior control of hydrocortisone-responding disorders by matching dosage with symptom intensity. J Inflamm Res. 2019 Jun 13;12:161-166. doi: 10.2147/JIR.S195165. eCollection 2019. https://www.dovepress.com/general-theory-of-inflammation-patient-self-administration-of-hydrocor-peer-reviewed-article-JIR (Full article)

MicroRNAs as biomarkers of pain intensity in patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Numerous experimental models have shown that microRNAs play an important role in regulating pain-processing in clinical pain disorders. In this study, we evaluated a set of micro-RNAs as diagnostic biomarkers of pain intensity in adolescents with chronic fatigue syndrome (CFS). We then correlated the expression of these microRNAs with the levels of inflammatory markers and pain-related comorbidities in adolescents with CSF and healthy controls (HCs).

METHODS: A total of 150 adolescents, aged 12-18 years, participated in this study between April 2016 and April 2017. The participants were classified into two groups: adolescents with CFS (n=100) and HCs (n=50). RT-PCR was used to evaluate the expression of miR-558, miR-146a, miR-150, miR-124, and miR-143. Immunoassay analysis was used to assess the levels of immune inflammatory markers IL-6, TNF-α, and COX-2.

RESULTS: Adolescents with CFS showed significantly higher pain thresholds than comparable non-fatigued HCs. Also, enjoy of life and relation to others as the life domains, showed lower pain interference in CFS patients. Differential expression of miR-558, miR-146a, miR-150, miR-124, and miR-143 was significantly down regulated and notably interfered with pain intensity and frequency in patients with CFS. Also, the expression of these miRNAs was significantly correlated with that of IL-6, TNF-α, and COX-2, which have been shown to mediate pain intensity in patients with CFS.

Girls with CSF showed significantly decreased expression levels of these miRNAs compared with the levels of boys with CSF. Girls with CSF also showed increased expression of inflammatory pain-related markers IL-6, TNF-α, and COX-2, compared with the levels of boys with CSF

CONCLUSIONS: The intensity and consequences of pain were influenced by differential expression of miR-558, miR-146a, miR-150, miR-124, and miR-143, which was directly, associated with higher expression of immune inflammatory related genes TNFα, IL-6, and COX-2 in adolescences with CFS. Further studies of larger patient cohorts will help clarify the role of miRNAs in the pathogenesis of CFS.

This article is protected by copyright. All rights reserved.

Source: Al-Rawaf HA, Alghadir AH, Gabr SA. MicroRNAs as biomarkers of pain intensity in patients with chronic fatigue syndrome. Pain Pract. 2019 Jul 8. doi: 10.1111/papr.12817. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31282597

Long Term Follow up of Young People With Chronic Fatigue Syndrome Attending a Pediatric Outpatient Service

Abstract:

Aim: To determine the reported duration of illness, the functional and educational long-term outcomes, predictive factors for recovery and seek feedback regarding management in pediatric/adolescent myalgic encepahalomyelitis/chronic fatigue syndrome (ME/CFS).

Methods: A cohort observational study of 784 young people, mean age 14.6 (6-18) years, with ME/CFS diagnosed at a specialist pediatric hospital and receiving regular care, was conducted with follow-up for a mean 8 (range 1-21) years after onset. Baseline symptoms, history, depression and anxiety questionnaires were available from 418. The remaining 366, did not have similar standardized baseline information. Questionnaires requested functional rating, persistent symptoms, duration of illness if “recovered,” social engagement and school/work attendance. Feedback was sought regarding management, support services, useful information, helpful interventions or personnel and use of alternative therapies. Reported recovery and function were compared with baseline information and between the two groups.

Results: Follow-up data were returned from 81.8%. There was no significant difference in functional score (if reported recovery) or illness duration related to provision of baseline data. The mean duration of illness was 5 (range 1-15) years in the 50% who reported recovery. By 5 years 38% and by 10 years 68% reported recovery. At 10 years the mean functional score was 8/10 (range 2-10) with 5% scoring <6. Depression, anxiety or severity of illness at diagnosis was not predictive of non-recovery. Designing and monitoring their own management plan that included educational, social, physical and enjoyable activities, as well as having symptom management and understanding professionals were highly valued. However, remaining engaged in an education system that flexibly accommodated their illness and aspirations was consistently reported as crucial for long term functioning.

Conclusions: ME/CFS in young people has a mean duration of 5 years (1-15) with 68% reporting recovery by 10 years. All improved functionally with 5% remaining very unwell and a further 20% significantly unwell. There were no obvious baseline predictors for recovery. However, depression, anxiety, orthostatic intolerance and to a lesser extent pain at follow up were identified as hampering recovery or function. Supportive professionals, remaining engaged in education and management strategies were identified as helpful.

Source: Rowe KS. Long Term Follow up of Young People With Chronic Fatigue Syndrome Attending a Pediatric Outpatient Service. Front Pediatr. 2019 Feb 21;7:21. doi: 10.3389/fped.2019.00021. eCollection 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393360/ (Full article)

Increased risk of chronic fatigue syndrome following burn injuries

Abstract:

BACKGROUND: The overlapping symptoms and pathophysiological similarities between burn injury and chronic fatigue syndrome (CFS) are noteworthy. Thus, this study explores the possible association between burn injury and the subsequent risk of CFS.

METHOD: We used data from the Taiwan National Health Insurance system to address the research topic. The exposure cohort comprised of 17,204 patients with new diagnoses of burn injury. Each patient was frequency matched according to age, sex, index year, and comorbidities with four participants from the general population who did not have a history of CFS (control cohort). Cox proportional hazards regression analysis was conducted to estimate the relationship between burn injury and the risk of subsequent CFS.

RESULT: The incidence of CFS in the exposure and control cohorts was 1.61 and 0.86 per 1000 person-years, respectively. The exposure cohort had a significantly higher overall risk of subsequent CFS than did the control cohort (adjusted hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.41-1.56). The risk of CFS in patients with burn injury in whichever stratification (including sex, age, and comorbidity) was also higher than that of the control cohort.

CONCLUSION: The findings from this population-based retrospective cohort study suggest that thermal injury is associated with an increased risk of subsequent CFS and provided a point of view suggesting burn injuries in sun- exposed areas such as the face and limbs had greater impact on subsequent development of CFS compared with trunk areas. In addition, extensively burned areas and visible scars were predictors of greater physiological and psychosocial that are needed to follow-up in the long run.

Source: Tsai SY, Lin CL, Shih SC, Hsu CW, Leong KH, Kuo CF, Lio CF, Chen YT, Hung YJ, Shi L. Increased risk of chronic fatigue syndrome following burn injuries. J Transl Med. 2018 Dec 5;16(1):342. doi: 10.1186/s12967-018-1713-2. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1713-2 (Full article)

The Abnormal Cardiac Index and Stroke Volume Index Changes During a Normal Tilt Table Test in ME/CFS Patients Compared to Healthy Volunteers, are Not Related to Deconditioning

Abstract:

1.1 Background. A small study in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) patients undergoing tilt testing, showed that, despite a normal tilt test, stroke volumes and cardiac output were lower than in healthy volunteers. Moreover, it was suggested that this difference was related to deconditioning of patients. Aim of the study. We performed table testing in 150 ME/CFS patients. Stroke volumes and cardiac output were related to the severity of the disease.

1.2 Methods and results. In the patients the severity of the disease was clinically evaluated according to the ME criteria and scored as mild, moderate or severe disease. In a subgroup of 109 patients this clinical diagnosis was confirmed by the physical functioning score of the Rand-36 questionnaire. Significantly lower physical functioning scores (indicating worse functioning) were observed in the more severely affected patients. Stroke Volume Index (SVI) and Cardiac Index (CI) were measured by suprasternal aortic Doppler imaging in the supine position, prior to the tilt, and twice during the tilt. Thirty-seven healthy volunteers underwent the same tilt protocol. In all patients and all healthy volunteers, a normal heart rate and blood pressure response was observed during the tilt. The decreases in SVI and CI during the tilt was significantly larger in patients compared to the SVI and CI decrease in HV. The decrease in SVI and CI were similar and not significantly different between the mild, moderate, and severe ME groups.

1.3 Conclusions. During a normal tilt table test decreases in SVI and CI decrease are significantly greater in ME/CFS patients than in HV, consistent with previous work. The absence of differences between patients with mild, moderate, and severe ME/CFS suggests that the decreases in stroke volumes and cardiac output are not related to deconditioning. Other factors like decreased blood volumes and autonomic dysfunction may cause this difference in the hemodynamic response between ME/CFS patients and HV.

3. Abbreviations

BMI : Body Mass Index

BSA : Body Surface Area

CFS : Chronic Fatigue Syndrome

CI : Cardiac Index

DBP : Diastolic Blood Pressure

HR : Heart Rate

HUT : Head-Up Tilt Test

HV : Healthy Volunteers

IOM : Institute of Medicine

MAP : Mean Blood Pressure

ME : Myalgic Encephalomyelitis

NMH : Neurally Mediated Hypotension

Normal BPHR : normal Blood Pressure and Heart Rate Response During HUT

OI : Orthostatic Intolerance

R36 Phys Funct : Rand-36 Physical Functioning Score

SBP : Systolic Blood Pressure

SVI : Stroke Volume Index

SVRI : Systemic Vascular Resistance Index

VTI : Time-Velocity Integral

Source: van Campen CMC, Visser FC (2018) The Abnormal Cardiac Index and Stroke Volume Index Changes During a Normal Tilt Table Test in ME/CFS Patients Compared to Healthy Volunteers, are Not Related to Deconditioning. J Thrombo Cir: JTC -107. DOI: 10.29011/ JTC -107. 000007 https://www.gavinpublishers.com/articles/Research-Article/Journal-of-Thrombosis-and-Circulation/The-Abnormal-Cardiac-Index-and-Stroke-Volume-Index-Changes-During-a-Normal-Tilt-Table-Test-in-ME-CFS-Patients-Compared-to-Healthy-Volunteers-are-Not-Related-to-Deconditioning (Full article)

Confirmatory factor analysis of a myalgic encephalomyelitis and chronic fatigue syndrome stigma scale

Abstract:

This study adapted a chronic illness stigma scale and explored its psychometric properties. The main purposes were to confirm the factor structure of the instrument with this population and address the previous factor intercorrelation discrepancies. Five hundred and fifty-four individuals with myalgic encephalomyelitis or chronic fatigue syndrome completed the adapted stigma scale.

Results document the stigma experienced by an international sample of individuals with myalgic encephalomyelitis and chronic fatigue syndrome. Factors demonstrated good internal consistency, and a model fit was found in a confirmatory factor analysis. Participants endorsed high levels of stigma, estrangement, and disclosure. Implications of these findings and future directions are discussed.

Source: Terman JM, Awsumb JM, Cotler J, Jason LA. Confirmatory factor analysis of a myalgic encephalomyelitis and chronic fatigue syndrome stigma scale. J Health Psychol. 2018 Sep 5:1359105318796906. doi: 10.1177/1359105318796906. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30183363

Poor self-reported sleep quality and health-related quality of life in patients with chronic fatigue syndrome/myalgic encephalomyelitis

Abstract:

Non-restorative sleep is a hallmark symptom of chronic fatigue syndrome/myalgic encephalomyelitis. However, little is known about self-reported sleep disturbances in these subjects. This study aimed to assess the self-reported sleep quality and its impact on quality of life in a Spanish community-based chronic fatigue syndrome/myalgic encephalomyelitis cohort.

A prospective cross-sectional cohort study was conducted in 1,455 Spanish chronic fatigue syndrome/myalgic encephalomyelitis patients. Sleep quality, fatigue, pain, functional capacity impairment, psychopathological status, anxiety/depression and health-related quality of life were assessed using validated subjective measures. The frequencies of muscular, cognitive, neurological, autonomic and immunological symptom clusters were above 80%.

High scores were recorded for pain, fatigue, psychopathological status, anxiety/depression, and low scores for functional capacity and quality of life, all of which correlated significantly (all p < 0.01) with quality of sleep as measured by the Pittsburgh Sleep Quality Index. Multivariate regression analysis showed that after adjusting for age and gender, the pain intensity (odds ratio, 1.11; p <0.05), psychopathological status (odds ratio, 1.85; p < 0.001), fibromyalgia (odds ratio, 1.39; p < 0.05), severe autonomic dysfunction (odds ratio, 1.72; p < 0.05), poor functional capacity (odds ratio, 0.98; p < 0.05) and quality of life (odds ratio, 0.96; both p < 0.001) were significantly associated with poor sleep quality.

These findings suggest that this large chronic fatigue syndrome/myalgic encephalomyelitis sample presents poor sleep quality, as assessed by the Pittsburgh Sleep Quality Index, and that this poor sleep quality is associated with many aspects of quality of life.

Source: Castro-Marrero J, Zaragozá MC, González-Garcia S, Aliste L, Sáez-Francàs N, Romero O, Ferré A, Fernández de Sevilla T, Alegre J.  Poor self-reported sleep quality and health-related quality of life in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J Sleep Res. 2018 May 16:e12703. doi: 10.1111/jsr.12703. [Epub ahead of print]  https://www.ncbi.nlm.nih.gov/pubmed/29770505

Comorbidity in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Nationwide Population-Based Cohort Study

Abstract:

BACKGROUND: Previous studies have shown evidence of comorbid conditions in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

OBJECTIVE: To estimate the prevalence of comorbidities and assess their associations using a nationwide population-based database of a Spanish CFS/ME cohort.

METHOD: A nationally representative, retrospective, cross-sectional cohort study (2008-2015) assessed 1757 Spanish subjects who met both the 1994 Centers for Disease Control and Prevention/Fukuda definition and 2003 Canadian Criteria for CFS/ME. Sociodemographic and clinical data, comorbidities, and patient-reported outcome measures at baseline were recorded. A cluster analysis based on baseline clinical variables was performed to classify patients with CFS/ME into 5 categories according to comorbidities. A multivariate logistic regression analysis was conducted adjusting for potential confounding effects such as age and sex; response and categorical predictor variables were also assessed.

RESULTS: A total of 1757 CFS/ME patients completed surveys were collected. We identified 5 CFS/ME clusters: group 1-fibromyalgia, myofascial pain, multiple chemical hypersensitivity, sicca syndrome, epicondylitis, and thyroiditis; group 2-alterations of ligaments and subcutaneous tissue, hypovitaminosis D, psychopathology, ligamentous hyperlaxity, and endometriosis. These 2 subgroups comprised mainly older women, with low educational level, unemployment, high levels of fatigue, and poor quality of life; group 3-with hardly any comorbidities, comprising mainly younger women, university students or those already employed, with lower levels of fatigue, and better quality of life; group 4-poorly defined comorbidities; and group 5-hypercholesterolemia.

CONCLUSION: Over 80% of a large population-based cohort of Spanish patients with CFS/ME presented comorbidities. Among the 5 subgroups created, the most interesting were groups 1-3. Future research should consider multidisciplinary approaches for the management and treatment of CFS/ME with comorbid conditions.

Copyright © 2017 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Source: Castro-Marrero J, Faro M, Aliste L, Sáez-Francàs N, Calvo N, Martínez-Martínez A, de Sevilla TF, Alegre J. Comorbidity in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Nationwide Population-Based Cohort Study. Psychosomatics. 2017 Apr 21. pii: S0033-3182(17)30118-4. doi: 10.1016/j.psym.2017.04.010. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28596045