Treatments of chronic fatigue syndrome and its debilitating comorbidities: a 12-year population-based study

Abstract:

Background: This study aims to provide 12-year nationwide epidemiology data to investigate the epidemiology and comorbidities of and therapeutic options for chronic fatigue syndrome (CFS) by analyzing the National Health Insurance Research Database.

Methods: 6306 patients identified as having CFS during the 2000-2012 period and 6306 controls (with similar distributions of age and sex) were analyzed.

Result: The patients with CFS were predominantly female and aged 35-64 years in Taiwan and presented a higher proportion of depression, anxiety disorder, insomnia, Crohn’s disease, ulcerative colitis, renal disease, type 2 diabetes, gout, dyslipidemia, rheumatoid arthritis, Sjogren syndrome, and herpes zoster. The use of selective serotonin receptor inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), Serotonin antagonist and reuptake inhibitors (SARIs), Tricyclic antidepressants (TCAs), benzodiazepine (BZD), Norepinephrine-dopamine reuptake inhibitors (NDRIs), muscle relaxants, analgesic drugs, psychotherapies, and exercise therapies was prescribed significantly more frequently in the CFS cohort than in the control group.

Conclusion: This large national study shared the mainstream therapies of CFS in Taiwan, we noticed these treatments reported effective to relieve symptoms in previous studies. Furthermore, our findings indicate that clinicians should have a heightened awareness of the comorbidities of CFS, especially in psychiatric problems.

Source: Leong KH, Yip HT, Kuo CF, Tsai SY. Treatments of chronic fatigue syndrome and its debilitating comorbidities: a 12-year population-based study. J Transl Med. 2022 Jun 11;20(1):268. doi: 10.1186/s12967-022-03461-0. PMID: 35690765. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03461-0  (Full study)

Symptom burden correlates to impairment of diffusion capacity and exercise intolerance in long COVID patients

Abstract:

After acute infection with the SARS-CoV-2 virus, a considerable number of patients remains symptomatic with pathological changes in various organ systems. This study aimed to relate the physical and mental burden of symptoms of long COVID patients to the findings of a somatic evaluation.

In patients with persistent long COVID symptoms three months after acute infection we assessed physical and mental health status using the SF-36 questionnaire. The cohort was dichotomised by the results (upper two quartiles vs. lower to quartiles) and compared with regard to transthoracic echocardiography, body plethysmography (including diffusion capacity), capillary blood gas analysis and 6-min walk test (6-MWT). From February 22 to September 13, 2021, 463 patients were prospectively examined, of which 367 completed the SF-36 questionnaire. A positive correlation between initial disease severity (need for hospitalization, intensive care medicine) and resulting symptom burden at follow-up could be demonstrated.

Patients with impaired subjective physical and mental status were significantly more likely to be women. There was a significant correlation between symptom severity and reduced exercise tolerance in the 6-MWT (495.6 ± 83.7 m vs 549.7 ± 71.6 m, p < 0.001) and diffusion capacity for carbon monoxide (85.6 ± 14.3% of target vs 94.5 ± 14.4, p < 0.001). In long COVID patients, initial disease severity is correlated with symptom burden after at least 3 months of follow-up. Highly symptomatic long COVID patients show impaired diffusion capacity and 6-MWT despite average or mildly affected mechanical lung parameters. It must be further differentiated whether this corresponds to a transient functional impairment or whether it is a matter of defined organ damage.

Source: Kersten, J., Wolf, A., Hoyo, L. et al. Symptom burden correlates to impairment of diffusion capacity and exercise intolerance in long COVID patients. Sci Rep 12, 8801 (2022). https://doi.org/10.1038/s41598-022-12839-5  https://www.nature.com/articles/s41598-022-12839-5 (Full text)

Restless legs syndrome is associated with long-COVID in women

Abstract:

Study Objectives: Sleep disturbance is common in long-COVID (LC). Restless legs syndrome (RLS) is characterized by sleep disturbance and has been reported after viral infections. Therefore, we evaluated RLS symptoms cross-sectionally in individuals with LC at both current and pre-COVID19 timepoints.

Methods: LC-focused Facebook adults were recruited for an online assessment of symptoms before COVID-19 infection and during their present LC state in a cross-sectional manner. The LC group documented baseline symptoms retrospectively. Questions were included about the presence/severity of RLS symptoms and assessments of fatigue, quality of life, and sleep apnea. A control group was recruited and included individuals ≥18 years of age who never had overt symptoms of COVID-19. Pregnancy was exclusion criteria for both groups.

Results: There were 136 LC participants (89.7% females, age 46.9 ±12.9 years) and 136 controls (65.4% females, age 49.2 ±15.5). RLS prevalence in LC-females was 5.7% pre-COVID-19 and 14.8% post-COVID-19 (p<0.01) vs. 6.7% in control-females. Severity of RLS was moderate in both groups. Logistic regression predicting post-COVID-19 RLS among LC-females failed to find significant effects of hospitalization, sleep apnea, neuropathic pain severity or use of antihistamines and antidepressants.

Conclusions: The baseline prevalence of RLS in LC-females was similar to the general population group as well as to patients in epidemiological studies. The prevalence significantly increased in the LC state. Post-infectious immunological mechanisms may be at play in the production for RLS symptoms.

Source: Leonard B. Weinstock, MD, FACG ; Jill B. Brook, MA ; Arthur S. Walters,  MD ;  Ashleigh Goris, RN, BSN, MPH, CIC, FAPIC ; Lawrence B. Afrin, MD ; Gerhard J. Molderings, MD. Restless legs syndrome is associated with long-COVID in women. Journal of Clinical Sleep Medicine. Published Online:January 25, 2022. https://doi.org/10.5664/jcsm.9898 https://jcsm.aasm.org/doi/pdf/10.5664/jcsm.9898 (Full study)

Long covid in adults discharged from UK hospitals after covid-19: a prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol

Abstract:

Background: This study sought to establish the long-term effects of Covid-19 following hospitalisation.

Methods: 327 hospitalised participants, with SARS-CoV-2 infection were recruited into a prospective multicentre cohort study at least 3 months post-discharge. The primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, disability (Washington group short scale), breathlessness (MRC Dyspnoea scale) and quality of life (EQ5D-5L).

Findings: 55% of participants reported not feeling fully recovered. 93% reported persistent symptoms, with fatigue the most common (83%), followed by breathlessness (54%). 47% reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24% of participants. The EQ5D-5L summary index was significantly worse following acute illness (median difference 0.1 points on a scale of 0 to 1, IQR: -0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age.

Interpretation: Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present in young, previously healthy working age adults, and were most common in younger females.

Source: Sigfrid L, Drake TM, Pauley E, Jesudason EC, Olliaro P, Lim WS, Gillesen A, Berry C, Lowe DJ, McPeake J, Lone N, Munblit D, Cevik M, Casey A, Bannister P, Russell CD, Goodwin L, Ho A, Turtle L, O’Hara ME, Hastie C, Donohue C, Spencer RG, Donegan C, Gummery A, Harrison J, Hardwick HE, Hastie CE, Carson G, Merson L, Baillie JK, Openshaw P, Harrison EM, Docherty AB, Semple MG, Scott JT; ISARIC4C investigators. Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Lancet Reg Health Eur. 2021 Sep;8:100186. doi: 10.1016/j.lanepe.2021.100186. Epub 2021 Aug 6. PMID: 34386785; PMCID: PMC8343377. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343377/ (Full text)

Covid-19: Middle aged women face greater risk of debilitating long term symptoms

Middle aged women have a higher risk of experiencing a range of debilitating ongoing symptoms, such as fatigue, breathlessness, muscle pain, anxiety, depression, and “brain fog” after hospital treatment for covid-19, suggest the findings of two unpublished studies available as preprints.

Seven in 10 patients admitted to hospital with covid-19 reported “long covid” symptoms an average of five months after discharge in the larger PHOSP-COVID study, and symptoms were more prevalent in women aged 40-60.1 White ethnicity, two or more comorbidities at admission, and receiving invasive ventilation while in hospital increased the risk, but severity of acute covid-19 disease did not seem to affect the likelihood of experiencing long covid symptoms.

Only 29% of the 1077 patients studied felt fully recovered when followed up, on average five months after discharge. Over a quarter had clinically significant symptoms of anxiety and depression, 12% had symptoms of post-traumatic stress disorder, 17% had at least mild cognitive impairment, 46% had lower physical performance than age and sex matched controls, and 20% had a new disability.

Before hospital admission 68% of patients had worked full time, but 18% of these had not returned to work and 19% had had to change their way of working because of longlasting effects.

The researchers grouped patients into four clusters according to the severity of their physical and mental symptoms post-covid: very severe (17% of patients), severe (21%), moderate with cognitive impairment (17%), and mild (46%).

Rachael Evans, National Institute for Health Research clinical scientist at the University of Leicester and a study author, said, “The symptoms are very real, but they don’t have a straightforward relationship with heart and lung damage, or certainly heart and lung damage can’t explain all the symptoms.”

Immune response

A smaller second study, from the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC), found that women under 50 were five times less likely to report feeling recovered, twice as likely to report worse fatigue, seven times more likely to become more breathless, and more likely to have greater disability than men of the same age who had been admitted to hospital with covid-19.2 Disability usually affected memory, mobility, communication, vision, or hearing. More than half of the 327 patients assessed in this study did not feel fully recovered when followed up on average seven months later, and persistent symptoms were reported by 93.3%, with fatigue and breathlessness the most common.

Chris Brightling, professor of respiratory medicine at the University of Leicester and a PHOSP-COVID study researcher, speculated that sex based differences in the immune response may be responsible for the higher prevalence of long covid symptoms in women, noting that autoimmune diseases were more prevalent in women than in men at age 40-60.

“Maybe there’s a difference in the immune response acutely, such that men are more likely to have a more severe condition at the time of the infection,” he told a press conference at the Science Media Centre on 24 March. “It may be that the immune response is different in women, so you then have a continued inflammatory reaction that then leads to a higher likelihood of having long covid.”

Higher levels of C reactive protein, a marker of systemic inflammation, were seen in patients in the most severe long covid symptoms. Brightling said that a number of immune and chronic inflammatory conditions can also cause elevated C reactive protein.

About 450 000 people have been admitted to hospital with covid-19 in the UK, so a “very large” proportion of these would potentially be affected by long covid, he said, adding, “Clearly there’s an even larger number of people that have had covid in the community, and a portion of those will also have long covid.”

Source: Torjesen ICovid-19: Middle aged women face greater risk of debilitating long term symptoms doi:10.1136/bmj.n829 https://www.bmj.com/content/372/bmj.n829 (Full text)

Estimating total morbidity burden of COVID-19: relative importance of death and disability

Abstract:

Objective: Calculations of disease burden of COVID-19, used to allocate scarce resources, have historically considered only mortality. However, survivors often develop postinfectious ‘long-COVID’ similar to chronic fatigue syndrome; physical sequelae such as heart damage, or both. This paper quantifies relative contributions of acute case fatality, delayed case fatality, and disability to total morbidity per COVID-19 case.

Study design and setting: Healthy life years lost per COVID-19 case were computed as the sum of (incidence*disability weight*duration) for death and long-COVID by sex and 10-year age category in three plausible scenarios.

Results: In all models, acute mortality was only a small share of total morbidity. For lifelong moderate symptoms, healthy years lost per COVID-19 case ranged from 0.92 (male in his 30s) to 5.71 (girl under 10) and were 3.5 and 3.6 for the oldest females and males. At higher symptom severities, young people and females bore larger shares of morbidity; if survivors’ later mortality increased, morbidity increased most in young people of both sexes.

Conclusions: Under most conditions most COVID-19 morbidity was in survivors. Future research should investigate incidence, risk factors, and clinical course of long-COVID to elucidate total disease burden, and decisionmakers should allocate scarce resources to minimize total morbidity. WHAT IS NEW; KEY FINDINGS: : Under most plausible model scenarios, most COVID-19 morbidity (death + disability) is likely to be due to disability (‘long-COVID’) or delayed death due to organ damage, rather than immediate death. Only if long-COVID resolves (atypical of postinfectious syndromes) is morbidity higher in old than young WHAT THIS ADDS TO WHAT IS KNOWN: : While COVID-19 deaths are numerous, they likely cause less morbidity overall than does disability or organ damage in survivors. Morbidity is highest in females, especially those infected young.

What should change now: Scarce resources such as vaccines should be allocated to minimize morbidity rather than focusing solely on mortality. Data on long-COVID, especially its sex bias, should be collected and publicized.

Source: Smith MP. Estimating total morbidity burden of COVID-19: relative importance of death and disability. J Clin Epidemiol. 2021 Oct 26:S0895-4356(21)00339-5. doi: 10.1016/j.jclinepi.2021.10.018. Epub ahead of print. PMID: 34715312. https://pubmed.ncbi.nlm.nih.gov/34715312/

Female Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Idiopathic Chronic Fatigue: Comparison of Responses to a Two-Day Cardiopulmonary Exercise Testing Protocol

Abstract:

Introduction: Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients, using the golden standard for measuring exercise intolerance: cardiopulmonary exercise testing (CPET). A 2-day CPET protocol has shown different results on day 2 in ME/CFS patients compared to sedentary controls. No comparison is known between ME/CFS and idiopathic chronic fatigue (ICF) for 2-day CPET protocols. We compared ME/CFS patients with patients with chronic fatigue who did not fulfil the ME/CFS criteria in a male population and hypothesized a different pattern of response would be present during the 2nd day CPET.

Methods: Fifty-one female patients with ICF completed a 2-day CPET protocol and were compared to an age/sex-matched group of 50 female ME/CFS patients. Measures of oxygen consumption (VO2), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were collected at maximal (peak) and ventilatory threshold (VT) intensities.

Results: Baseline characteristics for both groups were similar for age, BMI, BSA, and disease duration. A significance difference was present in the number of patients with fibromyalgia (seven ME/CFS patients vs zero ICF patients). Heart rate at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between 0.002 and <0.0001). ME/CFS patients showed a deterioration of performance on CPET2 as reflected by VO2 and workload at peak exercise and ventilatory threshold, whereas ICF patients showed improved performance on CPET2 with no significant change in peak workload.

Conclusion: This study confirms that female ME/CFS patients have a reduction in exercise capacity in response to a second day CPET. These results are similar to published results in female ME/CFS populations. Patients diagnosed with ICF show a different response on day 2, more similar to sedentary and healthy controls.

Source: van Campen CLMC, Visser FC. Female Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Idiopathic Chronic Fatigue: Comparison of Responses to a Two-Day Cardiopulmonary Exercise Testing Protocol. Healthcare (Basel). 2021 Jun 5;9(6):682. doi: 10.3390/healthcare9060682. PMID: 34198913. https://pubmed.ncbi.nlm.nih.gov/34198913/

The effect of fatigue and fibromyalgia on sexual dysfunction in women with chronic fatigue syndrome

Abstract:

Sexual dysfunction in patients with chronic fatigue syndrome is attracting growing interest but, to date, few studies have analyzed it. For this reason, the authors evaluated sexual dysfunction in women with chronic fatigue syndrome (using the Golombok Rust Inventory of Sexual Satisfaction) and explore correlations with fatigue and other symptoms. Sexual dysfunction was greater in patients with chronic fatigue syndrome (n = 615) with a higher number of cognitive, neurological, and neurovegetative symptoms, concomitant fibromyalgia, Sjögren’s syndrome, or myofascial pain syndrome, and more intense fatigue (p <.05).

 

Source: Blazquez A, Ruiz E, Aliste L, García-Quintana A, Alegre J. The effect of fatigue and fibromyalgia on sexual dysfunction in women with chronic fatigue syndrome. J Sex Marital Ther. 2015;41(1):1-10. doi: 10.1080/0092623X.2013.864370. Epub 2014 Mar 11. https://www.ncbi.nlm.nih.gov/pubmed/24274008

 

Women with chronic fatigue syndrome and sexual dysfunction: past, present, and future

Abstract:

Sexual dysfunction is a problem experienced by patients with chronic fatigue syndrome (CFS). Some studies indicate that CFS has a direct influence on sexual dysfunction, particularly hypoactive sexual desire. At this time, data on this subject are scarce, but the concept is emerging that CFS interferes with several aspects of the patients’ life, particularly sexuality. Further randomized controlled studies are needed to improve our knowledge of sexual dysfunction in CFS, to define the true impact of this condition on the patient’s sex life, and to improve the therapeutic management of this aspect of the disease.

 

Source: Blazquez A, Alegre J, Ruiz E. Women with chronic fatigue syndrome and sexual dysfunction: past, present, and future. J Sex Marital Ther. 2009;35(5):347-59. doi: 10.1080/00926230903065179. https://www.ncbi.nlm.nih.gov/pubmed/20183003

 

Postexertional malaise in women with chronic fatigue syndrome

Abstract:

OBJECTIVE: Postexertional malaise (PEM) is a defining characteristic of chronic fatigue syndrome (CFS) that remains a source of some controversy. The purpose of this study was to explore the effects of an exercise challenge on CFS symptoms from a patient perspective.

METHODS: This study included 25 female CFS patients and 23 age-matched sedentary controls. All participants underwent a maximal cardiopulmonary exercise test. Subjects completed a health and well-being survey (SF-36) 7 days postexercise. Subjects also provided, approximately 7 days after testing, written answers to open-ended questions pertaining to physical and cognitive responses to the test and length of recovery. SF-36 data were compared using multivariate analyses. Written questionnaire responses were used to determine recovery time as well as number and type of symptoms experienced.

RESULTS: Written questionnaires revealed that within 24 hours of the test, 85% of controls indicated full recovery, in contrast to 0 CFS patients. The remaining 15% of controls recovered within 48 hours of the test. In contrast, only 1 CFS patient recovered within 48 hours. Symptoms reported after the exercise test included fatigue, light-headedness, muscular/joint pain, cognitive dysfunction, headache, nausea, physical weakness, trembling/instability, insomnia, and sore throat/glands. A significant multivariate effect for the SF-36 responses (p < 0.001) indicated lower functioning among the CFS patients, which was most pronounced for items measuring physiological function.

CONCLUSIONS: The results of this study suggest that PEM is both a real and an incapacitating condition for women with CFS and that their responses to exercise are distinctively different from those of sedentary controls.

Source: VanNess JM, Stevens SR, Bateman L, Stiles TL, Snell CR. Postexertional malaise in women with chronic fatigue syndrome. J Womens Health (Larchmt). 2010 Feb;19(2):239-44. doi: 10.1089/jwh.2009.1507. https://www.ncbi.nlm.nih.gov/pubmed/20095909