Tag: 2022

Herpesvirus and neurological manifestations in patients with severe coronavirus disease

Abstract:

Background: Certain clinical manifestations of coronavirus disease (COVID-19) mimic those associated with human herpesvirus (HHV) infection. In this study, we estimated the prevalence of herpesvirus in patients with COVID-19 and determined if coinfection is associated with poorer outcomes and neurological symptoms.

Methods: We analyzed samples of 53 patients diagnosed with COVID-19. The samples were evaluated for the presence of alphaherpesviruses, betaherpesviruses, and gammaherpesviruses, and the viral loads were quantified using quantitative polymerase chain reaction (qPCR) method.

Results: Among the patients, in 79.2% had detection at least one type of herpesvirus. HHV-6 (47.2%), cytomegalovirus (43.3%), and HHV-7 (39.6%) showed the highest detection rates. Patients with a high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) load were more likely to show herpes simplex virus 1 detection (p = 0.037). Among patients coinfected with SARS-CoV-2 and HHVs, 26.4% showed central nervous system-associated neurological symptoms and herpetic manifestations. A statistically significant association was observed between neurological changes and HHV-6 detection (p = 0.034).

Conclusions: The findings showed a high prevalence of herpesvirus in patients with COVID-19. Furthermore, even though SARS-CoV-2 and HHV coinfection was not associated with poorer outcomes, the findings demonstrated the association between neurological symptoms and HHV-6 detection.

Source: Carneiro VCS, Alves-Leon SV, Sarmento DJS, Coelho WLDCNP, Moreira ODC, Salvio AL, Ramos CHF, Ramos Filho CHF, Marques CAB, da Costa Gonçalves JP, Leon LAA, de Paula VS. Herpesvirus and neurological manifestations in patients with severe coronavirus disease. Virol J. 2022 Jun 8;19(1):101. doi: 10.1186/s12985-022-01828-9. PMID: 35676707; PMCID: PMC9174631. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174631/  (Full text)

Cognitive task performance and subjective cognitive symptoms in individuals with Chronic Fatigue Syndrome or Fibromyalgia: A cross-sectional analysis of the Lifelines cohort study

Abstract:

Objective: This study examined cognitive task performance and self-reported cognitive functioning in individuals with chronic fatigue syndrome (CFS) and fibromyalgia (FM) in a population-based sample and investigated the role of mood and anxiety disorders as well as severity of the physical symptoms.

Methods: This study was performed in 79,966 participants (Mean age: 52.9, SD = ±12.6 years, 59.2% women) from the Lifelines general-population. Symptoms consistent with the diagnostic criteria for CFS and FM were assessed using questionnaires. Two comparison groups were used: participants with self-reported medical disorders with well-defined pathophysiology (i.e., multiple sclerosis and rheumatic arthritis) and controls without these diseases. Objective task-performance was based on the computerized CogState cognitive battery and subjective cognitive symptoms using the concentration subscale of the Checklist Individual Strength.

Results: Cognitive task performance was poorer in individuals with CFS vs. controls without disease and controls with a medical disorder, although the severity of cognitive dysfunction was mild. Participants meeting criteria for CFS (n = 2,461) or FM (n = 4,295) reported more subjective cognitive symptoms compared to controls without a medical disorder (d = 1.53, 95%CI = 1.49-1.57 for CFS; d = 1.25, 95%CI = 1.22-1.29 for FM) and participants with a medical disease (d = 0.62, 95%CI = 0.46-0.79 for CFS; d = 0.75, 95%CI = 0.70-0.80 for FM). These differences remained essentially the same when excluding participants with comorbid mood or anxiety disorders or adjusting for physical symptom severity.

Conclusions: Subjective cognitive symptoms and to a lesser extent suboptimal cognitive task performance are more prevalent in individuals with CFS or FM compared to controls without these conditions.

Source: Joustra ML, Hartman CA, Bakker SJL, Rosmalen JGM. Cognitive task performance and subjective cognitive symptoms in individuals with Chronic Fatigue Syndrome or Fibromyalgia: A cross-sectional analysis of the Lifelines cohort study. Psychosom Med. 2022 Aug 2. doi: 10.1097/PSY.0000000000001117. Epub ahead of print. PMID: 35980775.  https://pubmed.ncbi.nlm.nih.gov/35980775/

Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients

Summary:

Background: COVID-19 is associated with increased risks of neurological and psychiatric sequelae in the weeks and months thereafter. How long these risks remain, whether they affect children and adults similarly, and whether SARS-CoV-2 variants differ in their risk profiles remains unclear.

Methods: In this analysis of 2-year retrospective cohort studies, we extracted data from the TriNetX electronic health records network, an international network of de-identified data from health-care records of approximately 89 million patients collected from hospital, primary care, and specialist providers (mostly from the USA, but also from Australia, the UK, Spain, Bulgaria, India, Malaysia, and Taiwan). A cohort of patients of any age with COVID-19 diagnosed between Jan 20, 2020, and April 13, 2022, was identified and propensity-score matched (1:1) to a contemporaneous cohort of patients with any other respiratory infection. Matching was done on the basis of demographic factors, risk factors for COVID-19 and severe COVID-19 illness, and vaccination status. Analyses were stratified by age group (age <18 years [children], 18–64 years [adults], and ≥65 years [older adults]) and date of diagnosis. We assessed the risks of 14 neurological and psychiatric diagnoses after SARS-CoV-2 infection and compared these risks with the matched comparator cohort. The 2-year risk trajectories were represented by time-varying hazard ratios (HRs) and summarised using the 6-month constant HRs (representing the risks in the earlier phase of follow-up, which have not yet been well characterised in children), the risk horizon for each outcome (ie, the time at which the HR returns to 1), and the time to equal incidence in the two cohorts. We also estimated how many people died after a neurological or psychiatric diagnosis during follow-up in each age group. Finally, we compared matched cohorts of patients diagnosed with COVID-19 directly before and after the emergence of the alpha (B.1.1.7), delta (B.1.617.2), and omicron (B.1.1.529) variants.

Findings: We identified 1 487 712 patients with a recorded diagnosis of COVID-19 during the study period, of whom 1 284 437 (185 748 children, 856 588 adults, and 242 101 older adults; overall mean age 42·5 years [SD 21·9]; 741 806 [57·8%] were female and 542 192 [42·2%] were male) were adequately matched with an equal number of patients with another respiratory infection. The risk trajectories of outcomes after SARS-CoV-2 infection in the whole cohort differed substantially. While most outcomes had HRs significantly greater than 1 after 6 months (with the exception of encephalitis; Guillain-Barré syndrome; nerve, nerve root, and plexus disorder; and parkinsonism), their risk horizons and time to equal incidence varied greatly. Risks of the common psychiatric disorders returned to baseline after 1–2 months (mood disorders at 43 days, anxiety disorders at 58 days) and subsequently reached an equal overall incidence to the matched comparison group (mood disorders at 457 days, anxiety disorders at 417 days).

By contrast, risks of cognitive deficit (known as brain fog), dementia, psychotic disorders, and epilepsy or seizures were still increased at the end of the 2-year follow-up period. Post-COVID-19 risk trajectories differed in children compared with adults: in the 6 months after SARS-CoV-2 infection, children were not at an increased risk of mood (HR 1·02 [95% CI 0·94–1·10) or anxiety (1·00 [0·94–1·06]) disorders, but did have an increased risk of cognitive deficit, insomnia, intracranial haemorrhage, ischaemic stroke, nerve, nerve root, and plexus disorders, psychotic disorders, and epilepsy or seizures (HRs ranging from 1·20 [1·09–1·33] to 2·16 [1·46–3·19]). Unlike adults, cognitive deficit in children had a finite risk horizon (75 days) and a finite time to equal incidence (491 days).

A sizeable proportion of older adults who received a neurological or psychiatric diagnosis, in either cohort, subsequently died, especially those diagnosed with dementia or epilepsy or seizures. Risk profiles were similar just before versus just after the emergence of the alpha variant (n=47 675 in each cohort). Just after (vs just before) the emergence of the delta variant (n=44 835 in each cohort), increased risks of ischaemic stroke, epilepsy or seizures, cognitive deficit, insomnia, and anxiety disorders were observed, compounded by an increased death rate. With omicron (n=39 845 in each cohort), there was a lower death rate than just before emergence of the variant, but the risks of neurological and psychiatric outcomes remained similar.

Interpretation: This analysis of 2-year retrospective cohort studies of individuals diagnosed with COVID-19 showed that the increased incidence of mood and anxiety disorders was transient, with no overall excess of these diagnoses compared with other respiratory infections. In contrast, the increased risk of psychotic disorder, cognitive deficit, dementia, and epilepsy or seizures persisted throughout. The differing trajectories suggest a different pathogenesis for these outcomes. Children have a more benign overall profile of psychiatric risk than do adults and older adults, but their sustained higher risk of some diagnoses is of concern. The fact that neurological and psychiatric outcomes were similar during the delta and omicron waves indicates that the burden on the health-care system might continue even with variants that are less severe in other respects. Our findings are relevant to understanding individual-level and population-level risks of neurological and psychiatric disorders after SARS-CoV-2 infection and can help inform our responses to them.

Source: Maxime Taquet, PhD, Rebecca Sillett, BA, Lena Zhu, BS, Jacob Mendel, MMath, Isabella Camplisson, BS, Quentin Dercon, MSc, et al. Open Access Published: August 17, 2022 DOI: https://doi.org/10.1016/S2215-0366(22)00260-7 https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(22)00260-7/fulltext# (Full text)

Repeated maximal exercise tests of peak oxygen consumption in people with myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and meta-analysis

Abstract:

Background: Repeated maximal exercise separated by 24 hours may be useful in identifying possible objective markers in people with ME/CFS that are not present in healthy controls.

Aim: We aimed to synthesise studies in which the test-to-retest (24 hours) changes in VO2 and work rate have been compared between people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and controls.

Methods: Seven databases (CINAHL, PubMed, PsycINFO, Web of Knowledge, Embase, Scopus and MEDLINE) were searched. Included studies were observational studies that assessed adults over the age of 18 years with a clinical diagnosis of ME/CFS compared to healthy controls. The methodological quality of included studies was assessed using the Systematic Appraisal of Quality for Observational Research critical appraisal framework. Data from included studies were synthesised using a random effects meta-analysis.

Results: The pooled mean decrease in peak work rate (five studies), measured at retest, was greater in ME/CFS by −8.55 (95% CI −15.38 to –1.72) W. The pooled mean decrease in work rate at anaerobic threshold (four studies) measured at retest was greater in ME/CFS by −21 (95%CI −38 to −4, tau = 9.8) W. The likelihood that a future study in a similar setting would report a difference in work rate at anaerobic threshold which would exceed a minimal clinically important difference (10 W) is 78% (95% CI 40%–91%).

Conclusion: Synthesised data indicate that people with ME/CFS demonstrate a clinically significant test–retest reduction in work rate at the anaerobic threshold when compared to apparently healthy controls.

Source: John Derek Franklin & Michael Graham (2022) Repeated maximal exercise tests of peak oxygen consumption in people with myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review and meta-analysis, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2022.2108628  https://www.tandfonline.com/doi/full/10.1080/21641846.2022.2108628 (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is common in post-acute sequelae of SARS-CoV-2 infection (PASC): Results from a post-COVID-19 multidisciplinary clinic

Summary:

Background The global prevalence of PASC is estimated to be present in 0·43 and based on the WHO estimation of 470 million worldwide COVID-19 infections, corresponds to around 200 million people experiencing long COVID symptoms. Despite this, its clinical features are not well defined.

Methods We collected retrospective data from 140 patients with PASC in a post-COVID-19 clinic on demographics, risk factors, illness severity (graded as one-mild to five-severe), functional status, and 29 symptoms and principal component symptoms cluster analysis. The Institute of Medicine (IOM) 2015 criteria were used to determine the ME/CFS phenotype.

Findings The median age was 47 years, 59·0% were female; 49·3% White, 17·2% Hispanic, 14·9% Asian, and 6·7% Black. Only 12·7% required hospitalization. Seventy-two (53·5%) patients had no known comorbid conditions. Forty-five (33·9%) were significantly debilitated. The median duration of symptoms was 285·5 days, and the number of symptoms was 12. The most common symptoms were fatigue (86·5%), post-exertional malaise (82·8%), brain fog (81·2%), unrefreshing sleep (76·7%), and lethargy (74·6%). Forty-three percent fit the criteria for ME/CFS.

Interpretations Most PASC patients evaluated at our clinic had no comorbid condition and were not hospitalized for acute COVID-19. One-third of patients experienced a severe decline in their functional status. About 43% had the ME/CFS subtype.

Source:  H Bonilla, TC Quach, A Tiwari, AE Bonilla, M Miglis, P Yang, L Eggert, H Sharifi, A Horomanski, A Subramanian, L Smirnoff, N Simpson, H Halawi, O Sum-Ping, A Kalinowski, Z Patel, R Shafer, L. Geng. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is common in post-acute sequelae of SARS-CoV-2 infection (PASC): Results from a post-COVID-19 multidisciplinary clinic. medRxiv 2022.08.03.22278363; doi: https://doi.org/10.1101/2022.08.03.22278363

Persistent capillary rarefication in long COVID syndrome

Abstract:

Background: Recent studies have highlighted Coronavirus disease 2019 (COVID-19) as a multisystemic vascular disease. Up to 60% of the patients suffer from long-term sequelae and persistent symptoms even 6 months after the initial infection.

Methods: This prospective, observational study included 58 participants, 27 of whom were long COVID patients with persistent symptoms > 12 weeks after recovery from PCR-confirmed SARS-CoV-2 infection. Fifteen healthy volunteers and a historical cohort of critically ill COVID-19 patients (n = 16) served as controls. All participants underwent sublingual videomicroscopy using sidestream dark field imaging. A newly developed version of Glycocheck™ software was used to quantify vascular density, perfused boundary region (PBR-an inverse variable of endothelial glycocalyx dimensions), red blood cell velocity (VRBC) and the microvascular health score (MVHS™) in sublingual microvessels with diameters 4-25 µm.

Measurements and main results: Although dimensions of the glycocalyx were comparable to those of healthy controls, a µm-precise analysis showed a significant decrease of vascular density, that exclusively affected very small capillaries (D5: – 45.16%; D6: – 35.60%; D7: – 22.79%). Plotting VRBC of capillaries and feed vessels showed that the number of capillaries perfused in long COVID patients was comparable to that of critically ill COVID-19 patients and did not respond adequately to local variations of tissue metabolic demand. MVHS was markedly reduced in the long COVID cohort (healthy 3.87 vs. long COVID 2.72 points; p = 0.002).

Conclusions: Our current data strongly suggest that COVID-19 leaves a persistent capillary rarefication even 18 months after infection. Whether, to what extent, and when the observed damage might be reversible remains unclear.

Source: Osiaevi I, Schulze A, Evers G, Harmening K, Vink H, Kümpers P, Mohr M, Rovas A. Persistent capillary rarefication in long COVID syndrome. Angiogenesis. 2022 Aug 11:1–9. doi: 10.1007/s10456-022-09850-9. Epub ahead of print. PMID: 35951203; PMCID: PMC9366128. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9366128/ (Full text)

Predictors of Chronic Fatigue Syndrome and Mood Disturbance After Acute Infection

Abstract:

Prospective cohort studies following individuals from acute infections have documented a prevalent post-infective fatigue state meeting diagnostic criteria for chronic fatigue syndrome (CFS) – that is, a post-infective fatigue syndrome (PIFS). The Dubbo Infection Outcomes Study (DIOS) was a prospective cohort following individuals from acute infection with Epstein-Barr virus (EBV), Ross River virus (RRV), or Q fever through to assessment of caseness for CFS designated by physician and psychiatrist assessments at 6 months. Previous studies in DIOS have revealed that functional genetic polymorphisms in both immunological (pro- and anti-inflammatory cytokines) and neurological (the purinergic receptor, P2X7) genes are associated with both the severity of the acute infection and subsequent prolonged illness.

Principal components analysis was applied to self-report data from DIOS to describe the severity and course of both the overall illness and concurrent mood disturbance. Associations between demographics and acute infection characteristics, with prolonged illness course as well as the PIFS outcome were examined using multivariable statistics. Genetic haplotype-driven functional variations in the neuropeptide Y (NPY) gene previously shown to be associated with brain responses to stress, and to trait anxiety were also examined as predictors.

The sample included 484 subjects (51% female, median age 32, IQR 19-44), of whom 90 (19%) met diagnostic criteria for CFS at 6 months. Participants with greater overall illness severity and concurrent mood disturbance in the acute illness had a more prolonged illness severity (HR = 0.39, 95% CI: 0.34-0.46, p < 0.001) and mood disturbance (HR = 0.36, 95% CI: 0.30-0.42, p < 0.001), respectively. Baseline illness severity and RRV infection were associated with delayed recovery.

Female gender and mood disturbance in the acute illness were associated with prolonged mood disturbance. Logistic regression showed that the odds of an individual being diagnosed with PIFS increased with greater baseline illness severity (OR = 2.24, 95% CI: 1.71-2.94, p < 0.001). There was no association between the NPY haplotypes with overall illness severity or mood disturbance either during the acute illness phase or with prolonged illness (p > 0.05). Severe acute infective illnesses predicted prolonged illness, prolonged mood disturbance and PIFS. These factors may facilitate early intervention to manage both PIFS and mood disturbances.

Source: Sandler CX, Cvejic E, Valencia BM, Li H, Hickie IB, Lloyd AR. Predictors of Chronic Fatigue Syndrome and Mood Disturbance After Acute Infection. Front Neurol. 2022 Jul 25;13:935442. doi: 10.3389/fneur.2022.935442. PMID: 35959390; PMCID: PMC9359311. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9359311/ (Full text)

Special Issue “Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Diagnosis and Treatment”

Introduction:
Chronic fatigue syndrome, or myalgic encephalomyelitis (CFS/ME), is a debilitating disease with unknown causes that is more common in women and tends to develop between patients’ mid-20s and mid-40s. From the perspectives on the etiology and pathophysiology, CFS/ME has been labeled differently, which has influenced changes in case definitions and terminologies. CFS/ME is characterized by persistent asthenia with associated musculoskeletal pain, cognitive disturbance (including attention, memory, and concentration), psychological troubles (depression, anxiety), sleep disorders, and a variety of neurovegetative symptoms. The best appropriate therapeutic is an integrative approach, based on a personalized medical plane that includes distinct groups of procedures: educational, cognitive-behavioral, pharmacological and non-pharmacological such as occupational therapy and rehabilitation. CFS/ME has some common clinical features with fibromyalgia, and a differential diagnosis is difficult for General Practitioners (GPs) [1,2].
The recent opinion is that CFS/ME pathogenesis is dependent on several factors or causes. Different studies have shown evidence for an alteration in immunity system in patients with CFS/ME. A modification in cytokine subsets, a diminished activity of natural killer (NK) lymphocytes, the detection of autoantibodies and a decreased response of T cells to mitogens and specific antigens have been observed. An increased level of pro-inflammatory cytokines may explain some of the clinical features, such as fatigue and flulike symptoms, with an effect on NK activity. Anomalous activation of the T lymphocyte profile and a reduction in antibody-dependent cell-mediated cytotoxicity have been reported. An increased number of CD8+ cytotoxic T lymphocytes and CD38 and HLA-DR activation markers have been demonstrated, and a reduced CD11b expression associated with an increased expression of CD28+ T subsets has been described [3]. An interest towards CFS/ME is increased with the recent pandemic by SARS-CoV-2 because, after the acute phase of disease, some patients have clinical features similar to CFS/ME called Long-COVID, characterized by tiredness, brain fog and headache. There is debate on common aspect between these pathologies but in especially a possible effect of COVID-19 on CFS/ME and the consequences [4].
This Special Issue on CFS/ME collects 18 papers with an interdisciplinary view on the current demographic and epidemiological data and immunological characteristics of CFS/ME and examines the different pathogenic hypotheses, as well as giving information about the latest knowledge on diagnostic investigations, pharmacological, integrative, physical, cognitive-behavioral and psychological curative approaches.
It is known that CFS/ME affects young adults, but there are little studies in pediatric and adolescent age. Australian colleagues Elisha K. Josev and colleagues have carried out a case-controlled follow-up study on the health, wellbeing and prognosis of Australian adolescents with CFS/ME on the comprehension of the important relation between physical and psychological health factors to adolescent’ long-term outcome for approaching future prevention, management and treatment [5]. Concerning epidemiological data, there is little information for Asian countries such Korea and Japan. Eun-Jn Lim and Chang-Gue Son evaluate and match the prevalence of CFS/ME in Korea and Japan, performing a meta-analysis analyzing the main characteristics of these nations [6].
The emerging data of the involvement of immune system confirmed the hypothesis that CFS/ME is an autoimmune disease; recent studies have shown the role of autoantibodies towards the vegetative nervous system. Freitag H. and colleagues reported the reactivity of autoantibodies to vasoregulative G-Protein-Coupled Receptor correlates with autonomic dysfunction, clinical gravity and disability in CFS/ME patients [7]. Another paper, by Kujawski S. and collaborators, studies the differences in CFS patients applying post-exertional malaise (PEM) as indicators of aortic stiffness, autonomic nervous system function and severity of fatigue [8]. Always on the role of the autonomic nervous system dysfunction, Jessica Van Oosterwijck et al. published a paper showing decreased parasympathetic reactivation from physical exercise that could be correlated with a bad prognosis or high risk for adverse cardiac event [8]. Varesi A. and colleagues investigated the emerging role of the modified composition of gut microbiota in relationship with genetic, infection, immunological and other influences that have seen in CFS/ME individuals [9]. The authors discuss the change and the potential therapeutic application of treating the gut in CFS/ME patients [10].
A collection of papers investigates the importance of the diagnostic tools in clinical practice. We start with Baklund H. I. et al., who evaluated the blood test in relationship with clinical features and diagnostic classification, suggesting muscle damage and metabolic abnormalities [11].
A potential blood diagnostic tool, by Castro-Marrero J. and his Spanish collaborators, could be the complement C1 examining in CFS/ME three-symptom clusters, identified as severe, moderate and mild, presenting important differences in five blood parameters [12]. Another objective measurement for PEM, which is a hallmark of CFS/ME, is the application of the two-days cardiopulmonary exercise test (CPET) to assess functional impairment: Eun-Jin Lim and Korean collaborators, in their paper, published the results of a meta-analysis on this diagnostic tool [13]. Moreover, Do-Young Kim and his Korean colleagues examined a systematic review to provide an overview of the adoption of the main measurements in RCTs for CFS/ME. Around 40% of RCTs utilized multiple primary measurements. This information could be helpful in clinical practice in the design of medical studies for CFS/ME-linked therapeutic development [14].
The therapy of CFS/ME is problematic due to lack of knowledge on the etiopathogenesis of this disease, with application of the unconventional and conventional treatments: Tirelli and colleagues compared the application of oxygen–ozone autohemotherapy (O2-O3-AHT) in male vs. female patients, evaluating the differences in their responses to this approach [15]. The effects of exercise from a structured activity program have been disputed; Kujawski S. et al., with a multidisciplinary study, examined the impact of a personalized program of activities associated with cardiovascular, mitochondrial and fatigue parameters, showing a reduction in fatigue and an improving functional performance [16]. An important conventional therapeutic approach is the effect of s.c. IgG self-treatment in ME/CFS patients with IgG/IgG subgroup deficiency. The aim of Scheibenbogen C. and her German collaborators was to study the IgG administration for its immunomodulatory effects. [17].
There are few studies relationship CFS/ME patients and COVID-19 patients [18]. Araja D. and Latvian collaborators researched undiagnosed CFS/ME patients, hypothesizing the expansion of post-viral CFS as an effect of COVID-19 and its social impact. The Latvian research results show that patients with CFS/ME are not a risk group for COVID-19; however, COVID-19 causes symptoms similar to CFS/ME. They concluded that CFS/ME creates a significant social consequence, considering the direct medical costs of undiagnosed patients. At the same time, COVID-19 is responsible for long-lasting complications and a chronic course, such as post-viral CFS [19].
Deumer U-S et al. discuss the role of the gut microbiota on disease progression, highlighting a potential biomarker in non-coding RNA (ncRNA) as a probable diagnostic tool and suggesting the possibility that SARS-CoV-2 infection may result in symptoms similar to CFS [20].
CFS/ME has an overlap with Fibromyalgia, and differential diagnosis is difficult for some clinicians because the diagnosis of fibromyalgia is based only on clinical features that are characterized by widespread pain, fatigue, stiffness and troubles in cognitive functions, such as attention, executive function and verbal memory deficits [21]. It is important to add more tests beyond the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) test in fibromyalgia patients to assess the relationship between physical and cognitive performance, as reported by Murillo-Garcia A. and colleagues [22]. Another potential diagnostic tool is studied by Martin-Brufau R. and collaborators using electroencephalography for patients with fibromyalgia that present lower levels of brain activity with reduced connectivity than controls. The Spanish group identified a possible neurophysiological pattern that could adapt to the clinical features of the disease [23]. The therapeutic approach to this disease is a difficult choice. Rodriguez-Mansilla J. and Spanish collaborators studied the effects of non-pharmacological treatment in terms of the effectiveness of an exercise program compared to wellness activities by improving pain, flexibility, static balance, perceived effort and quality of life in patients with fibromyalgia. Participants in the active exercise program performed better than exercise for well-being [24]. This proposal in fibromyalgia is associated with other conventional treatments based on a multidisciplinary approach.
In conclusion, the papers published within this research topic, with the major contribution of the members of the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE), give us the recent highlight perspective and opportunities for the discovery and development of possible specific biomarkers, diagnostic and therapeutic approaches for these immunological disorders.
Source: Lorusso L, Ricevuti G. Special Issue “Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Diagnosis and Treatment”. J Clin Med. 2022 Aug 4;11(15):4563. doi: 10.3390/jcm11154563. PMID: 35956178. https://www.mdpi.com/2077-0383/11/15/4563/htm (Full text)

Distinguishing features of Long COVID identified through immune profiling

Abstract:

SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease called post-acute sequelae of COVID-19 (PASC) or Long COVID. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Here, 215 individuals were included in an exploratory, cross-sectional study to perform multi-dimensional immune phenotyping in conjunction with machine learning methods to identify key immunological features distinguishing Long COVID.

Marked differences were noted in specific circulating myeloid and lymphocyte populations relative to matched control groups, as well as evidence of elevated humoral responses directed against SARS-CoV-2 among participants with Long COVID. Further, unexpected increases were observed in antibody responses directed against non-SARS-CoV-2 viral pathogens, particularly Epstein-Barr virus.

Analysis of circulating immune mediators and various hormones also revealed pronounced differences, with levels of cortisol being uniformly lower among participants with Long COVID relative to matched control groups. Integration of immune phenotyping data into unbiased machine learning models identified significant distinguishing features critical in accurate classification of Long COVID, with decreased levels of cortisol being the most significant individual predictor. These findings will help guide additional studies into the pathobiology of Long COVID and may aid in the future development of objective biomarkers for Long COVID.

Source: Jon Klein, Jamie Wood, Jillian Jaycox, Peiwen Lu, Rahul M. Dhodapkar, Jeffrey R. Gehlhausen, Alexandra Tabachnikova, Laura Tabacof, Amyn A. Malik, Kathy Kamath, Kerrie Greene, Valter Silva Monteiro, Mario Pena-Hernandez, Tianyang Mao, Bornali Bhattacharjee, Takehiro Takahashi, Carolina Lucas, Julio Silva, Dayna Mccarthy, Erica Breyman, Jenna Tosto-Mancuso, Yile Dai, Emily Perotti, Koray Akduman, Tiffany Tzeng, Lan Xu, Inci Yildirim, Harlan M. Krumholz, John Shon, Ruslan Medzhitov, Saad B. Omer, David van Dijk, Aaron M. Ring, David Putrino, Akiko Iwasaki. Distinguishing features of Long COVID identified through immune profiling. medRxiv 2022.08.09.22278592; doi: https://doi.org/10.1101/2022.08.09.22278592

In Schizophrenia, Chronic Fatigue Syndrome- and Fibromyalgia-Like Symptoms are Driven by Breakdown of the Paracellular Pathway with Increased Zonulin and Immune Activation-Associated Neurotoxicity

Abstract:

Background: A meaningful part of schizophrenia patients suffer from physiosomatic symptoms (formerly named psychosomatic) which are reminiscent of chronic fatigue syndrome and fibromyalgia (FF) and are associated with signs of immune activation and increased levels of tryptophan catabolites (TRYCATs).

Aims: To examine whether FF symptoms in schizophrenia are associated with breakdown of the paracellular pathway, zonulin, lowered natural IgM responses to oxidative specific epitopes (OSEs); and whether FF symptoms belong to the behavioral-cognitive-physical-psychosocial-(BCPS)-worsening index consisting of indices of a general cognitive decline (G-CoDe), symptomatome of schizophrenia, and quality of life (QoL)-phenomenome.

Methods: FF symptoms were assessed using the Fibromyalgia and Chronic Fatigue Rating scale in 80 schizophrenia patients and 40 healthy controls and serum cytokines/chemokines, IgA levels to TRYCATs, IgM to OSEs, zonulin and transcellular/paracellular (TRANS/PARA) molecules were assayed using ELISA methods.

Results: A large part (42.3%) of the variance in the total FF score was explained by the regression on the PARA/TRANS ratio, pro-inflammatory cytokines, IgM to zonulin, IgA to TRYCATs (all positively) and IgM to OSEs (inversely). There were highly significant correlations between the total FF score and G-CoDe, symtopmatome, QoL phenomenome and BCPS-worsening score. FF symptoms belong to a common core shared by G-CoDe, symtopmatome, and QoL phenomenome.

Discussion: The physio-somatic symptoms of schizophrenia are driven by various pathways including increased zonulin, breakdown of the paracellular tight-junctions pathway, immune activation with induction of the TRYCAT pathway, and consequent neurotoxicity. It is concluded that FF symptoms are part of the phenome of schizophrenia and BCPS-worsening as well.

Source: Maes M, Andrés-Rodríguez L, Vojdani A, Sirivichayakul S, Barbosa DS, Kanchanatawan B. In Schizophrenia, Chronic Fatigue Syndrome- and Fibromyalgia-Like Symptoms are Driven by Breakdown of the Paracellular Pathway with Increased Zonulin and Immune Activation-Associated Neurotoxicity. CNS Neurol Disord Drug Targets. 2022 Aug 6. doi: 10.2174/1871527321666220806100600. Epub ahead of print. PMID: 35946099.