Tag: 2023

Understanding Long COVID Syndrome: An Up to the Minute Fret

Abstract:

The Severe Acute Respiratory Syndrome Corona Virus 2 (SARSCoV-2) virus-induced corona virus disease 2019 (COVID-19) has had a global spread. Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) rst emerged in Wuhan, China, in December 2019, and the infection spread rapidly across the world. The disease caused by the virus was named corona virus disease in 2019, and was declared a global pandemic by the World Health Organization (WHO) in March 2020. While the symptoms are mild or moderate in most patients, severe pneumonia can develop in 15%, and Acute Respiratory Distress Syndrome (ARDS), septic shock, and multiple organ failure in 5%. A comprehensive strategy for precautions includes hand washing, social distancing, isolation and mask-wearing. Besides, vaccines play an essential role in preventing the spread.

Long COVID or long-haul COVID (also known as post-COVID-19 syndrome, post-COVID-19 condition, post-acute sequelae of COVID-19 (PASC), or chronic COVID syndrome (CCS) is a condition characterized by long-term health problems persisting or appearing after the typical recovery period of COVID-19. Although studies into long COVID are under way, as of May 2022 there is no consensus on the definition of the term.

Long COVID has been described as having the potential to affect nearly every organ system, causing further conditions (sequelae) including respiratory system disorders, nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, musculoskeletal pain, and anemia. The most commonly reported symptoms of long COVID are fatigue and memory problems. Many other symptoms have also been reported, including malaise, headaches, shortness of breath, anosmia (loss of smell), parosmia (distorted smell), muscle weakness, low-grade fever, and cognitive dysfunction. Overall, it is considered by default to be a diagnosis of exclusion.

Source: Gomes, Richmond. (2023). Understanding Long COVID Syndrome: An Up to the Minute Fret. 04. 1-7.  https://www.researchgate.net/publication/369037934_Understanding_Long_COVID_Syndrome_An_Up_to_the_Minute_Fret (Full text)

Ambient air pollution exposure linked to long COVID among young adults: a nested survey in a population-based cohort in Sweden

Summary:

Background: Post COVID-19 conditions, also known as long COVID, are of public health concern, but little is known about their underlying risk factors. We aimed to investigate associations of air pollution exposure with long COVID among Swedish young adults.

Methods: We used data from the BAMSE (Children, Allergy, Environment, Stockholm, Epidemiology [in Swedish]) cohort. From October 2021 to February 2022 participants answered a web-questionnaire focusing on persistent symptoms following acute SARS-CoV-2 infection. Long COVID was defined as symptoms after confirmed infection with SARS-CoV-2 lasting for two months or longer. Ambient air pollution levels (particulate matter ≤2.5 μm [PM2.5], ≤10 μm [PM10], black carbon [BC] and nitrogen oxides [NOx]) at individual-level addresses were estimated using dispersion modelling.

Findings: A total of 753 participants with SARS-CoV-2 infection were included of whom 116 (15.4%) reported having long COVID. The most common symptoms were altered smell/taste (n = 80, 10.6%), dyspnea (n = 36, 4.8%) and fatigue (n = 34, 4.5%). Median annual PM2.5 exposure in 2019 (pre-pandemic) was 6.39 (interquartile range [IQR] 6.06–6.71) μg/m3. Adjusted Odds Ratios (95% confidence intervals) of PM2.5 per IQR increase were 1.28 (1.02–1.60) for long COVID, 1.65 (1.09–2.50) for dyspnea symptoms and 1.29 (0.97–1.70) for altered smell/taste. Positive associations were found for the other air pollutants and remained consistent across sensitivity analyses. Associations tended to be stronger among participants with asthma, and those having had COVID during 2020 (versus 2021).

Interpretation: Ambient long-term PM2.5 exposure may affect the risk of long COVID in young adults, supporting efforts for continuously improving air quality.

Source: Zhebin Yu, Sandra Ekström, Tom Bellander, Petter Ljungman, Göran Pershagen, Kristina Eneroth et al. Ambient air pollution exposure linked to long COVID among young adults: a nested survey in a population-based cohort in Sweden. The Lancet. Published: March 07, 2023 DOI:https://doi.org/10.1016/j.lanepe.2023.100608 (Full text)

Autoimmunity in Long Covid and POTS

Abstract:

Orthostatic intolerance and other autonomic dysfunction syndromes are emerging as distinct symptom clusters in Long Covid. Often accompanying these are common, multi-system constitutional features such as fatigue, malaise and skin rashes which can signify generalised immune dysregulation. At the same time, multiple autoantibodies are identified in both Covid-related autonomic disorders and non-Covid autonomic disorders, implying a possible underlying autoimmune pathology. The lack of specificity of these findings precludes direct interpretations of cause and association, but prevalence with its supporting evidence is compelling.

In this review, we discuss the role of the autonomic nervous and immune systems in Covid and Long Covid and their potential influence on symptoms and clinical practice. Additionally, overlap with non-Covid autonomic dysfunction is considered. Understanding these new disorders can inform both neuro-immunology and Long Covid management.

Source: Fatema-Zahra El-Rhermoul, Artur Fedorowski, Philip Eardley, Patricia Taraborrelli, Dimitrios Panagopoulos, Richard Sutton, Phang Boon Lim, Melanie Dani, Autoimmunity in Long Covid and POTS, Oxford Open Immunology, 2023;, iqad002, https://doi.org/10.1093/oxfimm/iqad002 (Full text available as PDF file)

A neuroinflammatory paradigm can explain Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome and Post-COVID-19 Fatigue Syndrome

Abstract

This thesis illustrates the development of a neuroinflammatory paradigm for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), applicable to Long-COVID related “Post-COVID-19 Fatigue Syndrome” (PCFS).

The brain being devoid of nociceptors, in combination with neuroimaging technology lacking sufficient sensitivity, helps to explain why the chronic but low-level neuroinflammation purported to be present in the brains of ME/CFS (and PCFS) sufferers has gone unreported by patients, and has been largely undetected by scientists, until more recently. Over-activation of microglia and astrocytes is increasingly being proposed to be at the heart of ME/CFS (and PCFS) pathophysiology.

A key Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) study (2014) provided evidence of glial-cell over-activity, implicating neuroinflammation within the brain’s limbic system, of ME/CFS patients. Other cerebral spinal fluid and neuroimaging studies, including a more recent Magnetic Resonance Spectroscopy (MRS)/MRI Thermometry study (2019), have added support to this concept.

Resultant dysfunction of the limbic system and its closely-connected hypothalamus, which in turn leads to a disturbed autonomic nervous system (ANS) and dysfunctional hypothalamic-pituitary-adrenal-axis (HPA-axis) could then account for the diverse range of symptoms reported in ME/CFS (and PCFS). These symptoms include chronic fatigue, flu-like malaise, mood, memory and cognitive problems (limbic system), sleep, taste, visual and thermostatic-control problems (hypothalamus), gastro-intestinal disturbance, cardiovascular problems and hypotension (ANS), as well as increased frequency of urination and lower blood cortisol levels (HPA-axis).

A dysfunctional hypothalamic paraventricular nucleus (PVN), a potentially vulnerable site, within the brains of genetically susceptible people, which functions normally as a stress-control integrator, is proposed to be at the core of ME/CFS (and PCFS) aetiology and pathophysiology.

It is proposed that all triggers of ME/CFS, be they viral (Epstein-Barr Virus is the most common trigger), or non-viral; including other infectious diseases, multiple vaccinations, emotional trauma or chemical toxin shock, share a common triggering mechanism. They are each proposed to manifest themselves as severe physiological stressors, which by a combination of humoral and neural routes, target, the hypothalamic PVN, of genetically susceptible individuals. By exceeding an intrinsic stress-threshold pertaining to the complex neurological circuitry, within the hypothalamic PVN, the triggering stressor is proposed to overload it into a (permanently) iii dysfunctional state.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which causes Coronavirus Disease 2019 (COVID-19), in common with the triggering stressors of ME/CFS, also manifests itself as a severe physiological stressor, due to a cytokine surge at the site of the primary infection (the lungs). This particular stressor is, also, proposed to target the hypothalamic PVN, in genetically susceptible people, thus triggering PCFS. Life’s ongoing physiological stressors, such as physical, mental overexercise, chemical toxin exposure, emotional and financial stress, all of which are known to exacerbate and perpetuate ME/CFS (as well as PCFS) could do so by then targeting a now “compromised” (possibly inflamed) stress-sensitive hypothalamic PVN, by similar routes.

Then if an alternative, but variable (according to fluctuating neuroinflammation of the hypothalamic PVN, itself) stress threshold was exceeded, commonly reported post-exertional malaise (PEM) episodes, more problematic flare-ups, and even more severe prolonged and characteristic relapses could ensue.

It is proposed that a dysfunctional hypothalamic PVN, thereby, acts as an epicentre to a radiating neuroinflammatory response within the brains of ME/CFS (and PCFS) sufferers. A neuroinflammatory pathway, as proposed to be shared by the early-onset stages of several progressive neuroinflammatory (neurodegenerative) diseases could also be shared by ME/CFS, and PCFS. Indeed, this pathway could be shared by other potentially nonprogressive neuroinflammatory disorders, such as the closely-related fibromyalgia, mental health disorders, epilepsy, and migraines.

Might then the “drivers” of the inflammatory process, which sustain glial-cell activation (and neuroinflammation), in ME/CFS (and PCFS), be the perpetuating stressors, themselves, acting in combination with a now “compromised” and stress-sensitive hypothalamic PVN? If so, what then might be the mechanistic detail linking a stressor-targeted hypothalamic PVN and microglial activation in ME/CFS (and PCFS)?

One attractive scenario requiring further investigation involves the release of corticotrophin releasing hormone (CRH), which is released naturally by the hypothalamic PVN due to stress. The chronic release of CRH from a stress-sensitive, dysfunctional hypothalamic PVN might induce microglia activation, leading to chronic neuroinflammation, via the stimulation of mast-cells.

Two papers were published in relation to this neuroinflammatory paradigm for ME/CFS (2018, 2019), followed by another paper (2021), in which a paradigm was presented to explain the more recently emergent, but equally perplexing, Long-COVID related “PostCOVID-19 Fatigue Syndrome” (PCFS).

The neuroinflammatory model presented is both iv coherent and unifying for all triggering stressors and perpetuating stressors of ME/CFS (& PCFS), without the need for subtypes (as many other models require), but it does require validation. To this effect, it is hoped that this neuroinflammatory model will be both thought-provoking, as well as providing a framework for scientific researchers to test, critique, modify, and develop, into the future.

More brain-focussed research, using increasingly sophisticated neuroimaging technology (especially enhanced PET/MRI) is recommended. Then, a brain-signature for both ME/CFS (and PCFS) might even become attainable, within the next decade, perhaps.

Long-COVID related PCFS, affecting millions of people worldwide, presents a golden opportunity for in-depth longitudinal neuroimaging studies (following patients through relapse-recovery cycles) to develop a better understanding of PCFS (and ME/CFS) pathophysiology.

Source: Mackay, A. A neuroinflammatory paradigm can explain Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome and Post-COVID-19 Fatigue Syndrome. PhD Thesis. University of Otago, New Zealand.  https://ourarchive.otago.ac.nz/bitstream/handle/10523/15089/MackayAngus2021PhD.pdf?sequence=1&isAllowed=y (PDF file)

Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Background and Objectives: Post-exertional malaise (PEM) is the hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but there has been little effort to quantitate the duration of PEM symptoms following a known exertional stressor.

Using a Symptom Severity Scale (SSS) that includes nine common symptoms of ME/CFS, we sought to characterize the duration and severity of PEM symptoms following two cardiopulmonary exercise tests separated by 24 h (2-day CPET).

Materials and Methods: Eighty persons with ME/CFS and 64 controls (CTL) underwent a 2-day CPET. ME/CFS subjects met the Canadian Clinical Criteria for diagnosis of ME/CFS; controls were healthy but not participating in regular physical activity. All subjects who met maximal effort criteria on both CPETs were included.

SSS scores were obtained at baseline, immediately prior to both CPETs, the day after the second CPET, and every two days after the CPET-1 for 10 days.

Results: There was a highly significant difference in judged recovery time (ME/CFS = 12.7 ± 1.2 d; CTL = 2.1 ± 0.2 d, mean ± s.e.m., Chi2 = 90.1, p < 0.0001).

The range of ME/CFS patient recovery was 1–64 days, while the range in CTL was 1–10 days; one subject with ME/CFS had not recovered after one year and was not included in the analysis.

Less than 10% of subjects with ME/CFS took more than three weeks to recover. There was no difference in recovery time based on the level of pre-test symptoms prior to CPET-1 (F = 1.12, p = 0.33).

Mean SSS scores at baseline were significantly higher than at pre-CPET-1 (5.70 ± 0.16 vs. 4.02 ± 0.18, p < 0.0001). Pharmacokinetic models showed an extremely prolonged decay of the PEM response (Chi2 > 22, p < 0.0001) to the 2-day CPET.

Conclusions: ME/CFS subjects took an average of about two weeks to recover from a 2-day CPET, whereas sedentary controls needed only two days. These data quantitate the prolonged recovery time in ME/CFS and improve the ability to obtain well-informed consent prior to doing exercise testing in persons with ME/CFS. Quantitative monitoring of PEM symptoms may provide a method to help manage PEM.

Source: Moore GE, Keller BA, Stevens J, Mao X, Stevens SR, Chia JK, Levine SM, Franconi CJ, Hanson MR. Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Medicina. 2023; 59(3):571. https://doi.org/10.3390/medicina59030571 (Full text)

Objective sleep measures in chronic fatigue syndrome patients: A systematic review and meta-analysis

Abstract:

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report disrupted and unrefreshing sleep in association with worsened fatigue symptoms. However, the nature and magnitude of sleep architecture alteration in ME/CFS is not known, with studies using objective sleep measures in ME/CFS generating contradictory results.

The current manuscript aimed to review and meta-analyse of case-control studies with objective sleep measures in ME/CSF. A search was conducted in PubMed, Scopus, Medline, Google Scholar, and Psychoinfo databases.

After review, 24 studies were included in the meta-analysis, including 20 studies with 801 adults (ME/CFS = 426; controls = 375), and 4 studies with 477 adolescents (ME/CFS = 242; controls = 235), who underwent objective measurement of sleep.

Adult ME/CFS patients spend longer time in bed, longer sleep onset latency, longer awake time after sleep onset, decreased sleep efficiency, decreased stage 2 sleep, increased Stage 3, and longer rapid eye movement sleep latency.

However, adolescent ME/CFS patients had longer time in bed, longer total sleep time, longer sleep onset latency, and reduced sleep efficiency.

The meta-analysis results demonstrate that sleep is altered in ME/CFS, with changes seeming to differ between adolescent and adults, and suggesting sympathetic and parasympathetic nervous system alterations in ME/CFS.

Source: Abdalla Z. Mohamed, Thu Andersen, Sanja Radovic, Peter Del Fante, Richard Kwiatek, Vince Calhoun, Sandeep Bhuta, Daniel F. Hermens, Jim Lagopoulos, Zack Shan. Objective sleep measures in chronic fatigue syndrome patients: A systematic review and meta-analysis. Sleep Medicine Reviews, 2023, 101771.  https://www.sciencedirect.com/science/article/abs/pii/S1087079223000278

Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition arising in susceptible people, predominantly following viral infection, but also other stressful events. The susceptibility factors discussed here are both genetic and environmental although not well understood.

While the dysfunctional physiology in ME/CFS is becoming clearer, understanding has been hampered by different combinations of symptoms in each affected person.

A common core set of mainly neurological symptoms forms the modern clinical case definition, in the absence of an accessible molecular diagnostic test. This landscape has prompted interest in whether ME/CFS patients can be classified into a particular phenotype/subtype that might assist better management of their illness and suggest preferred therapeutic options.

Currently, the same promising drugs, nutraceuticals, or behavioral therapies available can be beneficial, have no effect, or be detrimental to each individual patient. We have shown that individuals with the same disease profile exhibit unique molecular changes and physiological responses to stress, exercise and even vaccination.

Key features of ME/CFS discussed here are the possible mechanisms determining the shift of an immune/inflammatory response from transient to chronic in ME/CFS, and how the brain and CNS manifests the neurological symptoms, likely with activation of its specific immune system and resulting neuroinflammation.

The many cases of the post viral ME/CFS-like condition, Long COVID, following SARS-CoV-2 infection, and the intense research interest and investment in understanding this condition, provide exciting opportunities for the development of new therapeutics that will benefit ME/CFS patients.

Source: Tate WP, Walker MOM, Peppercorn K, Blair ALH, Edgar CD. Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID. International Journal of Molecular Sciences. 2023; 24(6):5124. https://doi.org/10.3390/ijms24065124 (Full text)

Myalgic Encephalitis/Chronic Fatigue Syndrome: Diagnostic and Therapeutic Approach and Biological Research

Abstract:

Myalgic encephalitis/chronic fatigue syndrome, an intractable disease characterized by profound fatigue, sleep disturbance, cognitive impairment, and orthostatic intolerance, among other features, often occurs after infectious episodes. Patients experience various types of chronic pain; however, post-exertional malaise is the most significant feature, which requires pacing. In this article, I summarize the current diagnostic and therapeutic approaches and describe recent biological research in this domain.

Source: Sato W. [Myalgic Encephalitis/Chronic Fatigue Syndrome: Diagnostic and Therapeutic Approach and Biological Research]. Brain Nerve. 2023 Mar;75(3):217-225. Japanese. doi: 10.11477/mf.1416202311. PMID: 36890757. https://pubmed.ncbi.nlm.nih.gov/36890757/ [Article in Japanese]

Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID

Abstract:

Background: COVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID).

Methods: We assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalization and up to 9 months of convalescence following COVID-19, respiratory syncytial virus (RSV) or influenza A (flu). Progressive fibrosing interstitial lung disease (PFILD) patients were included a positive control for severe, ongoing lung injury.

Results: Monocyte alterations in acute COVID-19 patients included aberrant expression of leucocyte migration molecules, continuing into convalescence (n=142) and corresponding to specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of chemokine receptor CXCR6 (p<0.0001) and adhesion molecule PSGL-1 (p<0.01), alongside preferential migration of monocytes towards CXCR6 ligand CXCL16 (p<0.05) which is abundantly expressed in the lung. Monocyte CXCR6 and lung CXCL16 were heightened in PFILD patients (p<0.001) confirming a role for the CXCR6-CXCL16 axis in ongoing lung injury. Conversely, monocytes from long COVID patients with ongoing fatigue exhibited sustained reduction of the prostaglandin-generating enzyme COX-2 (p<0.01) and CXCR2 expression (p<0.05). These monocyte changes were not present in RSV or flu convalescence.

Conclusions: Our data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.

Source: Scott NA, Pearmain L, Knight SB, Brand O, Morgan DJ, Jagger C, Harbach S, Khan S, Shuwa HA, Franklin M, Kästele V, Williams T, Prise I, McClure FA, Hackney P, Smith L, Menon M, Konkel JE, Lawless C, Wilson J, Mathioudakis AG, Stanel SC, Ustianowski A, Lindergard G, Brij S, Diar Bakerly N, Dark P, Brightling C, Rivera-Ortega P, Lord GM, Horsley A; CIRCO; Piper Hanley K, Felton T, Simpson A, Grainger JR, Hussell T, Mann ER. Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID. Eur Respir J. 2023 Mar 15:2202226. doi: 10.1183/13993003.02226-2022. Epub ahead of print. PMID: 36922030. https://erj.ersjournals.com/content/early/2023/02/23/13993003.02226-2022 (Full article available as PDF file)

Demographic And Clinical Factors Associated With Long COVID

Abstract:

Risk factors for postacute sequelae of SARS-CoV-2 infection (“long COVID”) in community-dwelling populations remain poorly understood. Large-scale data, follow-up, comparison groups, and a consensus definition of long COVID are often lacking. Using data from the OptumLabs Data Warehouse on a nationwide sample of commercial and Medicare Advantage enrollees from the period January 2019 through March 2022, we examined demographic and clinical factors associated with long COVID, using two definitions of people who suffer symptoms long after they were first diagnosed with COVID-19 (“long haulers”).

We identified 8,329 long haulers using the narrow definition (diagnosis code), 207,537 long haulers using the broad definition (symptom based), and 600,161 non–long haulers (comparison group).

On average, long haulers were older and more likely female, with more comorbidities. Among narrow-definition long haulers, the leading risk factors for long COVID included hypertension, chronic lung disease, obesity, diabetes, and depression. Their time between initial COVID-19 diagnosis and diagnosis of long COVID averaged 250 days, with racial and ethnic differences. Broad-definition long haulers exhibited similar risk factors. Distinguishing long COVID from the progression of underlying conditions can be challenging, but further study may advance the evidence base related to the identification, causes, and consequences of long COVID.

Source: Song Z, Giuriato M. Demographic And Clinical Factors Associated With Long COVID. Health Aff (Millwood). 2023 Mar;42(3):433-442. doi: 10.1377/hlthaff.2022.00991. PMID: 36877912. https://pubmed.ncbi.nlm.nih.gov/36877912/