Long-Term COVID 19 Sequelae in Adolescents: the Overlap with Orthostatic Intolerance and ME/CFS

Abstract:

Purpose of review: To discuss emerging understandings of adolescent long COVID or post-COVID-19 conditions, including proposed clinical definitions, common symptoms, epidemiology, overlaps with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance, and preliminary guidance on management.

Recent findings: The recent World Health Organization clinical case definition of post-COVID-19 condition requires a history of probable or confirmed SARS-CoV-2 infection, with symptoms starting within 3 months of the onset of COVID-19. Symptoms must last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms of the post-COVID-19 condition include, but are not limited to, fatigue, shortness of breath, and cognitive dysfunction. These symptoms generally have an impact on everyday functioning. The incidence of prolonged symptoms following SARS-CoV-2 infection has proven challenging to define, but it is now clear that those with relatively mild initial infections, without severe initial respiratory disease or end-organ injury, can still develop chronic impairments, with symptoms that overlap with conditions like ME/CFS (profound fatigue, unrefreshing sleep, post-exertional malaise, cognitive dysfunction, and orthostatic intolerance).

Summary: We do not yet have a clear understanding of the mechanisms by which individuals develop post-COVID-19 conditions. There may be several distinct types of long COVID that require different treatments. At this point, there is no single pharmacologic agent to effectively treat all symptoms. Because some presentations of post-COVID-19 conditions mimic disorders such as ME/CFS, treatment guidelines for this and related conditions can be helpful for managing post-COVID-19 symptoms.

Supplementary information: The online version contains supplementary material available at 10.1007/s40124-022-00261-4.

Source: Morrow AK, Malone LA, Kokorelis C, Petracek LS, Eastin EF, Lobner KL, Neuendorff L, Rowe PC. Long-Term COVID 19 Sequelae in Adolescents: the Overlap with Orthostatic Intolerance and ME/CFS. Curr Pediatr Rep. 2022 Mar 9:1-14. doi: 10.1007/s40124-022-00261-4. Epub ahead of print. PMID: 35287333; PMCID: PMC8906524. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8906524/ (Full text)

Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review

Abstract:

Creatine monohydrate (CrM) is one of the most widely used nutritional supplements among active individuals and athletes to improve high-intensity exercise performance and training adaptations. However, research suggests that CrM supplementation may also serve as a therapeutic tool in the management of some chronic and traumatic diseases. Creatine supplementation has been reported to improve high-energy phosphate availability as well as have antioxidative, neuroprotective, anti-lactatic, and calcium-homoeostatic effects. These characteristics may have a direct impact on mitochondrion’s survival and health particularly during stressful conditions such as ischemia and injury.

This narrative review discusses current scientific evidence for use or supplemental CrM as a therapeutic agent during conditions associated with mitochondrial dysfunction. Based on this analysis, it appears that CrM supplementation may have a role in improving cellular bioenergetics in several mitochondrial dysfunction-related diseases, ischemic conditions, and injury pathology and thereby could provide therapeutic benefit in the management of these conditions. However, larger clinical trials are needed to explore these potential therapeutic applications before definitive conclusions can be drawn.

Source: Marshall RP, Droste JN, Giessing J, Kreider RB. Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review. Nutrients. 2022 Jan 26;14(3):529. doi: 10.3390/nu14030529. PMID: 35276888. https://www.mdpi.com/2072-6643/14/3/529/htm (Full text)

Recursive Debility: Symptoms, Patient Activism, and the Incomplete Medicalization of ME/CFS

Abstract:

This article examines the contestation of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Lacking consistent diagnostic definitions, agreed-on biological indicators, or approved treatments, ME/CFS is an incompletely medicalized condition. It is defined by intractable and debilitating exhaustion after any form of exertion. Through an ethnographic exploration of an American ME/CFS patient activist group, I develop the concept of “recursive debility.” Symptoms form the very basis for disease activist groupings in the absence of biomarkers, but they also present a significant barrier to traditional forms of activism. Ironically, then, debilitation blocks the means through which debilitation might end. Patients contest systems of knowledge but always in bodies that experience exhaustion without end. This article presents a disability studies intervention in suggesting that the recursivity of debility demonstrates the profound interdependence of the bodily aspects of impairment and the sociopolitical aspects of disability.

Source: Rogers EL. Recursive Debility: Symptoms, Patient Activism, and the Incomplete Medicalization of ME/CFS. Med Anthropol Q. 2022 Mar 8. doi: 10.1111/maq.12701. Epub ahead of print. PMID: 35262958. https://pubmed.ncbi.nlm.nih.gov/35262958/

Predictors for Developing Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome following Infectious Mononucleosis

Abstract:

Background: About 10% of individuals who contract infectious mononucleosis (IM) have symptoms 6 months later that meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).  Our study for the first time examined whether it is possible to predict who will develop ME/CFS following IM.

Methods: We have reported on a prospectively recruited cohort of 4,501 college students, of which 238 (5.3%) developed IM.  Those who developed IM were followed-up at six months to determine whether they recovered or met criteria for ME/CFS. The present study focuses on 48 students who after six months had a diagnosis of ME/CFS, and a matched control group of 58 students who had no further symptoms after their IM. All of these 106 students  had data at baseline (at least 6 weeks prior to the development of IM), when experiencing IM, and 6 months following IM. Of those who did not recover from IM, there were two groups: 30 were classified as ME/CFS and 18 were classified as severe ME/CFS. We measured the results of 7 questionnaires, physical examination findings, the severity of mononucleosis and cytokine analyses at baseline (pre-illness) and at the time of IM.  We examined predictors (e.g., pre-illness variables as well as variables at onset of IM) of  those who developed ME/CFS and severe ME/CFS following IM.

Results: From analyses using receiver operating characteristic statistics, the students who had had severe gastrointestinal symptoms of stomach pain, bloating, and an irritable bowel at baseline  and who also had abnormally low levels of the immune markers IL-13 and/or IL-5 at baseline, as well as severe gastrointestinal symptoms when then contracted IM,  were found to have a nearly 80% chance of having severe ME/CFS persisting six months following IM.

Conclusions: Our findings are consistent with emerging literature that gastrointestinal distress and autonomic symptoms, along with several immune markers, may be implicated in the development of severe ME/CFS.

Source: Jason, Leonard & Cotler, Joseph & Islam, Mohammed & Furst, Jacob & Katz, Ben. (2022). Predictors for Developing Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome following Infectious Mononucleosis. Journal of Rehabilitation Therapy. 4. 1-5. 10.29245/2767-5122/2021/1.1129. https://www.rehabiljournal.com/articles/predictors-for-developing-severe-myalgic-encephalomyelitischronic-fatigue-syndrome-following-infectious-mononucleosis.html  (Full text)

Omicron BA.2 (B.1.1.529.2): high potential to becoming the next dominating variant

Abstract:

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly replaced the Delta variant as a dominating SARS-CoV-2 variant because of natural selection, which favors the variant with higher infectivity and stronger vaccine breakthrough ability. Omicron has three lineages or subvariants, BA.1 (B.1.1.529.1), BA.2 (B.1.1.529.2), and BA.3 (B.1.1.529.3). Among them, BA.1 is the currently prevailing subvariant. BA.2 shares 32 mutations with BA.1 but has 28 distinct ones. BA.3 shares most of its mutations with BA.1 and BA.2 except for one. BA.2 is found to be able to alarmingly reinfect patients originally infected by Omicron BA.1. An important question is whether BA.2 or BA.3 will become a new dominating “variant of concern”. Currently, no experimental data has been reported about BA.2 and BA.3. We construct a novel algebraic topology-based deep learning model trained with tens of thousands of mutational and deep mutational data to systematically evaluate BA.2’s and BA.3’s infectivity, vaccine breakthrough capability, and antibody resistance.

Our comparative analysis of all main variants namely, Alpha, Beta, Gamma, Delta, Lambda, Mu, BA.1, BA.2, and BA.3, unveils that BA.2 is about 1.5 and 4.2 times as contagious as BA.1 and Delta, respectively. It is also 30% and 17-fold more capable than BA.1 and Delta, respectively, to escape current vaccines. Therefore, we project that Omicron BA.2 is on its path to becoming the next dominating variant. We forecast that like Omicron BA.1, BA.2 will also seriously compromise most existing mAbs, except for sotrovimab developed by GlaxoSmithKline.

Source: Chen, Jiahui, and Guo-Wei Wei. “Omicron BA.2 (B.1.1.529.2): high potential to becoming the next dominating variant.” Research square rs.3.rs-1362445. 23 Feb. 2022, doi:10.21203/rs.3.rs-1362445/v1. Preprint. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887081/ (Full text)

Long-term immunologic effects of SARS-CoV-2 infection: leveraging translational research methodology to address emerging questions

Abstract:

The current era of COVID-19 is characterized by emerging variants of concern, waning vaccine- and natural infection-induced immunity, debate over the timing and necessity of vaccine boosting, and the emergence of post-acute sequelae of SARS-CoV-2 infection. As a result, there is an ongoing need for research to promote understanding of the immunology of both natural infection and prevention, especially as SARS-CoV-2 immunology is a rapidly changing field, with new questions arising as the pandemic continues to grow in complexity.

The next phase of COVID-19 immunology research will need focus on clearer characterization of the immune processes defining acute illness, development of a better understanding of the immunologic processes driving protracted symptoms and prolonged recovery (ie, post-acute sequelae of SARS-CoV-2 infection), and a growing focus on the impact of therapeutic and prophylactic interventions on the long-term consequences of SARS-CoV-2 infection.

In this review, we address what is known about the long-term immune consequences of SARS-CoV-2 infection and propose how experience studying the translational immunology of other infections might inform the approach to some of the key questions that remain.

Source: Peluso MJ, Donatelli J, Henrich TJ. Long-term immunologic effects of SARS-CoV-2 infection: leveraging translational research methodology to address emerging questions. Transl Res. 2022 Mar;241:1-12. doi: 10.1016/j.trsl.2021.11.006. Epub 2021 Nov 12. PMID: 34780969; PMCID: PMC8588584.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8588584/ (Full text)

Long-term follow-up of dynamic brain changes in patients recovered from COVID-19 without neurological manifestations

Abstract:

BACKGROUND. After the initial surge in COVID-19 cases, large numbers of patients were discharged from a hospital without assessment of recovery. Now, an increasing number of patients report postacute neurological sequelae, known as “long COVID” — even those without specific neurological manifestations in the acute phase.

METHODS. Dynamic brain changes are crucial for a better understanding and early prevention of “long COVID.” Here, we explored the cross-sectional and longitudinal consequences of COVID-19 on the brain in 34 discharged patients without neurological manifestations. Gray matter morphology, cerebral blood flow (CBF), and volumes of white matter tracts were investigated using advanced magnetic resonance imaging techniques to explore dynamic brain changes from 3 to 10 months after discharge.

RESULTS. Overall, the differences of cortical thickness were dynamic and finally returned to the baseline. For cortical CBF, hypoperfusion in severe cases observed at 3 months tended to recover at 10 months. Subcortical nuclei and white matter differences between groups and within subjects showed various trends, including recoverable and long-term unrecovered differences. After a 10-month recovery period, a reduced volume of nuclei in severe cases was still more extensive and profound than that in mild cases.

CONCLUSION. Our study provides objective neuroimaging evidence for the coexistence of recoverable and long-term unrecovered changes in 10-month effects of COVID-19 on the brain. The remaining potential abnormalities still deserve public attention, which is critically important for a better understanding of “long COVID” and early clinical guidance toward complete recovery.

Source: Tian Tian, et al. Long-term follow-up of dynamic brain changes in patients recovered from COVID-19 without neurological manifestations. Published February 22, 2022
Citation Information: JCI Insight. 2022;7(4):e155827. https://doi.org/10.1172/jci.insight.155827. (Full text)

Long COVID 12 months after discharge: persistent symptoms in patients hospitalised due to COVID-19 and patients hospitalised due to other causes—a multicentre cohort study

Abstract:

Background: Long-term-specific sequelae or persistent symptoms (SPS) after hospitalisation due to COVID-19 are not known. The aim of this study was to explore the presence of SPS 12 months after discharge in survivors hospitalised due to COVID-19 and compare it with survivors hospitalised due to other causes.

Methods: Prospective cohort study, the Andalusian Cohort of Hospitalised patients for COVID-19 (ANCOHVID study), conducted in 4 hospitals and 29 primary care centres in Andalusia, Spain. The sample was composed of 906 adult patients; 453 patients hospitalised due to COVID-19 (exposed) and 453 hospitalised due to other causes (non-exposed) from March 1 to April 15, 2020, and discharged alive. The main outcomes were (1) the prevalence of SPS at 12 months after discharge and (2) the incidence of SPS after discharge. Outcome data at 12 months were compared between the exposed and non-exposed cohorts. Risk ratios were calculated, and bivariate analyses were performed.

Results: A total of 163 (36.1%) and 160 (35.3%) patients of the exposed and non-exposed cohorts, respectively, showed at least one SPS at 12 months after discharge. The SPS with higher prevalence in the subgroup of patients hospitalised due to COVID-19 12 months after discharge were persistent pharyngeal symptoms (p<0.001), neurological SPS (p=0.049), confusion or memory loss (p=0.043), thrombotic events (p=0.025) and anxiety (p=0.046). The incidence of SPS was higher for the exposed cohort regarding pharyngeal symptoms (risk ratio, 8.00; 95% CI, 1.85 to 36.12), confusion or memory loss (risk ratio, 3.50; 95% CI, 1.16 to 10.55) and anxiety symptoms (risk ratio, 2.36; 95% CI, 1.28 to 4.34).

Conclusions: There was a similar frequency of long-term SPS after discharge at 12 months, regardless of the cause of admission (COVID-19 or other causes). Nevertheless, some symptoms that were found to be more associated with COVID-19, such as memory loss or anxiety, merit further investigation. These results should guide future follow-up of COVID-19 patients after hospital discharge.

Source: Rivera-Izquierdo, M., Láinez-Ramos-Bossini, A.J., de Alba, I.GF. et al. Long COVID 12 months after discharge: persistent symptoms in patients hospitalised due to COVID-19 and patients hospitalised due to other causes—a multicentre cohort study. BMC Med 20, 92 (2022). https://doi.org/10.1186/s12916-022-02292-6  (Full text)

Neural Dysregulation in Post-Covid Fatigue

Abstract:

Following infection from SARS-CoV-2, a substantial minority of people develop lingering after-effects known as ‘long COVID’. Fatigue is a common complaint with substantial impact on daily life, but the neural mechanisms behind post-COVID fatigue remain unclear. We recruited volunteers with self-reported fatigue after a mild COVID infection and carried out a battery of behavioural and neurophysiological tests assessing the central, peripheral and autonomic nervous systems. In comparison to age and gender matched volunteers without fatigue, we show underactivity in specific cortical circuits, dysregulation of autonomic function, and myopathic change in skeletal muscles. Cluster analysis revealed no sub-groupings, suggesting post-COVID fatigue is a single entity with individual variation, rather than a small number of distinct syndromes. These abnormalities on objective tests may indicate novel avenues for principled therapeutic intervention, and could act as fast and reliable biomarkers for diagnosing and monitoring the progression of fatigue over time.

Source: Anne M.E. Baker, Natalie J. Maffitt, Alessandro Del Vecchio, Katherine M. McKeating, Mark R. Baker, Stuart N. Baker, Demetris S. Soteropoulos. Neural Dysregulation in Post-Covid Fatigue.
medRxiv 2022.02.18.22271040; doi: https://doi.org/10.1101/2022.02.18.22271040 https://www.medrxiv.org/content/10.1101/2022.02.18.22271040v1.full-text (Full text)

Chronic cerebral aspects of long COVID, post-stroke syndromes and similar states share their pathogenesis and perispinal etanercept treatment logic

Abstract:

The chronic neurological aspects of traumatic brain injury, post-stroke syndromes, long COVID-19, persistent Lyme disease, and influenza encephalopathy having close pathophysiological parallels that warrant being investigated in an integrated manner. A mechanism, common to all, for this persistence of the range of symptoms common to these conditions is described. While TNF maintains cerebral homeostasis, its excessive production through either pathogen-associated molecular patterns or damage-associated molecular patterns activity associates with the persistence of the symptoms common across both infectious and non-infectious conditions.

The case is made that this shared chronicity arises from a positive feedback loop causing the persistence of the activation of microglia by the TNF that these cells generate. Lowering this excess TNF is the logical way to reducing this persistent, TNF-maintained, microglial activation. While too large to negotiate the blood-brain barrier effectively, the specific anti-TNF biological, etanercept, shows promise when administered by the perispinal route, which allows it to bypass this obstruction.

Source: Clark IA. Chronic cerebral aspects of long COVID, post-stroke syndromes and similar states share their pathogenesis and perispinal etanercept treatment logic. Pharmacol Res Perspect. 2022 Apr;10(2):e00926. doi: 10.1002/prp2.926. PMID: 35174650; PMCID: PMC8850677. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8850677/ (Full text)