Tag: long Covid

Overlapping conditions in Long COVID at a multisite academic center

Abstract:

Background: Many patients experience persistent symptoms after COVID-19, a syndrome referred to as Long COVID (LC). The goal of this study was to identify novel new or worsening comorbidities self-reported in patients with LC.

Methods: Patients diagnosed with LC (n = 732) at the Mayo Long COVID Care Clinic in Rochester, Minnesota and Jacksonville, Florida were sent questionnaires to assess the development of new or worsening comorbidities following COVID-19 compared to patients with SARS-CoV-2 that did not develop LC (controls). Both groups were also asked questions screening for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), generalized joint hypermobility (GJH) and orthostatic intolerance. 247 people with LC (33.7%) and 40 controls (50%) responded to the surveys.

Results: In this study LC patients averaged 53 years of age and were predominantly White (95%) women (75%). The greatest prevalence of new or worsening comorbidities following SARS-CoV-2 infection in patients with LC vs. controls reported in this study were pain (94.4% vs. 0%, p < 0.001), neurological (92.4% vs. 15.4%, p < 0.001), sleep (82.8% vs. 5.3%, p < 0.001), skin (69.8% vs. 0%, p < 0.001), and genitourinary (60.6% vs. 25.0%, p = 0.029) issues. 58% of LC patients screened positive for ME/CFS vs. 0% of controls (p < 0.001), 27% positive for GJH compared to 10% of controls (p = 0.026), and a positive average score of 4.0 on orthostatic intolerance vs. 0 (p < 0.001). The majority of LC patients with ME/CFS were women (77%).

Conclusion: We found that comorbidities across 12 surveyed categories were increased in patients following SARS-CoV-2 infection. Our data also support the overlap of LC with ME/CFS, GJH, and orthostatic intolerance. We discuss the pathophysiologic, research, and clinical implications of identifying these conditions with LC.

Source: Grach SL, Dudenkov DV, Pollack B, Fairweather D, Aakre CA, Munipalli B, Croghan IT, Mueller MR, Overgaard JD, Bruno KA, Collins NM, Li Z, Hurt RT, Tal MC, Ganesh R, Knight DTR. Overlapping conditions in Long COVID at a multisite academic center. Front Neurol. 2024 Oct 25;15:1482917. doi: 10.3389/fneur.2024.1482917. PMID: 39524912; PMCID: PMC11543549. https://pmc.ncbi.nlm.nih.gov/articles/PMC11543549/ (Full text)

Infection-associated chronic conditions: Why Long Covid is our best chance to untangle Osler’s web

Abstract:

The recognition of Long Covid has renewed efforts to understand other infection-associated chronic conditions (IACCs). Here, we describe how studies of Long Covid and other IACCs might inform one another. We argue for the importance of a coordinated research agenda addressing these debilitating illnesses.

INTRODUCTION

For nearly a century, individuals with medically unexplained chronic conditions, particularly those thought to be attributable to presumably transient infectious pathogens, have faced bewilderment, skepticism, or outright dismissal from the medical establishment. Debilitating symptoms lasting for years have been reported after acute infections with viruses [enterovirus, Epstein-Barr virus (EBV), influenza virus, Ebola virus, dengue virus, chikungunya virus, West Nile virus, and severe acute respiratory syndrome coronavirus 1 (SARS-CoV)], bacteria (Borrelia and Anaplasma), and protozoa (Giardia) (1). Myalgic encephalomyelitis (ME), sometimes referred to as chronic fatigue syndrome (CFS), is perhaps the best example of a disabling syndrome that many experts believe follows an acute, often undiagnosed viral infection. Several names have been applied to these syndromes, including post-acute infection syndromes (PAIS), infection-associated chronic illnesses, and infection-associated chronic conditions (IACCs). Here, we will use IACCs.
Despite consistent reports regarding these conditions dating back nearly 100 years (2–4), the biomedical establishment has made limited progress in defining the epidemiology, natural history, and pathogenesis of most IACCs. No diagnostic tests are available, no widely accepted treatments exist, and industry engagement on finding a cure has been limited. In her 1996 book Osler’s Web, investigative journalist Hillary Johnson catalogued the challenges facing ME/CFS research (5), which can be applied to many IACCs. Barriers to progress included the inability to fit ME/CFS into existing disease paradigms, variability and inconsistency in case ascertainment, skepticism on the part of many clinicians and scientists, and intense stigma that kept many of those affected from seeking medical care. William Osler, the “father of modern medicine,” emphasized the importance of listening to patients to discern important features of their condition. However, contemporary medical practice relies heavily on diagnostic tests, which are currently inadequate to confirm the presence of an IACC. This results in people being neglected or misdiagnosed and prevents them from receiving appropriate care and support.
The year 2020 has the potential to be a turning point in this story. Shortly after the COVID-19 pandemic began, reports of individuals with prolonged COVID-attributed symptoms emerged, a condition now often referred to as Long Covid. The synchronicity of the inciting infection, universality of the exposure, and visibility, aided by social, popular, and scientific media (6), resulted in the ideal environment for a coordinated effort to understand this new IACC. Substantial investment in scientific effort is starting to pay off, with real progress in defining the epidemiology, natural history, and biology of Long Covid now emerging. After a Congressional appropriation, the US National Institutes of Health rapidly launched the Researching COVID to Enhance Recovery (RECOVER) initiative, which is the first large-scale program aimed at tackling an IACC. The progress to date has been hard-won, however, in part because there is no widely accepted clinical definition, biomarker, or diagnostic test for Long Covid. However, clinical trials, slow to start, are now being pursued in earnest. Although there is no guarantee that this momentum will be sustained without dedicated scientific and financial commitments (7), there is reason to believe that efforts to understand Long Covid have the potential to draw attention to, reframe, and revitalize the efforts to study other IACCs.
High-quality academic reviews of Long Covid are multiplying rapidly (8–12). Our goal in this Viewpoint is not to provide a comprehensive overview of the field but rather to place efforts to study Long Covid in the context of other IACCs. In doing so, we hope to outline several areas that we believe will require consideration as the field attempts to make progress in navigating what has been described as a “labyrinth” (5).
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Source: Michael J. Peluso et al. Infection-associated chronic conditions: Why Long Covid is our best chance to untangle Osler’s web. Sci. Transl. Med.16,eado2101(2024). DOI:10.1126/scitranslmed.ado2101

Stroop task and practice effects demonstrate cognitive dysfunction in long COVID and myalgic encephalomyelitis / chronic fatigue syndrome

Abstract:

Background: The Stroop task was used to investigate differences in cognitive function between Long COVID (LC), Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and healthy control subjects.

Methods: Subjects viewed four color words or neutral (XXXX) stimuli with the same (congruent) or different color ink (incongruent). Cognitive conflict was inferred from response times for pairings of prestimuli and subsequent stimuli. Overall effects were assessed by univariate analysis with time courses determined for binned response times.

Results: LC and ME/CFS had significantly longer response times than controls indicating cognitive dysfunction. Initial response times were ranked LC > ME > HC, and decreased according to power functions. At the end of the task (900s), times were ranked LC = ME > HC. Response times were significantly slower for stimuli following an incongruent prestimulus. Time series for Stroop effect, facilitation, interference, surprise index and practice power law parameters were generally similar in LC, ME/CFS and HC suggesting comparable patterns for recruitment of cognitive resources. The prestimulus data were analyzed and generated positive Stroop and interference effects that were distinct from stimulus effects.

Conclusion: LC and ME/CFS have global slowing of response times that cannot be overcome by practice suggesting impaired communications between network nodes during problem solving. Analysis of matched prestimulus – stimulus effects adds a new dimension for understanding cognitive conflict.

Brief summary: Cognitive dysfunction in Long COVID and ME/CFS was demonstrated using the Stroop task which found global slowing of response times and limitations of practice effects.

Source: Baraniuk JN, Thapaliya K, Inderyas M, Shan ZY, Barnden LR. Stroop task and practice effects demonstrate cognitive dysfunction in long COVID and myalgic encephalomyelitis / chronic fatigue syndrome. Sci Rep. 2024 Nov 5;14(1):26796. doi: 10.1038/s41598-024-75651-3. PMID: 39500939; PMCID: PMC11538523. https://pmc.ncbi.nlm.nih.gov/articles/PMC11538523/ (Full text)

Web-based telemedicine approach for treatment of post-COVID-19 in Thuringia (WATCH)

Abstract:

Objective: After infection with SARS-CoV-2, a substantial proportion of patients develop long-lasting sequelae. These sequelae include fatigue (potentially as severe as that seen in ME/CFS cases), cognitive dysfunction, and psychiatric symptoms. Because the pathophysiology of these sequelae remains unclear, existing therapeutic concepts address the symptoms through pacing strategies, cognitive training, and psychological therapy.

Methods: Here, we present a protocol for a digital multimodal structured intervention addressing common symptoms through three intervention modules: BRAIN, BODY, and SOUL. This intervention includes an assessment conducted via a mobile “post-COVID-19 bus” near the patient’s home, as well as the use of wearable devices and mobile applications to support pacing strategies and collection of data, including ecological momentary assessment.

Results: We will focus on physical component subscore of the SF36 as Quality of Life parameter as the primary outcome parameter for WATCH to take into account the holistic approach that is necessary for care of post-COVID patients.

Conclusion: In the current project, we present a protocol for a holistic and multimodal structured therapeutic concept which is easily accessible, and scalable for post-COVID patients.

Source: Reuken PA, Besteher B, Bleidorn J, Brockmann D, Finke K, Freytag A, Lehmann-Pohl K, Lemhöfer C, Mikolajczyk R, Puta C, Scherag A, Wiedermann M, Zippel-Schultz B, Stallmach A. Web-based telemedicine approach for treatment of post-COVID-19 in Thuringia (WATCH). Digit Health. 2024 Oct 14;10:20552076241291748. doi: 10.1177/20552076241291748. PMID: 39493638; PMCID: PMC11528766. https://pmc.ncbi.nlm.nih.gov/articles/PMC11528766/ (Full text)

Two-Day Cardiopulmonary Exercise Testing in Long COVID Post-Exertional Malaise Diagnosis

Abstract:

Background: Long COVID patients present with a myriad of symptoms that can include fatigue, exercise intolerance and post exertional malaise (PEM). Long COVID has been compared to other post viral syndromes, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), where a reduction in day 2 cardiopulmonary exercise test (CPET) performance of a two-day CPET protocol is suggested to be a result of PEM. We investigated cardiopulmonary and perceptual responses to a two-day CPET protocol in Long COVID patients.

Methods: 15 Long COVID patients [n=7 females; mean (SD) age: 53(11) yr; BMI = 32.2(8.5) kg/m2] performed a pulmonary function test and two ramp-incremental CPETs separated by 24hr. CPET variables included gas exchange threshold (GET), V̇O2peak and WRpeak. Ratings of perceived dyspnoea and leg effort were recorded at peak exercise using the modified 0-10 Borg Scale. PEM (past six months) was assessed using the modified DePaul Symptom Questionnaire (mDSQ). One-sample t-tests were used to test significance of mean difference between days (p<0.05).

Results: mDSQ revealed PEM in 80% of patients. Lung function was normal. Responses to day 1 CPET were consistent with the presence of aerobic deconditioning in 40% of patients (V̇O2peak <80% predicted, in the absence of evidence of cardiovascular and pulmonary limitations). There were no differences between day-1 and day-2 CPET responses (all p>0.05).

Conclusion: Post exertional malaise symptoms in Long COVID patients, in the absence of differences in two-day CPET responses separated by 24hours, suggests that post-exertional malaise is not due to impaired recovery of exercise capacity between days.

Source: Gattoni C, Abbasi A, Ferguson C, Lanks CW, Decato TW, Rossiter HB, Casaburi R, Stringer WW. Two-Day Cardiopulmonary Exercise Testing in Long COVID Post-Exertional Malaise Diagnosis. Respir Physiol Neurobiol. 2024 Oct 25:104362. doi: 10.1016/j.resp.2024.104362. Epub ahead of print. PMID: 39490617. https://www.sciencedirect.com/science/article/pii/S1569904824001551 (Full text)

Maximal oxidative capacity during exercise is associated with muscle power output in patients with long coronavirus disease 2019 (COVID-19) syndrome. A moderation analysis

Abstract:

Background & aims: Long COVID syndrome (LCS) involves persistent symptoms experienced by many patients after recovering from coronavirus disease 2019 (COVID-19). We aimed to assess skeletal muscle energy metabolism, which is closely related to substrate oxidation rates during exercise, in patients with LCS compared with healthy controls. We also examined whether muscle power output mediates the relationship between COVID-19 and skeletal muscle energy metabolism.

Methods: In this cross-sectional study, we enrolled 71 patients with LCS and 63 healthy controls. We assessed clinical characteristics such as body composition, physical activity, and muscle strength. We used cardiopulmonary exercise testing to evaluate substrate oxidation rates during graded exercise. We performed statistical analyses to compare group characteristics and peak fat oxidation differences based on power output.

Results: The two-way analysis of covariance (ANCOVA) results, adjusted for covariates, showed that the patients with LCS had lower absolute maximal fatty acid oxidation (MFO), relative MFO/fat free mass (FFM), absolute carbohydrates oxidation (CHox), relative CHox/FFM, and oxygen uptake (V˙˙O2) at maximum fat oxidation (g min-1) than the healthy controls (P < 0.05). Moderation analysis indicated that muscle power output significantly influenced the relationship between LCS and reduced peak fat oxidation (interaction β = -0.105 [95% confidence interval -0.174; -0.036]; P = 0.026). Therefore, when muscle power output was below 388 W, the effect of the LCS on MFO was significant (62% in our study sample P = 0.010). These findings suggest compromised mitochondrial bioenergetics and muscle function, represented by lower peak fat oxidation rates, in the patients with LCS compared with the healthy controls.

Conclusion: The patients with LCS had lower peak fat oxidation during exercise compared with the healthy controls, potentially indicating impairment in skeletal muscle function. The relationship between peak fat oxidation and LCS appears to be mediated predominantly by muscle power output. Additional research should continue investigating LCS pathogenesis and the functional role of mitochondria.

Source: Ramírez-Vélez R, Oscoz-Ochandorena S, García-Alonso Y, García-Alonso N, Legarra-Gorgoñon G, Oteiza J, Lorea AE, Izquierdo M, Correa-Rodríguez M. Maximal oxidative capacity during exercise is associated with muscle power output in patients with long coronavirus disease 2019 (COVID-19) syndrome. A moderation analysis. Clin Nutr ESPEN. 2023 Dec;58:253-262. doi: 10.1016/j.clnesp.2023.10.009. Epub 2023 Oct 14. PMID: 38057014. https://clinicalnutritionespen.com/article/S2405-4577(23)02166-6/fulltext (Full text)

Respiratory SARS-CoV-2 Infection Causes Skeletal Muscle Atrophy and Long-Lasting Energy Metabolism Suppression

Abstract:

Muscle fatigue represents the most prevalent symptom of long-term COVID, with elusive pathogenic mechanisms. We performed a longitudinal study to characterize histopathological and transcriptional changes in skeletal muscle in a hamster model of respiratory SARS-CoV-2 infection and compared them with influenza A virus (IAV) and mock infections.

Histopathological and bulk RNA sequencing analyses of leg muscles derived from infected animals at days 3, 30, and 60 post-infection showed no direct viral invasion but myofiber atrophy in the SARS-CoV-2 group, which was accompanied by persistent downregulation of the genes related to myofibers, ribosomal proteins, fatty acid β-oxidation, tricarboxylic acid cycle, and mitochondrial oxidative phosphorylation complexes.

While both SARS-CoV-2 and IAV infections induced acute and transient type I and II interferon responses in muscle, only the SARS-CoV-2 infection upregulated TNF-α/NF-κB but not IL-6 signaling in muscle. Treatment of C2C12 myotubes, a skeletal muscle cell line, with combined IFN-γ and TNF-α but not with IFN-γ or TNF-α alone markedly impaired mitochondrial function.

We conclude that a respiratory SARS-CoV-2 infection can cause myofiber atrophy and persistent energy metabolism suppression without direct viral invasion. The effects may be induced by the combined systemic interferon and TNF-α responses at the acute phase and may contribute to post-COVID-19 persistent muscle fatigue.

Source: Homma ST, Wang X, Frere JJ, Gower AC, Zhou J, Lim JK, tenOever BR, Zhou L. Respiratory SARS-CoV-2 Infection Causes Skeletal Muscle Atrophy and Long-Lasting Energy Metabolism Suppression. Biomedicines. 2024 Jun 28;12(7):1443. doi: 10.3390/biomedicines12071443. PMID: 39062017; PMCID: PMC11275164. https://pmc.ncbi.nlm.nih.gov/articles/PMC11275164/ (Full text)

Persistent Fatigue, Weakness, and Aberrant Muscle Mitochondria in Survivors of Critical COVID-19

Abstract:

Objectives: Persistent skeletal muscle dysfunction in survivors of critical illness due to acute respiratory failure is common, but biological data elucidating underlying mechanisms are limited. The objective of this study was to elucidate the prevalence of skeletal muscle weakness and fatigue in survivors of critical illness due to COVID-19 and determine if cellular changes associate with persistent skeletal muscle dysfunction.

Design: A prospective observational study in two phases: 1) survivors of critical COVID-19 participating in physical outcome measures while attending an ICU Recovery Clinic at short-term follow-up and 2) a nested cohort of patients performed comprehensive muscle and physical function assessments with a muscle biopsy; data were compared with non-COVID controls.

Setting: ICU Recovery Clinic and clinical laboratory.

Patients/subjects: Survivors of critical COVID-19 and non-COVID controls.

Interventions: None.

Measurements and main results: One hundred twenty patients with a median of 56 years old (interquartile range [IQR], 42-65 yr old), 43% female, and 33% individuals of underrepresented race attended follow-up 44 ± 17 days after discharge. Patients had a median Acute Physiology and Chronic Health Evaluation-II score of 24.0 (IQR, 16-29) and 98 patients (82%) required mechanical ventilation with a median duration of 14 days (IQR, 9-21 d). At short-term follow-up significant physical dysfunction was observed with 93% of patients reporting generalized fatigue and performing mean 218 ± 151 meters on 6-minute walk test (45% ± 30% of predicted). Eleven patients from this group agreed to participate in long-term assessment and muscle biopsy occurring a mean 267 ± 98 days after discharge. Muscle tissue from COVID exhibited a greater abundance of M2-like macrophages and satellite cells and lower activity of mitochondrial complex II and complex IV compared with controls.

Conclusions: Our findings suggest that aberrant repair and altered mitochondrial activity in skeletal muscle associates with long-term impairments in patients surviving an ICU admission for COVID-19.

Source: Mayer KP, Ismaeel A, Kalema AG, Montgomery-Yates AA, Soper MK, Kern PA, Starck JD, Slone SA, Morris PE, Dupont-Versteegden EE, Kosmac K. Persistent Fatigue, Weakness, and Aberrant Muscle Mitochondria in Survivors of Critical COVID-19. Crit Care Explor. 2024 Oct 16;6(10):e1164. doi: 10.1097/CCE.0000000000001164. PMID: 39412208; PMCID: PMC11487221. https://pmc.ncbi.nlm.nih.gov/articles/PMC11487221/ (Full text)

Epigenetic changes in patients with post-acute COVID-19 symptoms (PACS) and long-COVID: A systematic review

Abstract:

Background: Up to 30% of people infected with SARS-CoV-2 report disabling symptoms 2 years after the infection. Over 100 persistent symptoms have been associated with Post-Acute COVID-19 Symptoms (PACS) and/or long-COVID, showing a significant clinical heterogeneity. To develop effective, patient-targeted treatment, a better understanding of underlying mechanisms is needed. Epigenetics has helped elucidating the pathophysiology of several health conditions and it might help unravelling inter-individual differences in patients with PACS and long-COVID. As accumulating research is exploring epigenetic mechanisms in PACS and long-COVID, we systematically summarized the available literature on the topic.

Methods: We interrogated five databases (Medline, Embase, Web of Science, Scopus and medXriv/bioXriv) and followed PRISMA and SWiM guidelines to report our results.

Results: Eight studies were included in our review. Six studies explored DNA methylation in PACS and/or long-COVID, while two studies explored miRNA expression in long-COVID associated with lung complications. Sample sizes were mostly small and study quality was low or fair. The main limitation of the included studies was a poor characterization of the patient population that made a homogeneous synthesis of the literature challenging. However, studies on DNA methylation showed that mechanisms related to the immune and the autonomic nervous system, and cell metabolism might be implicated in the pathophysiology of PACS and long-COVID.

Conclusion: Epigenetic changes might help elucidating PACS and long-COVID underlying mechanisms, aid subgrouping, and point towards tailored treatments. Preliminary evidence is promising but scarce. Biological and epigenetic research on long-COVID will benefit millions of people suffering from long-COVID and has the potential to be transferable and benefit other conditions as well, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We urge future research to employ longitudinal designs and provide a better characterization of included patients.

Source: Shekhar Patil M, Richter E, Fanning L, Hendrix J, Wyns A, Barrero Santiago L, Nijs J, Godderis L, Polli A. Epigenetic changes in patients with post-acute COVID-19 symptoms (PACS) and long-COVID: A systematic review. Expert Rev Mol Med. 2024 Oct 22;26:e29. doi: 10.1017/erm.2024.32. PMID: 39435694. https://www.cambridge.org/core/journals/expert-reviews-in-molecular-medicine/article/epigenetic-changes-in-patients-with-postacute-covid19-symptoms-pacs-and-longcovid-a-systematic-review/BCF992CF0E491FC0AD0FEDC3A8AFFD4B (Full text)

A review of intravenous immunoglobulin in the treatment of neuroimmune conditions, acute COVID-19 infection, and post-acute sequelae of COVID-19 Syndrome

Abstract:

Intravenous immunoglobulin (IVIG) is an immunomodulatory therapy that has been studied in several neuroimmune conditions, such as Guillain-Barré Syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and multiple sclerosis. It has also been proposed as a potential treatment option for acute COVID-19 infection and post-acute sequelae of SARS-CoV-2 infection (PASC). IVIG is thought to function by providing the recipient with a pool of antibodies, which can, in turn, modulate immune responses through multiple mechanisms including neutralization of cytokines and autoantibodies, saturation of neonatal fragment crystallizable receptors, inhibition of complement activation, and regulation of T and B cell mediated inflammation.

In acute COVID-19, studies have shown that early administration of IVIG and plasmapheresis in severe cases can reduce the need for mechanical ventilation, shorten ICU and hospital stays, and lower mortality. Similarly, in PASC, while research is still in early stages, IVIG has been shown to alleviate persistent symptoms in small patient cohorts.

Furthermore, IVIG has shown benefits in another condition which has symptomatic overlap with PASC, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), though studies have yielded mixed results. It is important to note that IVIG can be associated with several potential adverse effects, such as anaphylaxis, headaches, thrombosis, liver enzyme elevations and renal complications. In addition, the high cost of IVIG can be a deterrent for payers and patients.

This review provides a comprehensive update on the use of IVIG in multiple neuroimmune conditions, ME/CFS, acute COVID-19, and PASC, as well as covers its history, production, pricing, and mechanisms of action. We also identify key areas of future research, including the need to optimize the use of Ig product dosing, timing, and patient selection across conditions, particularly in the context of COVID-19 and PASC.

Source: Morse BA, Motovilov K, Michael Brode W, Michael Tee F, Melamed E. A review of intravenous immunoglobulin in the treatment of neuroimmune conditions, acute COVID-19 infection, and post-acute sequelae of COVID-19 Syndrome. Brain Behav Immun. 2024 Oct 8:S0889-1591(24)00648-2. doi: 10.1016/j.bbi.2024.10.006. Epub ahead of print. PMID: 39389388. https://www.sciencedirect.com/science/article/abs/pii/S0889159124006482