Category: Overlapping Illnesses

Vascular “Long COVID”: A New Vessel Disease?

Abstract:

Vascular sequelae following (SARS-CoV-2 coronavirus disease) (COVID)-19 infection are considered as “Long Covid (LC)” disease, when occurring 12 weeks after the original infection. The paucity of specific data can be obviated by translating pathophysiological elements from the original Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) infection (In a microcirculatory system, a first “endotheliitis,” is often followed by production of “Neutrophil Extracellular Trap,” and can evolve into a more complex leukocytoklastic-like and hyperimmune vasculitis.

In medium/large-sized vessels, this corresponds to endothelial dysfunction, leading to an accelerated progression of pre-existing atherosclerotic plaques through an increased deposition of platelets, circulating inflammatory cells and proteins. Associated dysregulated immune and pro-coagulant conditions can directly cause thrombo-embolic arterial or venous complications. In order to implement appropriate treatment, physicians need to consider vascular pathologies observed after SARS-Cov-2 infections as possible “LC” disease.

Source: Zanini G, Selleri V, Roncati L, Coppi F, Nasi M, Farinetti A, Manenti A, Pinti M, Mattioli AV. Vascular “Long COVID”: A New Vessel Disease? Angiology. 2023 Jan 18:33197231153204. doi: 10.1177/00033197231153204. Epub ahead of print. PMID: 36652923. https://pubmed.ncbi.nlm.nih.gov/36652923/

Improvement of Long COVID symptoms over one year

Abstract:

Importance: Early and accurate diagnosis and treatment of Long COVID, clinically known as post-acute sequelae of COVID-19 (PASC), may mitigate progression to chronic diseases such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our objective was to determine the utility of the DePaul Symptom Questionnaire (DSQ) to assess the frequency and severity of common symptoms of ME/CFS, to diagnose and monitor symptoms in patients with PASC.

Methods: This prospective, observational cohort study enrolled 185 people that included 34 patients with PASC that had positive COVID-19 test and persistent symptoms of >3 months and 151 patients diagnosed with ME/CFS. PASC patients were followed over 1 year and responded to the DSQ at baseline and 12 months. ME/CFS patients responded to the DSQ at baseline and 1 year later. Changes in symptoms over time were analyzed using a fixed-effects model to compute difference-in-differences estimates between baseline and 1-year follow-up assessments.

Participants: Patients were defined as having PASC if they had a previous positive COVID-19 test, were experiencing symptoms of fatigue, post-exertional malaise, or other unwellness for at least 3 months, were not hospitalized for COVID-19, had no documented major medical or psychiatric diseases prior to COVID-19, and had no other active and untreated disease processes that could explain their symptoms. PASC patients were recruited in 2021. ME/CFS patients were recruited in 2017.

Results: At baseline, patients with PASC had similar symptom severity and frequency as patients with ME/CFS and satisfied ME/CFS diagnostic criteria. ME/CFS patients experienced significantly more severe unrefreshing sleep and flu-like symptoms. Five symptoms improved significantly over the course of 1 year for PASC patients including fatigue, post-exertional malaise, brain fog, irritable bowel symptoms and feeling unsteady. In contrast, there were no significant symptom improvements for ME/CFS patients.

Conclusion and relevance: There were considerable similarities between patients with PASC and ME/CFS at baseline. However, symptoms improved for PASC patients over the course of a year but not for ME/CFS patients. PASC patients with significant symptom improvement no longer met ME/CFS clinical diagnostic criteria. These findings indicate that the DSQ can be used to reliably assess and monitor PASC symptoms.

Source: Oliveira CR, Jason LA, Unutmaz D, Bateman L, Vernon SD. Improvement of Long COVID symptoms over one year. Front Med (Lausanne). 2023 Jan 9;9:1065620. doi: 10.3389/fmed.2022.1065620. PMID: 36698810; PMCID: PMC9868805. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9868805/ (Full text)

The Link Between Empty Sella Syndrome, Fibromyalgia, and Chronic Fatigue Syndrome: The Role of Increased Cerebrospinal Fluid Pressure

Abstract:

The etiopathogenesis of fibromyalgia (FM) and chronic fatigue syndrome (CFS) is not yet elucidated. Hypothalamo-pituitary-adrenal (HPA) axis dysfunction is reflected in the hormonal disturbances found in FM and CFS. Some study groups have introduced a novel hypothesis that moderate or intermittent intracranial hypertension may be involved in the etiopathogenesis of FM and CFS.

In these conditions, hormonal disturbances may be caused by the mechanical effect of increased cerebrospinal fluid pressure, which hampers blood flow in the pituitary gland. Severe intracranial pressure may compress the pituitary gland, resulting in primary empty sella (ES), potentially leading to pituitary hormone deficiencies.

The aim of this narrative review was to explore whether similar hormonal changes and symptoms exist between primary ES and FM or CFS and to link them to cerebrospinal fluid pressure dysregulation. A thorough search of the PubMed and Web of Science databases and the reference lists of the included studies revealed that several clinical characteristics were more prevalent in primary ES, FM or CFS patients than in controls, including increased cerebrospinal fluid pressure, obesity, female sex, headaches and migraine, fatigue, visual disturbances (visual acuity and eye motility abnormalities), vestibulocochlear disturbances (vertigo and neurosensorial hearing loss), and bodily pain (radicular pain and small-fiber neuropathy).

Furthermore, challenge tests of the pituitary gland showed similar abnormalities in all three conditions: blunted adrenocorticotropic hormone, cortisol, growth hormone, luteinizing hormone, and thyroid stimulating hormone responses and an increased prolactin response. The findings of this narrative review provide further support for the hypothesis that moderately or intermittently increased cerebrospinal fluid pressure is involved in the pathogenesis of FM and CFS and should stimulate further research into the etiopathogenesis of these conditions.

Source: Hulens M, Dankaerts W, Rasschaert R, Bruyninckx F, De Mulder P, Bervoets C. The Link Between Empty Sella Syndrome, Fibromyalgia, and Chronic Fatigue Syndrome: The Role of Increased Cerebrospinal Fluid Pressure. J Pain Res. 2023;16:205-219
https://doi.org/10.2147/JPR.S394321 https://www.dovepress.com/the-link-between-empty-sella-syndrome-fibromyalgia-and-chronic-fatigue-peer-reviewed-fulltext-article-JPR (Full text)

Hyperbaric oxygen therapy for long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial

Abstract:

Background: With ~ 50 million individuals suffering from post-COVID condition (PCC), low health related quality of life (HRQoL) is a vast problem. Common symptoms of PCC, that persists 3 months from the onset of COVID-19 are fatigue, shortness of breath and cognitive dysfunction. No effective treatment options have been widely adopted in clinical practice. Hyperbaric oxygen (HBO2) is a candidate drug.

Methods: The objective of this interim analysis is to describe our cohort and evaluate the safety of HBO2 for post covid condition. In an ongoing randomised, placebo-controlled, double blind, clinical trial, 20 previously healthy subjects with PCC were assigned to HBO2 or placebo. Primary endpoints are physical domains in RAND-36; Physical functioning (PF) and Role Physical (RP) at 13 weeks. Secondary endpoints include objective physical tests. Safety endpoints are occurrence, frequency, and seriousness of Adverse Events (AEs). An independent data safety monitoring board (DSMB) reviewed unblinded data. The trial complies with Good Clinical Practice. Safety endpoints are evaluated descriptively. Comparisons against norm data was done using t-test.

Results: Twenty subjects were randomised, they had very low HRQoL compared to norm data. Mean (SD) PF 31.75 (19.55) (95% Confidence interval; 22.60-40.90) vs 83.5 (23.9) p < 0.001 in Rand-36 PF and mean 0.00 (0.00) in RP. Very low physical performance compared to norm data. 6MWT 442 (180) (95% CI 358-525) vs 662 (18) meters p < 0.001. 31 AEs occurred in 60% of subjects. In 20 AEs, there were at least a possible relationship with the study drug, most commonly cough and chest pain/discomfort.

Conclusions: An (unexpectedly) high frequency of AEs was observed but the DSMB assessed HBO2 to have a favourable safety profile. Our data may help other researchers in designing trials.

Trial Registration ClinicalTrials.gov: NCT04842448. Registered 13 April 2021, https://clinicaltrials.gov/ct2/show/NCT04842448 . EudraCT: 2021-000764-30. Registered 21 May 2021, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-000764-30/SE.

Source: Kjellberg A, Hassler A, Boström E, El Gharbi S, Al-Ezerjawi S, Kowalski J, Rodriguez-Wallberg KA, Bruchfeld J, Ståhlberg M, Nygren-Bonnier M, Runold M, Lindholm P. Hyperbaric oxygen therapy for long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial. BMC Infect Dis. 2023 Jan 20;23(1):33. doi: 10.1186/s12879-023-08002-8. PMID: 36670365; PMCID: PMC9854077. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9854077/ (Full text)

Two-Years Follow-Up of Symptoms and Return to Work in Complex Post-COVID-19 Patients

Abstract:

Introduction: Many COVID-19 patients present with severe long-lasting symptoms. They might benefit from a coordination team to manage such complex situations, but late efficacy still needs to be determined.
Population and Methods: Out of 105 contacts, 45 patients had two phone consultations separated by personalized support 15 and 22 months, respectively, after COVID infection. Self-reported symptoms, feelings of improvement and ability to return to work allowed us to determine the efficacy of the therapeutic strategy proposed.
Results: Unlike what was expected, many post-COVID-19 patients directly contacted the coordination team and had significant pre-existing comorbidities. Despite exercise, respiratory, olfactory rehabilitations, cognition/speech therapy and/or psychological support, the more frequent self-reported symptoms (fatigue, neurocognitive disorders, muscles and joint pain) did not resolve. However, dyspnea, anxiety and chest pain were significantly reduced. Finally, 2/3 of the patients felt some degree of improvement and returned to work either partially or fully, but 1/3 remained complaining of symptoms and out of work as late as 22 months after COVID occurrence. All patients greatly appreciated the second phone consultation.
Conclusions: In such complex situations, besides early and adapted rehabilitations and psychological help allowing better symptom management, relatively simple actions such as a phone call might be very useful to reduce patients’ feelings of abandonment.
Source: Van Wambeke E, Bezler C, Kasprowicz A-M, Charles A-L, Andres E, Geny B. Two-Years Follow-Up of Symptoms and Return to Work in Complex Post-COVID-19 Patients. Journal of Clinical Medicine. 2023; 12(3):741. https://doi.org/10.3390/jcm12030741 https://www.mdpi.com/2077-0383/12/3/741 (Full text)

Long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Potential neurophysiological biomarkers for these enigmatic entities

Since early in the pandemic, fatigue has been recognized as one of the most common persistent complaints in individuals infected with SARS-CoV-2, and constitutes one main symptom of the so-called long-COVID syndrome. The term fatigue refers to a sustained feeling of tiredness, which can be present at rest; it is not directly related to physical activity, but can be exacerbated disproportionally by exertion.

Survivors of other recent coronavirus outbreaks, such as severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012 also developed chronic fatigue. These ‘post-infectious’ fatigue syndromes, including long-COVID, resemble myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a chronic disorder of unknown physiopathology characterized by fatigue, post-exertional malaise, chronic muscle or skeletal pain, and cognitive impairment (‘brain fog’).

Despite it being an extremely disabling symptom, the results of routine examinations are often normal in patients complaining of lingering fatigue, a phenomenon that has also led the medical-scientific community to view this condition with skepticism.

In physiology, fatigue is defined as a decrease in the maximal force-generating capacity of a muscle during exercise. It may result from peripheral processes distal to the neuromuscular junction and from central processes controlling the discharge rate of motoneurons.

Physical fatigue related to both central and peripheral nervous system dysfunction can be assessed with neurophysiological techniques including transcranial magnetic stimulation (TMS) of the motor cortex, electrical stimulation of nerve trunks or intramuscular nerve fibers, and electromyography (EMG) recordings.

In August 2021, the first study showing myopathic changes in quantitative EMG (qEMG) in long-COVID patients with musculoskeletal symptoms was published (). The same authors demonstrated myopathic qEMG features and histopathological changes in skeletal muscle biopsies in 16 patients with complaints of fatigue, myalgia, and/or weakness persisting for up to 14 months after mild to moderate COVID-19 (). The wide variety of histological changes in this study, including muscle fiber atrophy, mitochondrial changes, subsarcolemmal accumulation, inflammation, capillaries alteration, suggests that skeletal muscle may be a major target of SARS-CoV-2.

On the opposite side of the neuroaxis, dysfunction in the activity of the primary motor cortex and reduced corticomotor output may underlie fatigue.

The first TMS study on motor cortex physiology was conducted on 12 patients with long-term fatigue and ‘brain fog’ after severe COVID-19 (). It showed disruption of the physiological mechanism of post-contraction depression, i.e., the transient decrease in the amplitude of motor evoked potentials and prolongation of the cortical silent period after a fatiguing motor task, which depends on cortical inhibitory mechanisms and has the protective purpose of preventing muscle overload. Impairment of intracortical GABAergic activity, as indicated by disrupted long-interval intracortical inhibition, together with reduced excitability of the primary motor cortex was subsequently demonstrated in 67 patients with fatigue and cognitive difficulties after mild COVID-19 (). These patients also presented selective deficits in executive functions. Based on these findings, the authors proposed that fatigue depends on altered excitability and neurotransmission within the motor cortex at rest, and on abnormal reactivity to muscular exercise. In addition, reduced executive control may contribute to exacerbating poor physical performance and fatigue tolerance ().

These objective neurophysiological and histopathological findings showed for the first time that fatigue may due both to pathological processes in the muscle (the effector of the motor command) and/or at the site of motor command processing. The mechanisms of chronic dysfunction of neural and muscle cells may be sustained by inflammation or dysimmunity, triggered by SARS-COV-2 in predisposed individuals.

Immune-inflammatory and neuroendocrine mechanisms have also been implicated in ME/CFS. In particular, increased production of autoantibodies against CNS and autonomic nervous system targets, such as the ß2 adrenergic receptor (ß2AdR), have been documented (). As ß2AdR are important vasodilators, their functional disturbance may result in vasoconstriction and hypoxemia with chronic muscular and cerebral hypoperfusion.

The COVID-19 pandemic is likely to greatly increase the incidence of ME/CFS, so that the intense research on the pathophysiological mechanisms of fatigue in long-COVID can help to shed light on a poorly understood and underestimated syndrome.

Source: Versace V, Tankisi H. Long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Potential neurophysiological biomarkers for these enigmatic entities. Clin Neurophysiol. 2023 Jan 13;147:58-59. doi: 10.1016/j.clinph.2023.01.001. Epub ahead of print. PMID: 36657309; PMCID: PMC9838078. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9838078/ (Full text)

Vascular “Long COVID”: A New Vessel Disease?

Abstract:

Vascular sequelae following (SARS-CoV-2 coronavirus disease) (COVID)-19 infection are considered as “Long Covid (LC)” disease, when occurring 12 weeks after the original infection. The paucity of specific data can be obviated by translating pathophysiological elements from the original Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) infection (In a microcirculatory system, a first “endotheliitis,” is often followed by production of “Neutrophil Extracellular Trap,” and can evolve into a more complex leukocytoklastic-like and hyperimmune vasculitis. In medium/large-sized vessels, this corresponds to endothelial dysfunction, leading to an accelerated progression of pre-existing atherosclerotic plaques through an increased deposition of platelets, circulating inflammatory cells and proteins. Associated dysregulated immune and pro-coagulant conditions can directly cause thrombo-embolic arterial or venous complications. In order to implement appropriate treatment, physicians need to consider vascular pathologies observed after SARS-Cov-2 infections as possible “LC” disease.

Source: Zanini G, Selleri V, Roncati L, Coppi F, Nasi M, Farinetti A, Manenti A, Pinti M, Mattioli AV. Vascular “Long COVID”: A New Vessel Disease? Angiology. 2023 Jan 18:33197231153204. doi: 10.1177/00033197231153204. Epub ahead of print. PMID: 36652923. https://pubmed.ncbi.nlm.nih.gov/36652923/

Can Baseline IL-6 Levels Predict Long COVID in Subjects Hospitalized for SARS-CoV-2 Disease?

Abstract:

The immune response to infection plays a crucial role in the pathogenesis of COVID-19, but several patients develop a wide range of persistent symptoms, which is becoming a major global health and economic burden. However, reliable indicators are not yet available to predict the persistence of symptoms typical of the so-called long COVID. Our study aims to explore an eventual role of IL-6 levels as a marker of long COVID. Altogether, 184 patients admitted to the COVID Medicine Unit of the University Hospital in Palermo, Italy, from the 1st of September 2020, were analyzed.

Patients were divided into two groups according to the IL-6 serum levels (normal or elevated), considering the serum IL-6 levels measured during the first four days of hospitalization. In our study, higher serum IL-6 levels were associated with a doubled higher risk of long COVID (OR = 2.05; 95% CI: 1.04-4.50) and, in particular, they were associated with a higher incidence of mobility decline (OR = 2.55; 95% CI: 1.08-9.40) and PTSD (OR = 2.38; 95% CI: 1.06-8.61). The analysis of our case series confirmed the prominent role of IL-6 levels in response to SARS-CoV-2 infection, as predictors not only of COVID-19 disease severity and unfavorable outcomes, but also long COVID development trends.

Source: Giannitrapani L, Mirarchi L, Amodeo S, Licata A, Soresi M, Cavaleri F, Casalicchio S, Ciulla G, Ciuppa ME, Cervello M, Barbagallo M, Veronese N, The Comepa Group. Can Baseline IL-6 Levels Predict Long COVID in Subjects Hospitalized for SARS-CoV-2 Disease? Int J Mol Sci. 2023 Jan 15;24(2):1731. doi: 10.3390/ijms24021731. PMID: 36675242. https://www.mdpi.com/1422-0067/24/2/1731 (Full text)

Cortical Grey matter volume depletion links to neurological sequelae in post COVID-19 “long haulers”

Abstract:

Objective: COVID-19 (SARS-CoV-2) has been associated with neurological sequelae even in those patients with mild respiratory symptoms. Patients experiencing cognitive symptoms such as “brain fog” and other neurologic sequelae for 8 or more weeks define “long haulers”. There is limited information regarding damage to grey matter (GM) structures occurring in COVID-19 “long haulers”. Advanced imaging techniques can quantify brain volume depletions related to COVID-19 infection which is important as conventional Brain MRI often fails to identify disease correlates. 3-dimensional voxel-based morphometry (3D VBM) analyzes, segments and quantifies key brain volumes allowing comparisons between COVID-19 “long haulers” and normative data drawn from healthy controls, with values based on percentages of intracranial volume.

Methods: This is a retrospective single center study which analyzed 24 consecutive COVID-19 infected patients with long term neurologic symptoms. Each patient underwent Brain MRI with 3D VBM at median time of 85 days following laboratory confirmation. All patients had relatively mild respiratory symptoms not requiring oxygen supplementation, hospitalization, or assisted ventilation. 3D VBM was obtained for whole brain and forebrain parenchyma, cortical grey matter (CGM), hippocampus, and thalamus.

Results: The results demonstrate a statistically significant depletion of CGM volume in 24 COVID-19 infected patients. Reduced CGM volume likely influences their long term neurological sequelae and may impair post COVID-19 patient’s quality of life and productivity.

Conclusion: This study contributes to understanding effects of COVID-19 infection on patient’s neurocognitive and neurological function, with potential for producing serious long term personal and economic consequences, and ongoing challenges to public health systems.

Source: Rothstein TL. Cortical Grey matter volume depletion links to neurological sequelae in post COVID-19 “long haulers”. BMC Neurol. 2023 Jan 17;23(1):22. doi: 10.1186/s12883-023-03049-1. PMID: 36647063; PMCID: PMC9843113. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9843113/ (Full text)

Long COVID: Is There a Role for Antidepressants?

Abstract:

Two years into this historic pandemic, the scientific and healthcare communities continue to learn a great deal regarding COVID-19. The most urgent and immediate focus has been on vaccine development for disease prevention/mitigation and on identification of effective therapeutic interventions for acute phase of illness. However, attention is increasingly being placed on formulating treatment strategies for individuals who are post-COVID-19 and experiencing a syndrome of persistent symptoms that is being referred to as long COVID.

One strategy is to repurpose drugs which have been approved for other conditions and subsequently assess their safety and efficacy when applied to COVID-19. In this light, antidepressant medications have garnered attention amidst evidence supporting anti-inflammatory and anti-viral properties.

In this article, we present purported anti-inflammatory mechanisms of antidepressants, review studies appearing in the literature to date regarding antidepressants and acute COVID-19, and discuss the utility of antidepressants as a potential therapeutic resource for long COVID.

Source: Rivas-Vázquez R, Carrazana EJ, Blais MA, Rey GJ, RivasVázquez E, Quintana AA. Long COVID: Is There a Role for Antidepressants? Neurol Curr Res. 2022;2(3):1019. https://www.medtextpublications.com/open-access/long-covid-is-there-a-role-for-antidepressants-1249.pdf (Full text)