Endothelial dysfunction is the key of long COVID-19 symptoms: The results of TUN-EndCOV study

Abstract:

Background: The COVID-19 disease is a multisystem disease due to in part to the vascular endothelium injury. Lasting effects and long-term sequalae could persist after the infection and may be due to persistent endothelial dysfunction.

Purpose: Our study focused on the study of endothelial function measurement by digital thermal monitoring (DTM) of endothelial quality index with E4 diagnosis Polymath in a large cohort of long COVID-19 patients to determine whether long COVID-19 symptoms are due to endothelial dysfunction.

Methods: This is a prospective multicenter longitudinal observational cohort study. Endothelial function was evaluated with “E4-Diagnose” Polymath Tunisia based on the Endothelium Quality Index (EQI). A complete echocardiographic evaluation analysis was performed. Primary outcomes were defined as the occurrence of long COVID-19 symptoms in patients with endothelial dysfunction measured by EQI.

Results: A total of 798 patients were included in this study. Patients were included at an average time of 68.93 ± 43.1 days. The mean EQI was 2.02 ± 0.99 [0–5]. A total of 397 (49.7%) patients had poor or very poor EQI and 211 (26.4%) patients had very poor EQI. The median age was 49.94 ± 14.2 (18–80) years. A total of 618 patients (77.4%) had long COVID-19 symptoms. Patients with long COVID-19 symptoms had a reduced EQI (1.99 ± 0.97 vs. 2.09 ± 1.05, P = 0.24). Among long COVID-19 symptoms, fatigue was the most common symptom reported in 42.2%. Fatigue and chest pain were significantly associated to the endothelial dysfunction (P = 0.04 and 0.001 respectively). Patients with chest pain had significantly lower EQI (1.74 ± 1.0 vs. 2.09 ± 0.9, P ≤ 10−3) and LVGLS (−16.35 ± 3.0 vs. −17.16 ± 2.5, P = 0.04).

Conclusion: Long COVID-19 symptoms specifically chest pain and fatigue are due to persistent poor endothelial quality index. These findings allow a better care of patients with long COVID-19 symptoms.

Source: S. Charfeddine, H. Ibnhadjamor, S. Torjmen, S. Kraiem, R. Hammami, A. Bahloul, N. Kallel, N. Moussa, I. Touil, S. Milouchi, J. Elghoul, Z. Meddeb, Y. Thabet, J. Jdidi, K. Bouslema, S. Abdesselem, L. Abid. Endothelial dysfunction is the key of long COVID-19 symptoms: The results of TUN-EndCOV study. Archives of Cardiovascular Diseases Supplements, Volume 14, Issue 1, 2022, Page 126, ISSN 1878-6480, https://doi.org/10.1016/j.acvdsp.2021.10.004. (https://www.sciencedirect.com/science/article/pii/S187864802100642X)

Impaired systemic oxygen extraction long after mild COVID-19: potential perioperative implications

Editor:

The extraordinary number of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections world-wide has made it inevitable that patients who have recovered from COVID-19 will present for anaesthesia and surgery. Recent data indicate that in the United States alone, roughly one-third of the population had been infected by the end of 20201. With this in mind, we read with interest the recent correspondence by Silvapulle and colleagues2 underscoring the wide range of symptoms that often follow recovery from COVID-19 and the complexity of considering residual physiologic abnormalities when assessing perioperative risk. They note that patients suffering from “long COVID” have been reported to exhibit demonstrable abnormalities in several biomarkers as well as cardiac, neurologic, haematologic, renal, hepatic, and endocrine impairment. Based on current evidence, the authors suggest that patients previously experiencing mild COVID-19 but without clear evidence of these sequelae can be regarded as having minimal additional perioperative risk. In this context, the relatively young person who suffered mild COVID-19 a year earlier, complains of exertional fatigue but admits to being sedentary and unfit, and has no objective evidence of cardiopulmonary disease or other organ dysfunction will likely raise little concern.

While the morbidity and mortality associated with severe COVID-19 has appropriately received considerable attention, most SARS-CoV-2 infections result in relatively mild, self-limited symptoms not requiring hospitalization. Nonetheless, some of these patients subsequently experience persistent fatigue and reduced exercise capacity that is not attributable to cardiopulmonary impairment diagnosed by conventional means3. Several mechanisms have been proposed including anaemia, deconditioning, and red blood cell abnormalities4. However, many of the studies describing these mechanisms were conducted in patients following hospitalization and/or within a few months of recovery.

A central focus of perioperative management has always been maintenance of systemic oxygen delivery (DO2) and tissue perfusion. Toward this end, research has defined how the fundamental relationships between DO2, tissue oxygen consumption (VO2), and oxygen extraction (EO2) shift from the intraoperative setting where VO2 tends to be reduced, to the postoperative period when VO2 increases5. Although a range of postoperative complications has been linked to suboptimal tissue DO26,  7, the incidence of these complications appears relatively low in relation to the documented incidence of perioperative hypoxaemia8,  9, particularly when considered in light of potential coincidence with other common factors such as anaemia, hypovolaemia, and transient hypotension. A contributing factor may be that, as with most physiological systems, evolutionary pressure has yielded compensatory mechanisms for reduced DO2 to many organs. Under most circumstances, when DO2 is low, VO2 is maintained by augmented EO2 to prevent tissue hypoxia10. This compensatory EO2 reserve persists until limits that vary among tissue beds are reached and VO2 becomes DO2-dependent. Ultimately, in the perioperative setting where alterations in regional VO2/DO2 balance occur with regularity it is probable that this EO2 reserve is working continuously ‘behind the scenes’ for organ protection.

But what if this seemingly occult protective mechanism is impaired? Clinical experience imparts heightened suspicion of tissue vulnerability in patients with defined end-organ impairment or risk factors for reduced functional reserve such as aging, smoking, diabetes mellitus, or hypertension. But how does this affect that relatively young person who admits to being sedentary and unfit but has no objective evidence of cardiopulmonary disease, and whose only other notable medical history is mild COVID-19 a year earlier? A recent report proposed the existence of a specific “long COVID phenotype” with exertional intolerance and dyspnoea despite normal pulmonary function11, raising the question of whether there is more to this patient than meets the eye.

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Source: Paul M. Heerdt, Ben Shelley, Inderjit Singh. Impaired systemic oxygen extraction long after mild COVID-19: potential perioperative implications. Published: December 27, 2021. DOI:https://doi.org/10.1016/j.bja.2021.12.036

Disturbances in sleep, circadian rhythms and daytime functioning in relation to coronavirus infection and Long-COVID – A multinational ICOSS study

Abstract:

This protocol paper describes the second survey produced by the International Covid Sleep Study (ICOSS) group with the aim to examine the associations between SARS-CoV-2 infection and sleep, sleepiness, and circadian problems as potential predisposing factors for more severe COVID-19 disease profile and for development of Long-COVID in the general population. The survey consists of 47 questions on sleep, daytime sleepiness, circadian rhythm, health, mental wellbeing, life habits, and socioeconomic situation before and during the pandemic, and conditional questions to those reporting having had coronavirus infection, being vaccinated, or suffering from particular sleep symptoms or sleep disorders. Surveys will be administered online between May and November 2021 in Austria, Brazil, Bulgaria, Canada, China, Croatia, Finland, France, Germany, Israel, Italy, Japan, Norway, Portugal, Sweden and USA. Data collected by the survey will give valuable information on the open questions regarding COVID-19 disease risk factors, symptomatology and evolution of Long-COVID, and on other long-term consequences related to the pandemic.

Source: Merikanto I, Dauvilliers Y, Chung F, Holzinger B, De Gennaro L, Wing YK, Korman M, Partinen M; 2nd ICOSS members. Disturbances in sleep, circadian rhythms and daytime functioning in relation to coronavirus infection and Long-COVID – A multinational ICOSS study. J Sleep Res. 2021 Dec 28:e13542. doi: 10.1111/jsr.13542. Epub ahead of print. PMID: 34964184. https://pubmed.ncbi.nlm.nih.gov/34964184/

Multisystem Involvement in Post-acute Sequelae of COVID-19 (PASC)

Abstract:

Objective: To describe cerebrovascular, neuropathic and autonomic features of post-acute sequelae of COVID-19 (PASC).

Methods: This retrospective study evaluated consecutive patients with chronic fatigue, brain fog and orthostatic intolerance consistent with PASC. Controls included postural tachycardia syndrome patients (POTS) and healthy participants. Analyzed data included surveys and autonomic (Valsalva maneuver, deep breathing, sudomotor and tilt tests), cerebrovascular (cerebral blood flow velocity (CBFv) monitoring in middle cerebral artery), respiratory (capnography monitoring) and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/autoimmune markers.

Results: Nine PASC patients were evaluated 0.7±0.3 years after a mild COVID-19 infection, treated as home observations. Autonomic, pain, brain fog, fatigue and dyspnea surveys were abnormal in PASC and POTS (n=10), compared to controls (n=15). Tilt table test reproduced the majority of PASC symptoms. Orthostatic CBFv declined in PASC (-20.0±13.4%) and POTS (-20.3±15.1%), compared to controls (-3.0±7.5%,p=0.001) and was independent of end-tidal carbon dioxide in PASC, but caused by hyperventilation in POTS. Reduced orthostatic CBFv in PASC included both subjects without (n=6) and with (n=3) orthostatic tachycardia. Dysautonomia was frequent (100% in both PASC and POTS) but was milder in PASC (p=0.013). PASC and POTS cohorts diverged in frequency of small fiber neuropathy (89% vs. 60%) but not in inflammatory markers (67% vs. 70%). Supine and orthostatic hypocapnia was observed in PASC.

Interpretation: PASC following mild COVID-19 infection is associated with multisystem involvement including: 1) cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction; 2) small fiber neuropathy and related dysautonomia; 3) respiratory dysregulation; 4) chronic inflammation.

Source: Novak P, Mukerji SS, Alabsi HS, Systrom D, Marciano SP, Felsenstein D, Mullally WJ, Pilgrim DM. Multisystem Involvement in Post-acute Sequelae of COVID-19 (PASC). Ann Neurol. 2021 Dec 24. doi: 10.1002/ana.26286. Epub ahead of print. PMID: 34952975. https://pubmed.ncbi.nlm.nih.gov/34952975/

Biomedical Perspectives of Acute and Chronic Neurological and Neuropsychiatric Sequelae of COVID-19

Abstract:

The incidence of infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent for coronavirus disease 2019 (COVID-19), has dramatically escalated following the initial outbreak in China in late 2019, resulting in a global pandemic with millions of deaths. Although the majority of infected patients survive, and the rapid advent and deployment of vaccines have afforded increased immunity against SARS-CoV-2, long term sequelae of SARS-CoV-2 infection have become increasingly recognized. These include, but are not limited to, chronic pulmonary disease, cardiovascular disorders, and proinflammatory-associated neurological dysfunction that may lead to psychological and neurocognitive impairment. A major component of cognitive dysfunction is operationally categorized as “brain fog” which comprises difficulty with concentration, forgetfulness, confusion, depression, and fatigue.

Multiple parameters associated with long-term neuropsychiatric sequelae of SARS-CoV-2 infection have been detailed in clinical studies. Empirically elucidated mechanisms associated with the neuropsychiatric manifestations of COVID-19 are by nature complex, but broad based working models have focused on mitochondrial dysregulation leading to systemic reductions of metabolic activity and cellular bioenergetics within CNS structures. Multiple factors underlying the expression of brain fog may facilitate future pathogenic insults leading to repetitive cycles of viral and bacterial propagation. Interestingly, diverse neurocognitive sequelae associated with COVID-19 are not dissimilar from those observed in other historical pandemics, thereby providing a broad and integrative perspective on potential common mechanisms of CNS dysfunction subsequent to viral infection. Poor mental health status may be reciprocally linked to compromised immune processes and enhanced susceptibility to infection by diverse pathogens.

By extrapolation, we contend that COVID-19 may potentiate the severity of neurological/neurocognitive deficits in patients afflicted by well-studied neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Accordingly, the prevention, diagnosis, and management of sustained neuropsychiatric manifestations of COVID-19 are pivotal health care directives and provide a compelling rationale for careful monitoring of infected patients, as early mitigation efforts may reduce short- and long-term complications.

Source: Stefano GB, Büttiker P, Weissenberger S, Ptacek R, Wang F, Esch T, Bilfinger TV, Kream RM. Biomedical Perspectives of Acute and Chronic Neurological and Neuropsychiatric Sequelae of COVID-19. Curr Neuropharmacol. 2021 Dec 23. doi: 10.2174/1570159X20666211223130228. Epub ahead of print. PMID: 34951387. https://pubmed.ncbi.nlm.nih.gov/34951387/

Year-long COVID-19 infection reveals within-host evolution of SARS-CoV-2 in a patient with B cell depletion

Abstract:

B-cell depleting therapies may lead to prolonged disease and viral shedding in individuals infected with SARS-CoV-2 and this viral persistence raises concern for viral evolution. We report on the sequencing of early and late samples from a 335-day infection in an immunocompromised patient. The virus accumulated a unique deletion in the amino-terminal domain of the spike protein, and complete deletion of ORF7b and ORF8, the first report of its kind in an immunocompromised patient. Overall, the unique viral mutations found in this study highlight the importance of analyzing viral evolution in protracted SARS-CoV-2 infection, especially in immunosuppressed hosts.

Source: Nussenblatt V, Roder AE, Das S, de Wit E, Youn JH, Banakis S, Mushegian A, Mederos C, Wang W, Chung M, Pérez-Pérez L, Palmore T, Brudno JN, Kochenderfer JN, Ghedin E. Year-long COVID-19 infection reveals within-host evolution of SARS-CoV-2 in a patient with B cell depletion. J Infect Dis. 2021 Dec 23:jiab622. doi: 10.1093/infdis/jiab622. Epub ahead of print. PMID: 34940844. https://pubmed.ncbi.nlm.nih.gov/34940844/

Levocetirizine and montelukast in the COVID-19 treatment paradigm

Abstract:

Levocetirizine, a third-generation antihistamine, and montelukast, a leukotriene receptor antagonist, exhibit remarkable synergistic anti-inflammatory activity across a spectrum of signaling proteins, cell adhesion molecules, and leukocytes. By targeting cellular protein activity, they are uniquely positioned to treat the symptoms of COVID-19. Clinical data to date with an associated six-month follow-up, suggests the combination therapy may prevent the progression of the disease from mild to moderate to severe, as well as prevent/treat many of the aspects of ‘Long COVID,’ thereby cost effectively reducing both morbidity and mortality. To investigate patient outcomes, 53 consecutive COVID-19 test (+) cases (ages 3-90) from a well-established, single-center practice in Boston, Massachusetts, between March – November 2020, were treated with levocetirizine and montelukast in addition to then existing protocols [2]. The data set was retrospectively reviewed.

Thirty-four cases were considered mild (64%), 17 moderate (32%), and 2 (4%) severe. Several patients presented with significant comorbidities (obesity: n = 22, 41%; diabetes: n = 10, 19%; hypertension: n = 24, 45%). Among the cohort there were no exclusions, no intubations, and no deaths. The pilot study in Massachusetts encompassed the first COVID-19 wave which peaked on April 23, 2020 as well as the ascending portion of the second wave in the fall. During this period the average weekly COVID-19 case mortality rate (confirmed deaths/confirmed cases) varied considerably between 1 and 7.5% [37]. FDA has approved a multicenter, randomized, placebo-controlled, Phase 2 clinical trial design, replete with electronic diaries and laboratory metrics to explore scientific questions not addressed herein.

Source: May BC, Gallivan KH. Levocetirizine and montelukast in the COVID-19 treatment paradigm. Int Immunopharmacol. 2021 Dec 15;103:108412. doi: 10.1016/j.intimp.2021.108412. Epub ahead of print. PMID: 34942461; PMCID: PMC8673734. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673734/ (Full text)

Intravenous immunoglobulin as an important adjunct in the prevention and therapy of coronavirus 2019 disease

Abstract:

The coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenged globally with its morbidity and mortality. A small percentage of affected patients (20%) progress into the second stage of the disease clinically presenting with severe or fatal involvement of lung, heart and vascular system, all contributing to multiple-organ failure. The so-called ‘cytokines storm’ is considered the pathogenic basis of severe disease and it is a target for treatment with corticosteroids, immunotherapies and intravenous immunoglobulin (IVIg).

We provide an overview of the role of IVIg in the therapy of adult patients with COVID-19 disease. After discussing the possible underlying mechanisms of IVIg immunomodulation in COVID-19 disease, we review the studies in which IVIg was employed. Considering the latest evidence that show a link between new coronavirus and autoimmunity, we also discuss the use of IVIg in COVID-19 and anti-SARS-CoV-2 vaccination related autoimmune diseases and the post-COVID-19 syndrome.

The benefit of high-dose IVIg is evident in almost all studies with a rapid response, a reduction in mortality and improved pulmonary function in critically ill COVID-19 patients. It seems that an early administration of IVIg is crucial for a successful outcome. Studies’ limitations are represented by the small number of patients, the lack of control groups in some and the heterogeneity of included patients. IVIg treatment can reduce the stay in ICU and the demand for mechanical ventilation, thus contributing to attenuate the burden of the disease.

Source: Danieli MG, Piga MA, Paladini A, Longhi E, Mezzanotte C, Moroncini G, Shoenfeld Y. Intravenous immunoglobulin as an important adjunct in the prevention and therapy of coronavirus 2019 disease. Scand J Immunol. 2021 Nov;94(5):e13101. doi: 10.1111/sji.13101. Epub 2021 Sep 16. PMID: 34940980; PMCID: PMC8646640. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8646640/ (Full text)

An Open-Label, Pilot Trial of HRG80™ Red Ginseng in Chronic Fatigue Syndrome, Fibromyalgia, and Post-Viral Fatigue

Abstract:

Chronic fatigue syndrome and fibromyalgia (CFS/FMS) affect 2.1% of the world’s population and ~10–25% of people who have had COVID-19. Previous clinical data suggested that a unique Panax ginseng (C.A. Meyer, family Araliaceae) root extract (HRG80™ Red Ginseng) often resulted in marked improvement. We aimed to study this hydroponic form of red ginseng root, containing high levels of rare ginsenosides, for improving energy, cognition, and stamina. This open-label prospective study included participants with severe CFS/FMS who took a daily supplement of HRG80 capsules (200–400 mg) or tablets (100–200 mg) for one month.
A total of 188 subject patients completed the one-month treatment trial. Of these, 60.1% rated themselves as improved, with 13.3% rating themselves as being much better. In this group, the mean composite score improved from 11.9 to 18.8 (p < 0.001), with a 67% average increase in energy, 44% average increase in overall well-being, 48% average improvement in mental clarity, 58% average composite improvement in the previous three measurements (primary outcome measure), 46% average improvement in sleep, 33% average decrease in pain, and 72% average increase in stamina. Our study showed that HRG80 red ginseng root powder resulted in a marked improvement in people with CFS and fibromyalgia. This included the subgroup with post-viral CFS/FMS.
Source: Teitelbaum J, Goudie S. An Open-Label, Pilot Trial of HRG80™ Red Ginseng in Chronic Fatigue Syndrome, Fibromyalgia, and Post-Viral Fatigue. Pharmaceuticals. 2022; 15(1):43. https://doi.org/10.3390/ph15010043 (Full text)

Detection of herpes viruses in patients with myalgic encephalomyelitis /chronic fatigue syndrome in Belarus

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial chronic disease. The etiology and pathogenesis of ME/CFS are unknown. There are many theories for the occurrence of this disease. but the most convincing is the infectious or viral theory of the emergence of CFS.

The aim of this study is to detect of herpes viruses 6, 7 types and Epstein-Barr  to examine the prevalence HHV-6, HHV-7 and EBV infections in Belarus CFS patients.

We examined 30 patients with CFS in whom fatigue during  more than 2 years (7), more than 1 year (11) and more than 6 months (12). The diagnosis was made on clinical grounds using the Fukuda criteria.

The presence of markers the active forms  infection HHV-6 and HHV-7 in CFS patients with a long period of fatigue  were detected in 16.6% and 26.6% respectively. IgM  antibodies to HHV-6 and EBV. positive, in 16.6% and 6.7% respectively in patients with long-term illness. Detection of IgG antibodies indicates a quiet carrier state, latent phase.

Source: ORLOVA, Svetlana et al. Detection of herpes viruses in patients with myalgic encephalomyelitis /chronic fatigue syndrome in Belarus. Polish Journal of Applied Sciences, [S.l.], v. 6, n. 2, p. 50-53, dec. 2021. ISSN 2451-1544. Available at: <https://pjas.pwsip.edu.pl/index.php/pjas/article/view/176>. Date accessed: 10 jan. 2022. doi: https://doi.org/10.34668/PJAS.2020.6.2.08. (Full text)