Tag: 2021

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)

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Greatly Improved Fatigue Symptoms When Treated with Oxygen-Ozone Autohemotherapy

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic syndrome characterized by fatigue as its major and most outstanding symptom. Previous evidence has supported the ability of ozone to relief ME/CFS related fatigue in affected patients.
Methods: A number of 200 ME/CFS previously diagnosed patients, (mean age 33 ± 13 SD years) were consecutively treated with oxygen-ozone autohemotherapy (O2-O3-AHT). Fatigue was evaluated via an FSS 7-scoring questionnaire before and following 30 days after treatment.
Results: Almost half (43.5%) of the treated patients evolved their FSS scale from the worst (7) to the best (1) score, assessing the highest improvement from being treated with O2-O3-AHT. Furthermore 77.5% of patients experienced significant ameliorations of fatigue, of 4–6 delta score. No patient showed side effects, yet experienced long lasting fatigue disappearance, by three months follow up.
Conclusions: Treatment with O2-O3-AHT greatly improves ME/CFS related fatigue, aside from sex and age distribution.
Source: Tirelli U, Franzini M, Valdenassi L, Pandolfi S, Berretta M, Ricevuti G, Chirumbolo S. Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Greatly Improved Fatigue Symptoms When Treated with Oxygen-Ozone Autohemotherapy. Journal of Clinical Medicine. 2022; 11(1):29. https://doi.org/10.3390/jcm11010029  https://www.mdpi.com/2077-0383/11/1/29/htm (Full text)

Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue

Abstract:

Background: Epstein-Barr virus (EBV) causes infectious mononucleosis (IM) that can lead to chronic fatigue syndrome. The CEBA-project (Chronic fatigue following acute EBV infection in Adolescents) has followed 200 patients with IM and here we present an immunological profiling of adolescents with IM related to clinical characteristics.

Methods: Patients were sampled within 6 weeks of debut of symptoms and after 6 months. Peripheral blood mononuclear cells (PBMC) were cultured and stimulated in vitro (n=68), and supernatants analyzed for cytokine release. Plasma was analyzed for inflammatory markers (n=200). The Chalder Fatigue Questionnaire diagnosed patients with and without chronic fatigue at 6 months (CF+ and CF- group, respectively) (n=32 and n=91, in vitro and plasma cohorts, respectively.

Results: Broad activation of PBMC at baseline, with high levels of RANTES (Regulated on activation, normal T-cell expressed and secreted) in the CF+ group, and broad inflammatory response in plasma with high levels of T-cell markers was obeserved. At 6 months, there was an increased β-agonist response and RANTES was still elevated in cultures from the CF+ group. Plasma showed decrease of inflammatory markers except for CRP which was consistently elevated in the CF+ group.

Conclusion: Patients developing chronic fatigue after IM have signs of T-cell activation and low-grade chronic inflammation at baseline and after 6 months.

Clinical trial registration: https://clinicaltrials.gov/, identifier NCT02335437.

Source: Fevang B, Wyller VBB, Mollnes TE, Pedersen M, Asprusten TT, Michelsen A, Ueland T, Otterdal K. Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue. Front Immunol. 2021 Dec 20;12:715102. doi: 10.3389/fimmu.2021.715102. PMID: 34987499; PMCID: PMC8721200. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721200/ (Full text)

Physical, cognitive and mental health impacts of COVID-19 following hospitalisation – a multi-centre prospective cohort study

Abstract:

Background The impact of COVID-19 on physical and mental health, and employment following hospitalisation is poorly understood.

Methods PHOSP-COVID is a multi-centre, UK, observational study of adults discharged from hospital with a clinical diagnosis of COVID-19 involving an assessment between two- and seven-months later including detailed symptom, physiological and biochemical testing. Multivariable logistic regression was performed for patient-perceived recovery with age, sex, ethnicity, body mass index (BMI), co-morbidities, and severity of acute illness as co-variates. Cluster analysis was performed using outcomes for breathlessness, fatigue, mental health, cognition and physical function.

Findings We report findings of 1077 patients discharged in 2020, from the assessment undertaken a median 5 [IQR4 to 6] months later: 36% female, mean age 58 [SD 13] years, 69% white ethnicity, 27% mechanical ventilation, and 50% had at least two co-morbidities. At follow-up only 29% felt fully recovered, 20% had a new disability, and 19% experienced a health-related change in occupation. Factors associated with failure to recover were female, middle-age, white ethnicity, two or more co-morbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial and weakly related to acute severity. Four clusters were identified with different severities of mental and physical health impairment: 1) Very severe (17%), 2) Severe (21%), 3) Moderate with cognitive impairment (17%), 4) Mild (46%), with 3%, 7%, 36% and 43% feeling fully recovered, respectively. Persistent systemic inflammation determined by C-reactive protein was related to cluster severity, but not acute illness severity.

Interpretation We identified factors related to recovery from a hospital admission with COVID-19 and four different phenotypes relating to the severity of physical, mental, and cognitive health five months later. The implications for clinical care include the potential to stratify care and the need for a pro-active approach with wide-access to COVID-19 holistic clinical services.

Source: Sigfrid, Louise, et al. “Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol.” medRxiv (2021).  https://www.medrxiv.org/content/10.1101/2021.03.22.21254057v1.full-text (Full text)