Tag: covid-19

Multi-omics provide evidence for an anti-inflammatory immune signature and metabolic alterations in patients with Long COVID Syndrome; an exploratory study

Abstract:

Despite the increasing prevalence of patients with Long Covid Syndrome (LCS), to date the pathophysiology of the disease is still unclear, and therefore diagnosis and therapy are a complex effort without any standardization. To address these issues, we performed a broad exploratory screening study applying state-of-the-art post-genomic profiling methods to blood plasma derived from three groups: 1) healthy individuals vaccinated against SARS-CoV-2 without exposure to the full virus, 2) asymptomatic fully recovered patients at least three months after SARS-CoV-2 infection, 3) symptomatic patients at least 3 months after a SARS-CoV-2 infection, here designated as Long Covid Syndrome (LCS) patients.

Multiplex cytokine profiling indicated slightly elevated cytokine levels in recovered individuals in contrast to LCS patients, who displayed lowest levels of cytokines. Label-free proteome profiling corroborated an anti-inflammatory status in LCS characterized by low acute phase protein levels and a uniform down-regulation of macrophage-derived secreted proteins, a pattern also characteristic for chronic fatigue syndrome (CFS).

Along those lines, eicosanoid and docosanoid analysis revealed high levels of omega-3 fatty acids and a prevalence of anti-inflammatory oxylipins in LCS patients compared to the other study groups. Targeted metabolic profiling indicated low amino acid and triglyceride levels and deregulated acylcarnithines, characteristic for CFS and indicating mitochondrial stress in LCS patients. The anti-inflammatory osmolytes taurine and hypaphorine were significantly up-regulated in LCS patients.

In summary, here we present evidence for a specific anti-inflammatory and highly characteristic metabolic signature in LCS which could serve for future diagnostic purposes and help to establish rational therapeutic interventions in these patients.

Source: Johannes J Kovarik, Andrea Bileck, Gerhard Hagn, Samuel M Meier Menches, Tobias Frey, Anna Kaempf, Marlene Hollenstein, Tarik Shoumariyeh, Lukas Skos, Birgit Reiter, Marlene C Gerner, Andreas Spannbauer, Ena Hasimbegovic, Doreen Schmidl, Gerhard Garhoefer, Mariann Gyoengyoesi, Klaus G Schmetterer, Christopher Gerner. Multi-omics provide evidence for an anti-inflammatory immune signature and metabolic alterations in patients with Long COVID Syndrome; an exploratory study. medRxiv 2022.07.11.22277499; doi: https://doi.org/10.1101/2022.07.11.22277499 (Full study available as PDF file)

Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation

Abstract:

Long COVID (LC) describes the clinical phenotype of symptoms after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnostic and therapeutic options are limited, as the pathomechanism of LC is elusive. As the number of acute SARS-CoV-2 infections was and is large, LC will be a challenge for the healthcare system. Previous studies revealed an impaired blood flow, the formation of microclots, and autoimmune mechanisms as potential factors in this complex interplay. Since functionally active autoantibodies against G-protein-coupled receptors (GPCR-AAbs) were observed in patients after SARS-CoV-2 infection, this study aimed to correlate the appearance of GPCR-AAbs with capillary microcirculation.

The seropositivity of GPCR-AAbs was measured by an established cardiomyocyte bioassay in 42 patients with LC and 6 controls. Retinal microcirculation was measured by OCT-angiography and quantified as macula and peripapillary vessel density (VD) by the Erlangen-Angio Tool. A statistical analysis yielded impaired VD in patients with LC compared to the controls, which was accentuated in female persons. A significant decrease in macula and peripapillary VD for AAbs targeting adrenergic β2-receptor, MAS-receptor angiotensin-II-type-1 receptor, and adrenergic α1-receptor were observed. The present study might suggest that a seropositivity of GPCR-AAbs can be linked to an impaired retinal capillary microcirculation, potentially mirroring the systemic microcirculation with consecutive clinical symptoms.

Source: Szewczykowski C, Mardin C, Lucio M, Wallukat G, Hoffmanns J, Schröder T, Raith F, Rogge L, Heltmann F, Moritz M, Beitlich L, Schottenhamml J, Herrmann M, Harrer T, Ganslmayer M, Kruse FE, Kräter M, Guck J, Lämmer R, Zenkel M, Gießl A, Hohberger B. Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation. Int J Mol Sci. 2022 Jun 29;23(13):7209. doi: 10.3390/ijms23137209. PMID: 35806214. https://www.mdpi.com/1422-0067/23/13/7209/htm (Full text)

Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study

Abstract:

Background: Up to 37.7% of patients experience symptoms beyond 12 weeks after infection with SARS-CoV-2. To date care for people with long covid has centred around multidisciplinary rehabilitation, self care and self pacing. No pharmacotherapy has been shown to be beneficial.

Methods: In this single centre interventional pre post study, the safety of Low Dose Naltrexone (LDN) was explored in patients with Post COVID-19 Syndrome (PCS), defined by NICE as patients with ongoing symptoms 12 or more weeks after initial infections with SARS-CoV-2 where alternative explanation for symptoms cannot be found. Patients were recruited through a Post COVID clinic, had a baseline quality of life questionnaire in symmetrical Likert format, were prescribed 2 months (1 mg month one, 2 mg month two) of LDN and repeated the same questionnaire at the end of the second month. Patients were monitored to adverse events.

Findings: In total 52 patients participated of whom 40(76.9%) were female. The median age was 43.5 years(IQR 33.2–49). Healthcare workers represented the largest occupational cohort n = 16(34.8%). The median time from diagnosis of COVID-19 until enrolment was 333 days (IQR 171–396.5). Thirty-eight participants (73.1%) were known to commence LDN, two of whom (5.3%) stopped taking LDN post commencement due to new onset diarrhoea and also described fatigue. In total 36(69.2%) participants completed the questionnaire at the end of the two-month period. Improvement was seen in 6 of 7 parameters measured; recovery from COVID-19, limitation in activities of daily living, energy levels, pain levels, levels of concentration and sleep disturbance (p ≤ 0.001), improvement in mood approached but was not significant (p = 0.054).

Conclusions: LDN is safe in patients with PCS and may improve well-being and reduce symptomatology in this cohort. Randomised control trials are needed to further explore this.

Source: Brendan O’Kelly, Louise Vidal, Tina McHugh, James Woo, Gordana Avramovic, John S. Lambert. Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study. Brain, Behavior, & Immunity – Health; Volume 24, October 2022, 100485 https://www.sciencedirect.com/science/article/pii/S2666354622000758  (Full text)

Rapid improvement in severe long COVID following perispinal etanercept

Abstract:

Background: This study aimed to describe the neurological improvements in a patient with severe long COVID brain dysfunction following perispinal etanercept administration. Perispinal administration of etanercept, a novel method designed to enhance its brain delivery via carriage in the cerebrospinal venous system, has previously been shown to reduce chronic neurological dysfunction after stroke. Etanercept is a recombinant biologic that is capable of ameliorating two components of neuroinflammation: microglial activation and the excess bioactivity of tumor necrosis factor (TNF), a proinflammatory cytokine that is a key neuromodulator in the brain. Optimal synaptic and brain network function require physiological levels of TNF. Neuroinflammation, including brain microglial activation and excess central TNF, can be a consequence of stroke or peripheral infection, including infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19.

Methods: Standardized, validated measures, including the Montreal Cognitive Assessment, Beck Depression Index-II (BDI-II), Fatigue Assessment Scale, Controlled Oral Word Association Test, Trail Making Tests, Timed Finger-to-Nose Test, 20 meter Self-Paced Walk Test, 5 Times Sit-to-Stand Test and Grip Strength measured with a Jamar Dynamometer were used to quantitate changes in cognition, depression, fatigue and neurological function after a single 25mg perispinal etanercept dose in a patient with severe long COVID of 12 months duration.

Results: Following perispinal etanercept administration there was immediate neurological improvement. At 24 hours there were remarkable reductions in chronic post-COVID-19 fatigue and depression, and significant measureable improvements in cognition, executive function, phonemic verbal fluency, balance, gait, upper limb coordination and grip strength. Cognition, depression and fatigue were examined at 29 days; each remained substantially improved.

Conclusion: Perispinal etanercept is a promising treatment for the chronic neurologic dysfunction that may persist after resolution of acute COVID-19, including chronic cognitive dysfunction, fatigue, and depression. These results suggest that long COVID brain neuroinflammation is a potentially reversible pathology and viable treatment target. In view of the increasing unmet medical need, clinical trials of perispinal etanercept for long COVID are urgently necessary. The robust results of the present case suggest that perispinal etanercept clinical trials studying long COVID populations with severe fatigue, depression and cognitive dysfunction may have improved ability to detect a treatment effect. Positron emission tomographic methods that image brain microglial activation and measurements of cerebrospinal fluid proinflammatory cytokines may be useful for patient selection and correlation with treatment effects, as well as provide insight into the underlying pathophysiology.

Source: Tobinick E, Spengler RN, Ignatowski TA, Wassel M, Laborde S. Rapid improvement in severe long COVID following perispinal etanercept. Curr Med Res Opin. 2022 Jul 6:1-23. doi: 10.1080/03007995.2022.2096351. Epub ahead of print. PMID: 35791687.  https://pubmed.ncbi.nlm.nih.gov/35791687/

Functional decline, long term symptoms and course of frailty at 3-months follow-up in COVID-19 older survivors, a prospective observational cohort study

Abstract:

Background: Aging is one of the most important prognostic factors increasing the risk of clinical severity and mortality of COVID-19 infection. However, among patients over 75 years, little is known about post-acute functional decline.

Objective: The aim of this study was to identify factors associated with functional decline 3 months after COVID-19 onset, to identify long term COVID-19 symptoms and transitions between frailty statesafter COVID-19 onset in older hospitalized patients.

Methods: This prospective observational study included COVID-19 patients consecutively hospitalized from March to December 2020 in Acute Geriatric Ward in Nantes University Hospital. Functional decline, frailty status and long term symptoms were assessed at 3 month follow up. Functional status was assessed using the Activities of Daily Living simplified scale (ADL). Frailty status was evaluated using Clinical Frailty Scale (CFS). We performed multivariable analyses to identify factors associated with functional decline.

Results: Among the 318 patients hospitalized for COVID-19 infection, 198 were alive 3 months after discharge. At 3 months, functional decline occurred in 69 (36%) patients. In multivariable analysis, a significant association was found between functional decline and stroke (OR = 4,57, p = 0,003), history of depressive disorder (OR = 3,05, p = 0,016), complications (OR = 2,24, p = 0,039), length of stay (OR = 1,05, p = 0,025) and age (OR = 1,08, p = 0,028). At 3 months, 75 patients described long-term symptoms (49.0%). Of those with frailty (CFS scores ≥5) at 3-months follow-up, 30% were not frail at baseline. Increasing frailty defined by a worse CFS state between baseline and 3 months occurred in 41 patients (26.8%).

Conclusions: This study provides evidence that both the severity of the COVID-19 infection and preexisting medical conditions correlates with a functional decline at distance of the infection. This encourages practitioners to establish discharge personalized care plan based on a multidimensional geriatric assessment and in parallel on clinical severity evaluation.

Source: Prampart S, Le Gentil S, Bureau ML, Macchi C, Leroux C, Chapelet G, de Decker L, Rouaud A, Boureau AS. Functional decline, long term symptoms and course of frailty at 3-months follow-up in COVID-19 older survivors, a prospective observational cohort study. BMC Geriatr. 2022 Jun 30;22(1):542. doi: 10.1186/s12877-022-03197-y. PMID: 35768781. https://bmcgeriatr.biomedcentral.com/articles/10.1186/s12877-022-03197-y (Full text)

Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial

Abstract:

Background: There is no approved pharmaceutical intervention for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). Fatigue in these patients can last for decades. Long COVID may continue to ME/CFS, and currently, it is estimated that up to 20 million Americans have significant symptoms after COVID, and the most common symptom is fatigue. Anhydrous Enol-Oxaloacetate, (AEO) a nutritional supplement, has been anecdotally reported to relieve physical and mental fatigue and is diminished in ME/CFS patients. Here, we examine the use of higher dosage AEO as a medical food to relieve pathological fatigue.

Methods: ME/CFS and Long-COVID patients were enrolled in an open label dose escalating “Proof of Concept” non-randomized controlled clinical trial with 500 mg AEO capsules. Control was provided by a historical ME/CFS fatigue trial and supporting meta-analysis study, which showed average improvement with oral placebo using the Chalder Scale of 5.9% improvement from baseline. At baseline, 73.7% of the ME/CFS patients were women, average age was 47 and length of ME/CFS from diagnosis was 8.9 years. The Long-COVID patients were a random group that responded to social media advertising (Face Book) with symptoms for at least 6 months. ME/CFS patients were given separate doses of 500 mg BID (N = 23), 1,000 mg BID (N = 29) and 1000 mg TID (N = 24) AEO for six weeks. Long COVID patients were given 500 mg AEO BID (N = 22) and 1000 mg AEO (N = 21), again over a six-week period. The main outcome measure was to compare baseline scoring with results at 6 weeks with the Chalder Fatigue Score (Likert Scoring) versus historical placebo. The hypothesis being tested was formulated prior to data collection.

Results: 76 ME/CFS patients (73.7% women, median age of 47) showed an average reduction in fatigue at 6 weeks as measured by the “Chalder Fatigue Questionnaire” of 22.5% to 27.9% from baseline (P < 0.005) (Likert scoring). Both physical and mental fatigue were significantly improved over baseline and historical placebo. Fatigue amelioration in ME/CFS patients increased in a dose dependent manner from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID. Long COVID patients’ fatigue was significantly reduced by up to 46.8% in 6-weeks.

Conclusions: Significant reductions in physical and metal fatigue for ME/CFS and Long-COVID patients were seen after 6 weeks of treatment. As there has been little progress in providing fatigue relief for the millions of ME/CFS and Long COVID patients, anhydrous enol oxaloacetate may bridge this important medical need. Further study of oxaloacetate supplementation for the treatment of ME/CFS and Long COVID is warranted.

Source: Cash, A., Kaufman, D.L. Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial. J Transl Med 20, 295 (2022). https://doi.org/10.1186/s12967-022-03488-3  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03488-3 (Full text)

The effect of SARS-CoV-2 vaccination on post-acute sequelae of COVID-19 (PASC): A prospective cohort study

Abstract:

Background: Symptoms of post-acute sequelae of COVID-19 (PASC) may improve following SARS-CoV-2 vaccination. However few prospective data that also explore the underlying biological mechanism are available. We assessed the effect of vaccination on symptomatology of participants with PASC, and compared antibody dynamics between those with and without PASC.

Methods: RECoVERED is a prospective cohort study of adult patients with mild to critical COVID-19, enrolled from illness onset. Among participants with PASC, vaccinated participants were exact-matched 1:1 on age, sex, obesity status and time since illness onset to unvaccinated participants. Between matched pairs, we compared the monthly mean numbers of symptoms over a 3-month follow-up period, and, using exact logistic regression, the proportion of participants who fully recovered from PASC. Finally, we assessed the association between PACS status and rate of decay of spike- and RBD-binding IgG titers up to 9 months after illness onset using Bayesian hierarchical linear regression.

Findings: Of 349 enrolled participants, 316 (90.5%) had ≥3 months of follow-up, of whom 186 (58.9%) developed PASC. Among 36 matched pairs with PASC, the mean number of symptoms reported each month during 3 months of follow-up were comparable between vaccinated and unvaccinated groups. Odds of full recovery from PASC also did not differ between matched pairs (OR 1.57 [95%CI 0.46-5.84]) within 3 months after the matched time-point. The median half-life of spike- and RBD-binding IgG levels were, in days (95%CrI), 233 (183-324) and 181 (147-230) among participants with PASC, and 170 (125-252) and 144 (113-196) among those without PASC, respectively.

Interpretation: Our study found no strong evidence to suggest that vaccination improves symptoms of PASC. This was corroborated by comparable spike- and RBD-binding IgG waning trajectories between those with and without PASC, refuting any immunological basis for a therapeutic effect of vaccination on PASC.

Source: Wynberg E, Han AX, Boyd A, van Willigen HDG, Verveen A, Lebbink R, van der Straten K, Kootstra N, van Gils MJ, Russell C, Leenstra T, de Jong MD, de Bree GJ, Prins M; RECoVERED Study Group. The effect of SARS-CoV-2 vaccination on post-acute sequelae of COVID-19 (PASC): A prospective cohort study. Vaccine. 2022 Jun 7:S0264-410X(22)00748-4. doi: 10.1016/j.vaccine.2022.05.090. Epub ahead of print. PMID: 35725782; PMCID: PMC9170535. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170535/ (Full text)

The Role of Acupuncture for Long COVID: Mechanisms and Models

Abstract:

Objective: To establish an evidence-based role for acupuncture as a safe and effective treatment for managing Long COVID in the integrative medical setting.

Background: COVID-19 progresses to a chronic state, termed Long COVID, in about 30% of cases with estimates as high as 40% for prolonged illness. Symptoms are diverse and range over several body systems, including unrelenting fatigue, persistent malaise, chronic pain, and mood changes. Early clinical reports suggest acupuncture can effectively address both symptoms and the underlying causes of Long COVID.

Evidence: Historically, acupuncture is well defined in Traditional Chinese Medicine writings to treat influenza-like febrile illnesses. Contemporary scientific literature and case studies support the value of acupuncture for symptoms associated with acute and chronic respiratory viral infections, such as influenza, including SARS and COVID-19. Recent reports provide early evidence of acupuncture’s effectiveness in managing Long COVID symptoms and may also have disease-modifying benefits.

Conclusion: Acupuncture is a viable adjunctive health care modality as part of a multidisciplinary approach for symptom control and disease management to improve quality of life in Long COVID patients. Since acupuncture may favorably modify the length and outcome of this condition, the model of acupuncture presented in this article warrants broader use in the integrative clinical setting and for further research.

Source: James E. Williams and Jacques Moramarco. Medical Acupuncture. Jun 2022.159-166.http://doi.org/10.1089/acu.2021.0090 https://www.liebertpub.com/doi/full/10.1089/acu.2021.0090 (Full text)

Neurological long-COVID in the outpatient clinic: Two subtypes, two courses

Abstract:

Introduction: Symptoms referable to central and peripheral nervous system involvement are often evident both during the acute phase of COVID-19 infection and during long-COVID. In this study, we evaluated a population of patients with prior COVID-19 infection who showed signs and symptoms consistent with neurological long-COVID.

Methods: We prospectively collected demographic and acute phase course data from patients with prior COVID-19 infection who showed symptoms related to neurological involvement in the long-COVID phase. Firstly, we performed a multivariate logistic linear regression analysis to investigate the impact of demographic and clinical data, the severity of the acute COVID-19 infection and hospitalization course, on the post-COVID neurological symptoms at three months follow-up. Secondly, we performed an unsupervised clustering analysis to investigate whether there was evidence of different subtypes of neurological long COVID-19.

Results: One hundred and nine patients referred to the neurological post-COVID outpatient clinic. Clustering analysis on the most common neurological symptoms returned two well-separated and well-balanced clusters: long-COVID type 1 contains the subjects with memory disturbances, psychological impairment, headache, anosmia and ageusia, while long-COVID type 2 contains all the subjects with reported symptoms related to PNS involvement. The analysis of potential risk-factors among the demographic, clinical presentation, COVID 19 severity and hospitalization course variables showed that the number of comorbidities at onset, the BMI, the number of COVID-19 symptoms, the number of non-neurological complications and a more severe course of the acute infection were all, on average, higher for the cluster of subjects with reported symptoms related to PNS involvement.

Conclusion: We analyzed the characteristics of neurological long-COVID and presented a method to identify well-defined patient groups with distinct symptoms and risk factors. The proposed method could potentially enable treatment deployment by identifying the optimal interventions and services for well-defined patient groups, so alleviating long-COVID and easing recovery.

Source: Grisanti SG, Garbarino S, Barisione E, Aloè T, Grosso M, Schenone C, Pardini M, Biassoni E, Zaottini F, Picasso R, Morbelli S, Campi C, Pesce G, Massa F, Girtler N, Battaglini D, Cabona C, Bassetti M, Uccelli A, Schenone A, Piana M, Benedetti L. Neurological long-COVID in the outpatient clinic: Two subtypes, two courses. J Neurol Sci. 2022 Jun 3;439:120315. doi: 10.1016/j.jns.2022.120315. Epub ahead of print. PMID: 35717880; PMCID: PMC9212262. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9212262/ (Full text)

Detecting anti-SARS-CoV-2 antibodies in urine samples: A noninvasive and sensitive way to assay COVID-19 immune conversion

Abstract:

Serum-based ELISA (enzyme-linked immunosorbent assay) has been widely used to detect anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. However, to date, no study has investigated patient urine as a biological sample to detect SARS-CoV-2 virus-specific antibodies. An in-house urine-based ELISA was developed using recombinant SARS-CoV-2 nucleocapsid protein.

The presence of SARS-CoV-2 antibodies in urine was established, with 94% sensitivity and 100% specificity for the detection of anti-SARS-CoV-2 antibodies with the urine-based ELISA and 88% sensitivity and 100% specificity with a paired serum-based ELISA. The urine-based ELISA that detects anti-SARS-CoV-2 antibodies is a noninvasive method with potential application as a facile COVID-19 immunodiagnostic platform, which can be used to report the extent of exposure at the population level and/or to assess the risk of infection at the individual level.

Source: Ludolf F, Ramos FF, Bagno FF, Oliveira-da-Silva JA, Reis TAR, Christodoulides M, Vassallo PF, Ravetti CG, Nobre V, da Fonseca FG, Coelho EAF. Detecting anti-SARS-CoV-2 antibodies in urine samples: A noninvasive and sensitive way to assay COVID-19 immune conversion. Sci Adv. 2022 May 13;8(19):eabn7424. doi: 10.1126/sciadv.abn7424. Epub 2022 May 13. PMID: 35559681; PMCID: PMC9106288. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9106288/ (Full text)