Tag: long Covid

Lung diffusing capacities for nitric oxide and carbon monoxide at rest and post-walking in long COVID

Abstract:

Background: Approximately one-third of long coronavirus disease 2019 (long COVID) patients report breathlessness and fatigue even during activities of daily living. We hypothesised that abnormalities of combined diffusing capacity of the lung for nitric oxide (D LNO) and carbon monoxide (D LCO) at rest or after mild exercise are associated with breathlessness in patients with long COVID.

Methods: Single-breath combined D LNO and D LCO were measured at rest and immediately after a short bout of treadmill exercise simulating ordinary walking in 32 Caucasian patients with long COVID and dyspnoea at rest. 20 subjects served as a control group.

Results: At rest, combined D LNO, D LCO and alveolar volume (V A) were significantly lower in long COVID than in controls, with D LNO and D LCO being below the limits of normal in 69% and 41% of cases, respectively. Mean values of D LNO/V A and D LCO/V A in long COVID patients were less than controls, yet, in only 22% and 12% of long COVID patients were the values of D LNO/V A and D LCO/V A below the limits of normal. After treadmill exercise, D LNO, D LNO/D LCO, V A and heart rate increased significantly without differences between groups. D LNO remained below the limit of normal in 47% of long COVID patients.

Conclusion: These data suggest localised discrete loss of lung units in approximately half of long COVID patients, not completely explained by loss of V A or of alveolar-capillary recruitment during exercise.

Source: Barisione G, Brusasco V. Lung diffusing capacities for nitric oxide and carbon monoxide at rest and post-walking in long COVID. ERJ Open Res. 2023 Apr 17;9(2):00363-2022. doi: 10.1183/23120541.00363-2022. PMID: 37070120; PMCID: PMC9638122. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9638122/ (Full text)

Chronic Disease Self-Management of Post-Acute Sequelae of COVID-19 Among Older Adults: A Mixed-Methods Analysis

Abstract:

Introduction: Approximately 20-30% of individuals who contract acute coronavirus disease (COVID-19) infection develop longer term complications of their initial infection, referred to as Post-Acute Sequelae of SARS-CoV-2 infection (PASC). PASC is characterized by chronic, varying symptomatology.

Methods: Using a mixed methods study design, we aimed to gain insight into individuals’ experience with PASC, including cognitive issues, fatigue, and sleep disturbances. We explored whether our previously developed application (app), aimed at improving self-management skills among individuals with chronic diseases, is relevant for individuals with PASC and gained information to adapt the app for individuals with PASC. The study included 19 individuals, aged 40 years and older, recruited from our research participant database, Nova Southeastern University clinics, and community locations. We included this age range because older adults are more likely to have comorbid conditions, allowing us to better understand the impact of COVID-19 infection in these individuals. Participants completed seven standardized self-report questionnaires online, and an individual semi-structured interview via videoconferencing. Quantitative data were assessed using descriptive statistics and calculating individuals’ scores in relation to norms. Qualitative data were analyzed using a thematic analysis approach. Triangulation of the data was accomplished by calculating correlations between participants’ responses on self-report scales and themes found in semi-structured interviews.

Results: Themes included disruption of everyday life, diverse physical symptoms, and cognitive problems including brain fog, fatigue, coping, and emotional upset. Quantitative analysis demonstrated that participants experienced high levels of fatigue, negative mood, cognitive problems, and overall reduction in health-related quality of life (HRQOL). Correlation analyses revealed that individual interview responses were related to participants’ self-report of symptoms on standard questionnaires.

Discussion: Findings indicate that self-report questionnaires may reflect the experience of individuals with PASC and its impact. Additionally, further efforts to expand our prior mobile app are warranted among individuals with PASC.

Source: Thomas-Purcell K, Davenport R, Ayala V, Purcell D, Ownby RL. Chronic Disease Self-Management of Post-Acute Sequelae of COVID-19 Among Older Adults: A Mixed-Methods Analysis. Clin Interv Aging. 2023 Apr 14;18:607-617. doi: 10.2147/CIA.S393732. PMID: 37082741; PMCID: PMC10112475. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10112475/

Risk factors for post-COVID-19 condition (Long Covid) in children: a prospective cohort study

Abstract:

Background: Adults and children can develop post-Covid-19 condition (PCC) (also referred to as Long Covid). However, existing evidence is scarce, partly due to a lack of a standardised case definition, short follow up duration, and heterogenous study designs, resulting in wide variation of reported outcomes. The primary aim of this study was to characterise risk factors for PCC and longitudinal rates of recovery in a cohort of children and young people using a standardised protocol.

Methods: We performed a prospective “disease-based” cohort study between 01/02/2020 to 31/10/2022 including children aged 0-18 years old, with a previous diagnosis of Covid-19. Children with microbiologically confirmed SARS-CoV-2 infection, were invited for an in-clinic follow-up assessment at a paediatric post-covid clinic in Rome, Italy, at serial intervals (3-, 6-, 12- and 18-months post-onset). PCC was defined as persistence of otherwise unexplained symptoms for at least three months after initial infection. The statistical association between categorical variables was obtained by Chi-squared tests or Fisher’s exact tests. Multivariable logistic regressions are presented using odds ratios (OR) and 95% confidence interval (CI). Survival analysis was conducted using the Kaplan-Meier method.

Findings: 1243 children were included, median age: 7.5 (4-10.3) years old; 575 (46.3%) were females. Of these, 23% (294/1243) were diagnosed with PCC at three months post-onset. Among the study population, 143 patients remained symptomatic at six months, 38 at 12 months, and 15 at 18 months follow up evaluation. The following risk factors were associated with PCC: >10 years of age (OR 1.23; 95% CI 1.18-1.28), comorbidities (OR 1.68; 95% CI 1.14-2.50), and hospitalisation during the acute phase (OR 4.80; 95%CI 1.91-12.1). Using multivariable logistic regression, compared to the Omicron variant, all other variants were significantly associated with PCC at 3 and 6 months. At least one dose of vaccine was associated with a reduced, but not statistically significant risk of developing PCC.

Interpretation: In our study, acute-phase hospitalisation, pre-existing comorbidity, being infected with pre-Omicron variants and older age were associated with a higher risk of developing PCC. Most children recovered over time, but one-in-twenty of those with PCC at three months reported persistent symptoms 18 months post-Sars-CoV-2 infection. Omicron infection was associated with shorter recovery times. We did not find a strong protective effect of vaccination on PCC development. Although our cohort cannot be translated to all Italian children with PCC as more nationwide studies are needed, our findings highlight the need of new strategies to prevent and treat pediatric PCC are needed.

Funding: This study has been funded by Pfizer non-competitive grant, granted to DB (# 65925795).

Source: Morello R, Mariani F, Mastrantoni L, De Rose C, Zampino G, Munblit D, Sigfrid L, Valentini P, Buonsenso D. Risk factors for post-COVID-19 condition (Long Covid) in children: a prospective cohort study. EClinicalMedicine. 2023 May;59:101961. doi: 10.1016/j.eclinm.2023.101961. Epub 2023 Apr 14. PMID: 37073325; PMCID: PMC10101848. https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00138-4/fulltext (Full text)

Unique immune and inflammatory cytokine profiles may define long COVID syndrome

Abstract:

Purpose: Long COVID is estimated to occur in 5-10% of individuals after acute SARS-CoV-2 infection. However, the pathophysiology driving the disease process is poorly understood.

Methods: We evaluated urine and plasma inflammatory and immune cytokine profiles in 33 individuals with long COVID compared to 33 who were asymptomatic and recovered, and 34 without prior infection.

Results: Mean urinary leukotriene E4 was significantly elevated among individuals with long COVID compared to asymptomatic and recovered individuals (mean difference 774.2 pg/mL; SD 335.7) and individuals without prior SARS-CoV-2 infection (mean difference 503.1 pg/ml; SD 467.7). Plasma chemokine ligand 6 levels were elevated among individuals with long COVID compared to individuals with no prior SARS-CoV-2 infection (mean difference 0.59 units; SD 0.42). We found no significant difference in angiotensin-converting enzyme 2 antibody levels. Plasma tumor necrosis factor receptor-associated factor 2 (TRAF2) levels were reduced among individuals with long COVID compared to individuals who were asymptomatic and recovered (mean difference = 0.6 units, SD 0.46). Similarly, the mean level of Sarcoma Homology 2-B adapter protein 3 was 3.3 units (SD 1.24) among individuals with long COVID, lower than 4.2 units (SD 1.1) among individuals with recovered, asymptomatic COVID.

Conclusion: Our findings suggest that further studies should be conducted to evaluate the role of leukotriene E4 as a potential biomarker for a diagnostic test. Furthermore, based on reductions in TRAF2, long COVID may be driven in part by impaired TRAF2-dependent immune-mediated inflammation and potentially immune exhaustion.

Source: Allan-Blitz LT, Akbari O, Kojima N, Saavedra E, Chellamuthu P, Denny N, MacMullan MA, Hess V, Shacreaw M, Brobeck M, Turner F, Slepnev VI, Ibrayeva A, Klausner JD. Unique immune and inflammatory cytokine profiles may define long COVID syndrome. Clin Exp Med. 2023 Apr 16:1–6. doi: 10.1007/s10238-023-01065-6. Epub ahead of print. PMID: 37061998; PMCID: PMC10105906. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10105906/ (Full text)

Employment outcomes of people with Long Covid symptoms: community-based cohort study

Abstract:

Background Evidence on the long-term employment consequences of SARS-CoV-2 infection is lacking. We used data from a large, community-based sample in the UK to estimate associations between Long Covid and subsequent employment outcomes.

Methods This was an observational, longitudinal study using a pre-post design. We included UK COVID-19 Infection Survey participants who completed questionnaires on Long Covid from 3 February 2021 to 30 September 2022 when they were aged 16 to 64 years and not in full-time education. We used conditional logit modelling to explore the time-varying relationship between Long Covid status ≥12 weeks after a first test-confirmed SARS-CoV-2 infection (reference: pre-infection) and labour market inactivity (neither working nor looking for work) or workplace absence lasting ≥4 weeks.

Results Of 206,299 included participants (mean age 45 years, 54% female, 92% white), 15% were ever inactive in the labour market and 10% were ever long-term absent during follow-up. Compared with pre-infection, inactivity was higher in participants reporting Long Covid 30 to <40 weeks (adjusted odds ratio (aOR): 1.45; 95% CI: 1.17 to 1.81) or 40 to <52 weeks (1.34; 1.05 to 1.72) post-infection. Compared with pre-infection, reporting Long Covid was also associated with increased odds of long-term absence 18 to <24 weeks (1.40; 1.04 to 1.90) and 24 to <30 weeks (1.45; 1.03 to 2.04) post-infection, but not beyond 30 weeks. Combining with official statistics on Long Covid prevalence, our estimates translate to 27,000 (95% CI: 6,000 to 47,000) working-age adults in the UK being inactive because of their Long Covid symptoms in July 2022.

Conclusions Long Covid is likely to have contributed to reduced levels of participation in the UK labour market, though it is unlikely to be the sole driver. Further research is required to quantify the contribution of other factors, such as indirect health effects of the pandemic.

Source: Daniel Ayoubkhani, Francesco Zaccardi, Koen B. Pouwels, A. Sarah Walker, Donald Houston, Nisreen A. Alwan, Josh Martin, Kamlesh Khunti, Vahé Nafilyan. Employment outcomes of people with Long Covid symptoms: community-based cohort study.
medRxiv 2023.03.21.23287524; doi: https://doi.org/10.1101/2023.03.21.23287524 https://www.medrxiv.org/content/10.1101/2023.03.21.23287524v1.full-text (Full text)

NETosis induction reflects COVID-19 severity and Long COVID: insights from a two-center patient cohort study in Israel

Abstract:

Background: COVID-19 severity and its late complications continue to be poorly understood. Neutrophil extracellular traps (NETs) form in acute COVID-19, likely contributing to morbidity and mortality. This study evaluated immunothrombosis markers in a comprehensive cohort of acute and recovered COVID-19 patients, including the association of NETs with LongCOVID.

Methods: One-hundred-seventy-seven patients were recruited from clinical cohorts at two Israeli centers: acute COVID-19 (mild/moderate, severe/critical), convalescent COVID-19 (recovered and Long COVID), along with 54 non-COVID controls. Plasma was examined for markers of platelet activation, coagulation, and NETs. Ex vivo NETosis induction capability was evaluated after neutrophil incubation with patient plasma.

Results: Soluble P-selectin, Factor VIII, von Willebrand factor, and platelet factor 4 were significantly elevated in COVID-19 patients versus controls. Myeloperoxidase (MPO)-DNA complex levels were increased only in severe COVID-19 and did not differentiate between COVID-19 severities or correlate with thrombotic markers. NETosis induction levels strongly correlated with illness severity/duration, platelet activation markers, and coagulation factors, and were significantly reduced upon dexamethasone treatment and recovery. Long COVID patients maintained higher NETosis induction, but not NET fragments, compared to recovered convalescent patients.

Conclusions: Increased NETosis induction can be detected in Long COVID patients. NETosis induction appears to be a more sensitive NET measurement than MPO-DNA levels in COVID-19, differentiating between disease severity and Long COVID patients. Ongoing NETosis induction capability in Long COVID may provide insights into pathogenesis and serve as a surrogate marker for persistent pathology. This study emphasizes the need to explore neutrophil-targeted therapies in acute and chronic COVID-19.

Source: Krinsky N, Sizikov S, Nissim S, Dror A, Sas A, Prinz H, Pri-Or E, Perek S, Raz-Pasteur A, Lejbkowicz I, Cohen-Matsliah SI, Almog R, Chen N, Kurd R, Jarjou’i A, Rokach A, Ben-Chetrit E, Schroeder A, Caulin AF, Yost CC, Schiffman JD, Goldfeder M, Martinod K. NETosis induction reflects COVID-19 severity and Long COVID: insights from a two-center patient cohort study in Israel. J Thromb Haemost. 2023 Apr 11:S1538-7836(23)00274-X. doi: 10.1016/j.jtha.2023.02.033. Epub ahead of print. PMID: 37054916; PMCID: PMC10088279. https://www.jthjournal.org/article/S1538-7836(23)00274-X/fulltext (Full text available as PDF file)

Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study

Summary:

Background: ‘Long COVID’ describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID.

Methods: Patients with fatigue dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849.

Findings: Between December 15th 2021, and May 23th 2022, 60 participants were screened and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious, or led to treatment discontinuation.

Interpretation: Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there was a significant improvement in fatigue-based symptoms among patients living with Long COVID following a four week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID.

Source: Lucy E.M. Finnigan, Mark Philip Cassar, Margaret James Koziel, Joel Pradines, Hanan Lamlum, Karim Azer, et al. Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study. The Lancet, Published: April 14, 2023 DOI: https://doi.org/10.1016/j.eclinm.2023.101946 (Full text)

Exercise Intolerance Associated with Impaired Oxygen Extraction in Patients with Long COVID

Abstract:

Objective: Chronic mental and physical fatigue and post-exertional malaise are the more debilitating symptoms of long COVID-19. The study objective was to explore factors contributing to exercise intolerance in long COVID-19 to guide development of new therapies. Exercise capacity data of patients referred for a cardiopulmonary exercise test (CPET) and included in a COVID-19 Survivorship Registry at one urban health center were retrospectively analyzed.

Results: Most subjects did not meet normative criteria for a maximal test, consistent with suboptimal effort and early exercise termination. Mean O2 pulse peak % predicted (of 79 ± 12.9) was reduced, supporting impaired energy metabolism as a mechanism of exercise intolerance in long COVID, n=59. We further identified blunted rise in heart rate peak during maximal CPET. Our preliminary analyses support therapies that optimize bioenergetics and improve oxygen utilization for treating long COVID-19.

Source: Norweg A, Yao L, Barbuto S, Nordvig AS, Tarpey T, Collins E, Whiteson J, Sweeney G, Haas F, Leddy J. Exercise Intolerance Associated with Impaired Oxygen Extraction in Patients with Long COVID. Respir Physiol Neurobiol. 2023 Apr 17;313:104062. doi: 10.1016/j.resp.2023.104062. Epub ahead of print. PMID: 37076024; PMCID: PMC10108551. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10108551/ (Full text)

Low vitamin D levels are associated with Long COVID syndrome in COVID-19 survivors

Abstract:

Purpose: Long-COVID is an emerging syndrome affecting 50-70% of COVID-19 survivors which still lacks predicting factors. Due to the extra-skeletal effects of vitamin D, we retrospectively assessed in COVID-19 survivors 6-months after hospitalization the association between 25(OH)vitamin D levels and Long-COVID.

Methods: Long-COVID was defined according to NICE-guidelines. Fifty Long-COVID and 50 non-Long-COVID subjects matched on a 1:1-basis were enrolled from an outpatient-post-COVID clinic-cohort seen from August to November 2020. Therapies/comorbidities affecting calcium/vitamin-D/bone metabolism, and/or admission in ICU during hospitalization were exclusion criteria. 25(OH)vitamin D was measured at hospital-admission and 6-months after discharge.

Results: We observed lower 25(OH)vitamin D levels, evaluated at follow-up, in subjects with Long-COVID than those without (20.1vs23.2 ng/mL-p = 0.03). Regarding the affected health-areas evaluated in the entire cohort, we observed lower 25(OH)vitamin D levels in those with neurocognitive symptoms at follow-up (n.7) as compared to those without (n.93) (14.6vs20.6 ng/mL-p = 0.042). In patients presenting vitamin D deficiency (<20 ng/mL) both at admission and at follow-up (n.42), those affected by Long-COVID (n.22) presented lower 25(OH)vitamin D levels, at follow-up, compared to those not affected (n.20) (12.7vs15.2 ng/mL-p = 0.041). In multiple-regression analyses, lower 25(OH)vitamin D levels, at follow-up, resulted as the only variable significantly associated with Long-COVID in our cohort (p = 0.008, OR 1.09-CI 1.01-1.16).

Conclusions: COVID-19 survivors with Long-COVID have lower 25(OH)vitamin D levels as compared to matched-patients without Long-COVID. Our data suggest that vitamin D levels should be evaluated in COVID-19 patients after hospital-discharge. Role of vitamin D supplementation as preventive strategy of COVID-19 sequelae should be tested in randomized-controlled trials.

Source: di Filippo L, Frara S, Nannipieri F, Cotellessa A, Locatelli M, Rovere Querini P, Giustina A. Low vitamin D levels are associated with Long COVID syndrome in COVID-19 survivors. J Clin Endocrinol Metab. 2023 Apr 13:dgad207. doi: 10.1210/clinem/dgad207. Epub ahead of print. PMID: 37051747. https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgad207/7116659 (Full text available as PDF file)

Cytokine deficiencies in patients with Long-COVID

Abstract:

Up to half of individuals who contract SARS-CoV-2 develop symptoms of long-COVID approximately three months after initial infection. These symptoms are highly variable, and the mechanisms inducing them are yet to be understood. We compared plasma cytokine levels from individuals with long-COVID to healthy individuals and found that those with long-COVID had 100% reductions in circulating levels of Interferon Gamma (IFNγ) and Interleukin-8 (IL-8). Additionally, we found significant reductions in levels of IL-6, IL-2, IL-17, IL-13, and IL-4 in individuals with long-COVID.

We propose immune exhaustion as the driver of long-COVID, with the complete absence of IFNγ and IL-8 preventing the lungs and other organs from healing after acute infection, and reducing the ability to fight off subsequent infections, both contributing to the myriad of symptoms suffered by those with long-COVID.

Source: Williams ES, Martins TB, Shah KS, Hill HR, Coiras M, Spivak AM, Planelles V. Cytokine Deficiencies in Patients with Long-COVID. J Clin Cell Immunol. 2022;13(6):672. Epub 2022 Nov 18. PMID: 36742994; PMCID: PMC9894377. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894377/ (Full text)