Tag: 2022

Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-κB signaling

Abstract:

Long COVID, a type of Post-Acute Sequelae of SARS-CoV-2 (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the mechanisms that drive this inflammation remain unknown. Inflammation during acute Coronavirus Disease 2019 could be exacerbated by microbial translocation (from gut and/or lung) to blood. Whether microbial translocation contributes to inflammation during PASC is unknown.

We did not observe a significant elevation in plasma markers of bacterial translocation during PASC. However, we observed higher levels of fungal translocation – measured as β-glucan, a fungal cell wall polysaccharide – in the plasma of individuals experiencing PASC compared to those without PASC or SARS-CoV-2 negative controls. The higher β-glucan correlated with higher inflammation and elevated levels of host metabolites involved in activating N-Methyl-D-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neuro-toxic properties. Mechanistically, β-glucan can directly induce inflammation by binding to myeloid cells (via Dectin-1) and activating Syk/NF-κB signaling.

Using a Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared to plasma from negative controls. This higher NF-κB signaling was abrogated by Piceatannol (Syk inhibitor). These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

Source: Giron LB, Peluso MJ, Ding J, Kenny G, Zilberstein NF, Koshy J, Hong KY, Rasmussen H, Miller GE, Bishehsari F, Balk RA, Moy JN, Hoh R, Lu S, Goldman AR, Tang HY, Yee BC, Chenna A, Winslow JW, Petropoulos CJ, Kelly JD, Wasse H, Martin JN, Liu Q, Keshavarzian A, Landay A, Deeks SG, Henrich TJ, Abdel-Mohsen M. Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-κB signaling. JCI Insight. 2022 Jun 21:e160989. doi: 10.1172/jci.insight.160989. Epub ahead of print. PMID: 35727635. https://pubmed.ncbi.nlm.nih.gov/35727635/

Outcomes of SARS-CoV-2 Reinfection

Abstract:

First infection with SARS-CoV-2 is associated with increased risk of acute and post-acute death and sequelae in the pulmonary and extrapulmonary organ systems. However, whether reinfection adds to the risk incurred after the first infection is not clear. Here we use the national health care databases of the US Department of Veterans Affairs to build a cohort of people with first infection (n = 257,427), reinfection (2 or more infections, n = 38,926), and a non-infected control group (n = 5,396,855) to estimate risks and 6-month burdens of all-cause mortality, hospitalization, and a set of pre-specified incident outcomes.

We show that compared to people with first infection, reinfection contributes additional risks of all-cause mortality, hospitalization, and adverse health outcomes in the pulmonary and several extrapulmonary organ systems (cardiovascular disorders, coagulation and hematologic disorders, diabetes, fatigue, gastrointestinal disorders, kidney disorders, mental health disorders, musculoskeletal disorders, and neurologic disorders); the risks were evident in those who were unvaccinated, had 1 shot, or 2 or more shots prior to the second infection; the risks were most pronounced in the acute phase, but persisted in the post-acute phase of reinfection, and most were still evident at 6 months after reinfection.

Compared to non-infected controls, assessment of the cumulative risks of repeated infection showed that the risk and burden increased in a graded fashion according to the number of infections. The constellation of findings show that reinfection adds non-trivial risks of all-cause mortality, hospitalization, and adverse health outcomes in the acute and post-acute phase of the reinfection. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.

Source: Ziyad Al-Aly, Benjamin Bowe, Yan Xie et al. Outcomes of SARS-CoV-2 Reinfection, 17 June 2022, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-1749502/v1] https://www.researchsquare.com/article/rs-1749502/v1 (Full text available as PDF file)

Treatment of persistent COVID-19 in two B-cell-depleted patients with the monoclonal antibody Sotrovimab

Abstract:

Background: Patients having undergone B-cell-depletion with anti-CD20-antibodies have a higher risk of mortality, delayed viral clearance and prolonged infection due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report two cases of patients with persistent coronavirus disease 2019 (COVID-19) in association with B-cell-depletion that were treated with the monoclonal antibody Sotrovimab.

Case presentation: Both patients presented with chronic symptoms of COVID-19 such as dyspnea, fatigue, and chest pain. Nasopharyngeal swabs remained positive months after the initial infection with fluctuating cycle threshold (Ct) values around 30. Both patients received a single infusion with the monoclonal SARS-CoV-2 antibody Sotrovimab, which resulted in a rapid improvement of symptoms and inflammation markers as well as negative SARS-CoV-2 swabs. A follow-up after a month showed ongoing improvement of symptoms, persistent negative SARS-CoV-2 swabs, and positive serum antibodies.

Conclusion: Infusion with the monoclonal SARS-CoV-2 antibody led to rapid improvement in two patients with persistent COVID-19 after B-cell depletion.

Source: Totschnig D, Doberer D, Haberl R, Wenisch C, Valipour A. Treatment of persistent COVID-19 in two B-cell-depleted patients with the monoclonal antibody Sotrovimab. IDCases. 2022;29:e01528. doi: 10.1016/j.idcr.2022.e01528. Epub 2022 Jun 7. PMID: 35694274; PMCID: PMC9172259. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9172259/ (Full text)

What Do We Need to Know About Musculoskeletal Manifestations of COVID-19?: A Systematic Review

Abstract:

»: COVID-19 is a disease that is challenging science, health-care systems, and humanity. An astonishingly wide spectrum of manifestations of multi-organ damage, including musculoskeletal, can be associated with SARS-CoV-2.

»: In the acute phase of COVID-19, fatigue, myalgia, and arthralgia are the most common musculoskeletal symptoms.

»: Post-COVID-19 syndrome is a group of signs and symptoms that are present for >12 weeks. The associated musculoskeletal manifestations are fatigue, arthralgia, myalgia, new-onset back pain, muscle weakness, and poor physical performance.

»: Data on COVID-19 complications are growing due to large absolute numbers of cases and survivors in these 2 years of the pandemic. Additional musculoskeletal manifestations encountered are falls by the elderly, increased mortality after hip fracture, reduced bone mineral density and osteoporosis, acute sarcopenia, rhabdomyolysis, Guillain-Barré syndrome, muscle denervation atrophy, fibromyalgia, rheumatological disease triggering, septic arthritis, adhesive capsulitis, myositis, critical illness myopathy, onset of latent muscular dystrophy, osteonecrosis, soft-tissue abscess, urticarial vasculitis with musculoskeletal manifestations, and necrotizing autoimmune myositis.

»: A wide range of signs and symptoms involving the musculoskeletal system that affect quality of life and can result in a decrease in disability-adjusted life years. This powerful and unpredictable disease highlights the importance of multimodality imaging, continuing education, and multidisciplinary team care to support preventive measures, diagnosis, and treatment.

Source: Pires RE, Reis IGN, Waldolato GS, Pires DD, Bidolegui F, Giordano V. What Do We Need to Know About Musculoskeletal Manifestations of COVID-19?: A Systematic Review. JBJS Rev. 2022 Jun 3;10(6). doi: 10.2106/JBJS.RVW.22.00013. PMID: 35658089. https://pubmed.ncbi.nlm.nih.gov/35658089/

Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology

Abstract:

Background: Among post-COVID-19 symptoms, fatigue is reported as one of the most common, even after mild acute infection, and as the cause of fatigue, myopathy diagnosed by electromyography has been proposed in previous reports. This study aimed to explore the histopathological changes in patients with post-COVID-19 fatigue.

Methods: Sixteen patients (mean age:46 years) with post-COVID-19 complaints of fatigue, myalgia or weakness persisting for up to 14 months were included. In all patients, quantitative electromyography and muscle biopsies analysed with light and electron microscopy were taken.

Results: Muscle weakness was present in 50%, myopathic electromyography in 75% while in all patients, there were histological changes. Muscle fiber atrophy was found in 38%, and 56% showed indications of fiber regeneration. Mitochondrial changes, comprising loss of COX activity, subsarcollemmal accumulation and/or abnormal cristae, were present in 62%. Inflammation was found in 62%, seen as T-lymphocytes and/or muscle fiber HLA-ABC expression. In 75%, capillaries were affected involving basal lamina and cells. In two patients, uncommon amounts of basal lamina were found, not only surrounding muscle fibers but also around nerves and capillaries.

Conclusions: The wide variety of histological changes in this study suggest that skeletal muscles may be a major target of SARS-CoV-2 causing muscular post-COVID-19 symptoms. The mitochondrial changes, inflammation and capillary injury in muscle biopsies can cause fatigue in part due to reduced energy supply. Since most patients had mild-moderate acute affection, the new variants that might cause less severe acute disease could still have the ability to cause long-term myopathy.

Source: Hejbøl EK, Harbo T, Agergaard J, Madsen LB, Pedersen TH, Østergaard LJ, Andersen H, Schrøder HD, Tankisi H. Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology. Eur J Neurol. 2022 Jun 6. doi: 10.1111/ene.15435. Epub ahead of print. PMID: 35661354.  https://pubmed.ncbi.nlm.nih.gov/35661354/ https://pubmed.ncbi.nlm.nih.gov/35661354/ (Full text available as PDF file)

COVID-19 Infection: Its Lingering Symptoms in Adults

Abstract:

Background: Recent studies showed that a significant percentage of people who recovered from coronavirus disease 2019 (COVID-19) had lingering symptoms. Among patients diagnosed with COVID-19 infection, studies showed persistent symptoms both in patients hospitalized and in outpatient settings. In the studies done in the outpatient setting involving mild to moderate COVID-19 patients, there were significant variations regarding the exact percentage of people with lingering symptoms. Also, in the outpatient setting, not many studies were done on COVID-19 patients that assessed risk factors for having lingering symptoms. Given that a large percentage of people infected with COVID-19 infection do not get hospitalized, it is imperative that this lacuna be filled. We believe knowing the details of long-term symptoms of COVID-19 infection both from prevalence and predictors point of view, could allow the physicians, healthcare system and community to better prepare for managing and following these patients.

Materials and methods: Our study period was within 12 months after the first documented case of COVID-19 occurred in the State of Alabama. Our study population included patients who were diagnosed with a documented case of COVID-19 in this time period and were under the care of a single primary care provider at an ambulatory clinic. Among 80 patients who had documented COVID-19, three left the practice, two declined to participate in the study and three were deceased (two due to COVID-19 and one for other reasons). Therefore, the study population constituted 72 patients. A questionnaire was mailed to all 72 patients to see how many of them had symptoms three months and beyond of having COVID-19 infection. A chart review was conducted for the study participants to assess for “Comorbid conditions”, health conditions that were considered conclusively high risk for acute COVID-19 infection by US Center for Disease Control and Prevention (CDC).

Results: Fifty-three patients responded to the questionnaire; 27 patients (50.9%) reported lingering symptoms beyond three months of diagnosis with COVID-19 infection. The three most common symptoms reported were fatigue (56%), brain fog (48%), and shortness of breath (41%). The results also showed that women are more likely than men to have lingering symptoms. “Elderly” (≥65 years) patients were as likely as 18-64 years old patients to have lingering symptoms and the presence of one or more of the “Comorbid conditions” does not have any bearing on the occurrence of lingering symptoms.

Conclusion: Future studies should be done in a larger population to assess the findings that our study showed regarding “elderly” age and the presence of one or more “comorbid conditions” being independent variables of the occurrence of prolonged COVID-19 symptoms. We recommend studies be done assessing the prevalence and predictors for the long-term effects of the COVID-19 infection. This knowledge could help in preventing those long-term symptoms from occurring in the first place and also in preparing the patient, the physician and the community in managing the outcomes effectively.

Source: Yellumahanthi DK, Barnett B, Barnett S, Yellumahanthi S. COVID-19 Infection: Its Lingering Symptoms in Adults. Cureus. 2022 May 4;14(5):e24736. doi: 10.7759/cureus.24736. PMID: 35677013; PMCID: PMC9166577. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166577/ (Full text)

Inflammation during early post-acute COVID-19 is associated with reduced exercise capacity and Long COVID symptoms after 1 year

Abstract:

Background: Mechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 “PASC” or “Long COVID”) remain unclear. The purpose of this study was to elucidate the pathophysiology of cardiopulmonary PASC using multimodality cardiovascular imaging including cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring.

Methods: We performed CMR, CPET, and ambulatory rhythm monitoring among adults > 1 year after PCR-confirmed SARS-CoV-2 infection in the UCSF Long-Term Impact of Infection with Novel Coronavirus cohort (LIINC; NCT04362150 ) and correlated findings with previously measured biomarkers. We used logistic regression to estimate associations with PASC symptoms (dyspnea, chest pain, palpitations, and fatigue) adjusted for confounders and linear regression to estimate differences between those with and without symptoms adjusted for confounders.

Results: Out of 120 participants in the cohort, 46 participants (unselected for symptom status) had at least one advanced cardiac test performed at median 17 months following initial SARS-CoV-2 infection. Median age was 52 (IQR 42-61), 18 (39%) were female, and 6 (13%) were hospitalized for severe acute infection. On CMR (n=39), higher extracellular volume was associated with symptoms, but no evidence of late-gadolinium enhancement or differences in T1 or T2 mapping were demonstrated. We did not find arrhythmias on ambulatory monitoring. In contrast, on CPET (n=39), 13/23 (57%) with cardiopulmonary symptoms or fatigue had reduced exercise capacity (peak VO 2 <85% predicted) compared to 2/16 (13%) without symptoms (p=0.008). The adjusted difference in peak VO 2 was 5.9 ml/kg/min lower (-9.6 to -2.3; p=0.002) or -21% predicted (-35 to -7; p=0.006) among those with symptoms. Chronotropic incompetence was the primary abnormality among 9/15 (60%) with reduced peak VO 2 . Adjusted heart rate reserve <80% was associated with reduced exercise capacity (OR 15.6, 95%CI 1.30-187; p=0.03). Inflammatory markers (hsCRP, IL-6, TNF-α) and SARS-CoV-2 antibody levels measured early in PASC were negatively correlated with peak VO 2 more than 1 year later.

Conclusions: Cardiopulmonary symptoms and elevated inflammatory markers present early in PASC are associated with objectively reduced exercise capacity measured on cardiopulmonary exercise testing more than 1 year following COVID-19. Chronotropic incompetence may explain reduced exercise capacity among some individuals with PASC.

Clinical perspective: What is New? Elevated inflammatory markers in early post-acute COVID-19 are associated with reduced exercise capacity more than 1 year later. Impaired chronotropic response to exercise is associated with reduced exercise capacity and cardiopulmonary symptoms more than 1 year after SARS-CoV-2 infection. Findings on ambulatory rhythm monitoring point to perturbed autonomic function, while cardiac MRI findings argue against myocardial dysfunction and myocarditis.

Clinical implications: Cardiopulmonary testing to identify etiologies of persistent symptoms in post-acute sequalae of COVID-19 or “Long COVID” should be performed in a manner that allows for assessment of heart rate response to exercise. Therapeutic trials of anti-inflammatory and exercise strategies in PASC are urgently needed and should include assessment of symptoms and objective testing with cardiopulmonary exercise testing.

Source: Durstenfeld MS, Peluso MJ, Kaveti P, Hill C, Li D, Sander E, Swaminathan S, Arechiga VM, Sun K, Ma Y, Zepeda V, Lu S, Goldberg SA, Hoh R, Chenna A, Yee BC, Winslow JW, Petropoulos CJ, Win S, Kelly JD, Glidden DV, Henrich TJ, Martin JN, Lee YJ, Aras MA, Long CS, Grandis DJ, Deeks SG, Hsue PY. Inflammation during early post-acute COVID-19 is associated with reduced exercise capacity and Long COVID symptoms after 1 year. medRxiv [Preprint]. 2022 Jun 1:2022.05.17.22275235. doi: 10.1101/2022.05.17.22275235. PMID: 35677073; PMCID: PMC9176659. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9176659/ (Full text)

Autonomic function testing in long-COVID syndrome patients with orthostatic intolerance

Abstract:

The association between dysautonomia and long-COVID syndrome has gained considerable interest. This study retrospectively characterized the findings of autonomic reflex screen (ARS) in long-COVID patients presenting with orthostatic intolerance (OI). Fourteen patients were identified. All patients had normal cardiovagal function and 2 patients had abnormal sudomotor function. The head-up tilt table (HUTT) was significantly abnormal in 3 patients showing postural orthostatic tachycardia syndrome (POTS). CASS ranged from 0 to 2. The most common clinical scenario was symptoms of orthostatic intolerance without demonstrable HUTT orthostatic tachycardia or orthostatic hypotension (OH) (n = 8, 57 %). In our case series, most long-COVID patients presenting to our laboratory with OI had no significant HUTT abnormalities; only 3 patients met the criteria for POTS.

Source: Eldokla AM, Ali ST. Autonomic function testing in long-COVID syndrome patients with orthostatic intolerance. Auton Neurosci. 2022 Jun 2;241:102997. doi: 10.1016/j.autneu.2022.102997. Epub ahead of print. PMID: 35679657. https://pubmed.ncbi.nlm.nih.gov/35679657/

Long COVID in the long run – 23 months follow-up study of persistent symptoms

Abstract:

Symptoms of long COVID were found in 38% of 170 patients followed median 22.6 months. Most prevalent symptoms were fatigue, affected taste and smell, and difficulties remembering and concentrating. Predictors for long COVID were older age and number of symptoms in the acute phase. Long COVID may take many months, maybe years to resolve.

Source: Gunnhild Helmsdal, Katrin Dahl Hanusson, Marnar Fríðheim Kristiansen, Billa Mouritsardóttir Foldbo, Marjun Eivindardóttir Danielsen, Bjarni á Steig, Shahin Gaini, Marin Strøm, Pál Weihe, Maria Skaalum Petersen, Long COVID in the long run – 23 months follow-up study of persistent symptoms, Open Forum Infectious Diseases, 2022;, ofac270, https://doi.org/10.1093/ofid/ofac270 (Full text available as PDF file)

The relevance of headache as an onset symptom in COVID-19: a network analysis of data from the LONG-COVID-EXP-CM multicentre study

To the Editor,

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus primary affects the respiratory system; however, a multiorganic affection is evident. Neurological symptoms are frequent at the acute- and post-acute phases after infection [1]. Headache is a neurological symptom experienced as a COVID-19-onset symptom associated with a more benign course of the disease [2]; however, it has been also associated with a higher prevalence of post-COVID headache [3].

During the acute COVID-19 phase, headache often co-exists with other neurological symptoms, e.g., anosmia or ageusia [4]. The presence of anosmia as an onset symptom is also associated with lower mortality rate and a less severe disease, although it seems that patients with anosmia and ageusia represent a different group than those with headache [5]. In this letter, we applied a network analysis to determine the relevance of COVID-19-onset symptoms, including headache, as well as pre-existing medical co-morbidities in a sample of previously hospitalised COVID-19 patients.

The LONG-COVID-EXP-CM is a multicentre cohort study including individuals with a diagnosis of SARS-CoV-2 infection by RT-PCR technique and/or radiological findings hospitalised during the first wave of the pandemic in five hospitals of Madrid (Spain). Among all patients hospitalised during the first wave, a sample of 400 from each hospital was randomly selected. The Ethics Committee of all the hospitals approved the study (HCSC20/495E, HSO25112020, HUFA20/126, HUIL/092-20, HUF/EC1517). Verbal informed consent was obtained from participants for the use of their data in this analysis. Demographic data, pre-existing medical comorbidities, COVID-19 symptoms at hospital admission, days at hospital, and intensive care unit (ICU) admission were collected from hospital records.

The network included 28 nodes linked by edges weighted by partial correlation coefficients. The dataset as well as the related two vectors specifying the type (“g” for Gaussian, “p” for Poisson, “c” for categorical) and the number of levels (or categories) for each variable is provided. The mgm was estimated for order = 2 to only take pairwise interactions into account, using least absolute shrinkage and selection operator (LASSO, ℓ1-regularisation) that seeks to maximise specificity (to include as few false positives as possible) with rule = “AND” (which specifies whether the two estimates for an edge are combined with an “AND” or an “OR” rule). Since not all nodes in a network are equally important, centrality was assessed by calculating strength centrality (defined as the sum of weights of edges), betweenness centrality (defined as the total number of shortest paths that pass through the target node, moderated by the total number of shortest paths existing between any couple of nodes in the graph) and closeness centrality (defined as the inverse sum of the distances of shortest of the target node from all other nodes in the network).

Two thousand (n = 2000) patients were randomly selected and invited to participate. A total of 1969 (age:61 ± 16 years, 46.4% women) were included. The most common symptoms at hospital admission were fever (74.6%), dyspnoea (31.5%), myalgia (30.7%) and cough (27.9%). The network identified one group of variables grouping all COVID-19-onset symptoms at hospitalisation, and a second one grouping all pre-existing medical co-morbidities (Fig. 1). Multiple positive correlations between the variables in each group were found. The highest correlation (ρρ:5.87) in the medical co-morbidity group was between asthma (node 9) and rheumatological diseases (node 13). Within the COVID-19-onset symptoms group, headache (node 20) had several high correlations with fever (node 16, ρρ:5.981), dyspnoea (node 17, ρρ:5.617), anosmia (node 22, ρρ:5.2276 and ageusia (node 23, ρρ:4.660). No correlations between both groups of variables were seen. In the group of COVID-19-onset symptoms, headache was the node showing the highest strength centrality, highest betweenness centrality and highest closeness centrality (node 20, Fig. 2).

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Source: Fernández-de-las-Peñas, C., Varol, U., Gómez-Mayordomo, V. et al. The relevance of headache as an onset symptom in COVID-19: a network analysis of data from the LONG-COVID-EXP-CM multicentre study. Acta Neurol Belg (2022). https://doi.org/10.1007/s13760-022-01998-x  https://link.springer.com/article/10.1007/s13760-022-01998-x (Full text)