Category: Overlapping Illnesses

Clinical Characteristics and Mechanisms of Musculoskeletal Pain in Long COVID

Abstract:

Objective: Musculoskeletal (MSK) pain is being increasingly reported by patients as one of the most common persistent symptoms in post-COVID-19 syndrome or Long COVID. However, there is a lack of understanding of its prevalence, characteristics, and underlying pathophysiological mechanisms. The objective of this review is to identify and describe the features and characteristics of MSK pain in Long COVID patients.

Methods: The narrative review involved a literature search of the following online databases: MEDLINE (OVID), EMBASE (OVID), CINAHL, PsyclNFO, and Web of Science (December 2019 to February 2022). We included observational studies that investigated the prevalence, characteristics, risk factors and mechanisms of MSK pain in Long COVID. After screening and reviewing the initial literature search results, a total of 35 studies were included in this review.

Results: The overall reported prevalence of MSK pain in Long COVID ranged widely from 0.3% to 65.2%. The pain has been reported to be localized to a particular region or generalized and widespread. No consistent pattern of progression of MSK pain symptoms over time was identified. Female gender and higher BMI could be potential risk factors for Long COVID MSK pain, but no clear association has been found with age and ethnicity. Different pathophysiological mechanisms have been hypothesized to contribute to MSK pain in Long COVID including increased production of proinflammatory cytokines, immune cell hyperactivation, direct viral entry of neurological and MSK system cells, and psychological factors.

Conclusion: MSK pain is one of the most common symptoms in Long COVID. Most of the current literature on Long COVID focuses on reporting the prevalence of persistent MSK pain. Studies describing the pain characteristics are scarce. The precise mechanism of MSK pain in Long COVID is yet to be investigated. Future research must explore the characteristics, risk factors, natural progression, and underlying mechanisms of MSK pain in Long COVID.

Source: Khoja O, Silva Passadouro B, Mulvey M, Delis I, Astill S, Tan AL, Sivan M. Clinical Characteristics and Mechanisms of Musculoskeletal Pain in Long COVID. J Pain Res. 2022 Jun 17;15:1729-1748. doi: 10.2147/JPR.S365026. PMID: 35747600; PMCID: PMC9212788. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9212788/ (Full text)

Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2

The omicron variant of SARS-CoV-2 (PANGO B.1.1.529) spread rapidly across the world, out-competing former variants soon after it was first detected in November, 2021. According to the Our World in Data COVID-19 database, In Europe, the number of confirmed cases reported between December, 2021, and March, 2022 (omicron period) has exceeded all previously reported cases. Omicron appears to cause less severe acute illness than previous variants, at least in vaccinated populations. However, the potential for large numbers of people to experience long-term symptoms is a major concern, and health and workforce planners need information urgently to appropriately scale resource allocation.
In this case-control observational study, we set out to identify the relative odds of long-COVID (defined following the National Institute for Health and Care Excellence guidelines as having new or ongoing symptoms 4 weeks or more after the start of acute COVID-19) in the UK during the omicron period compared with the delta period. We used self-reported data from the COVID Symptom Study app. (King’s College London Research Ethics Management Application System number 18210, reference LRS-19/20-18210). Data were extracted and pre-processed using ExeTera13 (version 0.5.5).
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Source: Antonelli M, Pujol JC, Spector TD, Ourselin S, Steves CJ. Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2. Lancet. 2022 Jun 18;399(10343):2263-2264. doi: 10.1016/S0140-6736(22)00941-2. PMID: 35717982; PMCID: PMC9212672. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00941-2/fulltext (Full text)

Self-Reported Long COVID in the General Population: Sociodemographic and Health Correlates in a Cross-National Sample

Abstract:

We aimed to gain knowledge of possible sociodemographic predictors of long COVID and whether long COVID was associated with health outcomes almost two years after the pandemic outbreak. There were 1649 adults who participated in the study by completing a cross-sectional online survey disseminated openly in Norway, the UK, the USA, and Australia between November 2021 and January 2022.

Participants were defined as having long COVID based on self-reports that they had been infected by COVID-19 and were experiencing long-lasting COVID symptoms. Logistic regression analyses were used to examine possible sociodemographic predictors, and multivariate analysis of variance was used to examine whether long COVID status was associated with health outcomes. None of the sociodemographic variables was significantly associated with reporting long COVID. Having long COVID was associated with higher levels of psychological distress, fatigue, and perceived stress. The effect of long COVID on health outcomes was greater among men than among women.

In conclusion, long COVID appeared across sociodemographic groups. People with long COVID reported worsened health outcomes compared to those who had had COVID-19 but without long-term symptoms. Men experiencing long COVID appear to be particularly vulnerable to experiencing poorer health outcomes; health services may pay extra attention to potentially unnoticed needs for support among men experiencing long COVID.

Source: Bonsaksen T, Leung J, Price D, Ruffolo M, Lamph G, Kabelenga I, Thygesen H, Geirdal AØ. Self-Reported Long COVID in the General Population: Sociodemographic and Health Correlates in a Cross-National Sample. Life (Basel). 2022 Jun 15;12(6):901. doi: 10.3390/life12060901. PMID: 35743932. https://www.mdpi.com/2075-1729/12/6/901/htm (Full text)

Effect of SARS-CoV-2 proteins on vascular permeability

Abstract:

Severe acute respiratory syndrome (SARS)-CoV-2 infection leads to severe disease associated with cytokine storm, vascular dysfunction, coagulation, and progressive lung damage. It affects several vital organs, seemingly through a pathological effect on endothelial cells. The SARS-CoV-2 genome encodes 29 proteins, whose contribution to the disease manifestations, and especially endothelial complications, is unknown.

We cloned and expressed 26 of these proteins in human cells and characterized the endothelial response to overexpression of each, individually. Whereas most proteins induced significant changes in endothelial permeability, nsp2, nsp5_c145a (catalytic dead mutant of nsp5), and nsp7 also reduced CD31, and increased von Willebrand factor expression and IL-6, suggesting endothelial dysfunction. Using propagation-based analysis of a protein-protein interaction (PPI) network, we predicted the endothelial proteins affected by the viral proteins that potentially mediate these effects. We further applied our PPI model to identify the role of each SARS-CoV-2 protein in other tissues affected by coronavirus disease (COVID-19).

While validating the PPI network model, we found that the tight junction (TJ) proteins cadherin-5, ZO-1, and β-catenin are affected by nsp2, nsp5_c145a, and nsp7 consistent with the model prediction. Overall, this work identifies the SARS-CoV-2 proteins that might be most detrimental in terms of endothelial dysfunction, thereby shedding light on vascular aspects of COVID-19.

Source: Rauti R, Shahoha M, Leichtmann-Bardoogo Y, Nasser R, Paz E, Tamir R, Miller V, Babich T, Shaked K, Ehrlich A, Ioannidis K, Nahmias Y, Sharan R, Ashery U, Maoz BM. Effect of SARS-CoV-2 proteins on vascular permeability. Elife. 2021 Oct 25;10:e69314. doi: 10.7554/eLife.69314. PMID: 34694226; PMCID: PMC8545399. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545399/ (Full text)

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)