long covid complications – Page 5 – American ME and CFS Society

Long-term implications of COVID-19 on bone health: pathophysiology and therapeutics

Abstract:

Background: SARS-CoV-2 is a highly infectious respiratory virus associated with coronavirus disease (COVID-19). Discoveries in the field revealed that inflammatory conditions exert a negative impact on bone metabolism; however, only limited studies reported the consequences of SARS-CoV-2 infection on skeletal homeostasis. Inflammatory immune cells (T helper—Th17 cells and macrophages) and their signature cytokines such as interleukin (IL)-6, IL-17, and tumor necrosis factor-alpha (TNF-α) are the major contributors to the cytokine storm observed in COVID-19 disease. Our group along with others has proven that an enhanced population of both inflammatory innate (Dendritic cells—DCs, macrophages, etc.) and adaptive (Th1, Th17, etc.) immune cells, along with their signature cytokines (IL-17, TNF-α, IFN-γ, IL-6, etc.), are associated with various inflammatory bone loss conditions. Moreover, several pieces of evidence suggest that SARS-CoV-2 infects various organs of the body via angiotensin-converting enzyme 2 (ACE2) receptors including bone cells (osteoblasts—OBs and osteoclasts—OCs). This evidence thus clearly highlights both the direct and indirect impact of SARS-CoV-2 on the physiological bone remodeling process. Moreover, data from the previous SARS-CoV outbreak in 2002–2004 revealed the long-term negative impact (decreased bone mineral density—BMDs) of these infections on bone health.

Methodology: We used the keywords “immunopathogenesis of SARS-CoV-2,” “SARS-CoV-2 and bone cells,” “factors influencing bone health and COVID-19,” “GUT microbiota,” and “COVID-19 and Bone health” to integrate the topics for making this review article by searching the following electronic databases: PubMed, Google Scholar, and Scopus.

Conclusion: Current evidence and reports indicate the direct relation between SARS-CoV-2 infection and bone health and thus warrant future research in this field. It would be imperative to assess the post-COVID-19 fracture risk of SARS-CoV-2-infected individuals by simultaneously monitoring them for bone metabolism/biochemical markers. Importantly, several emerging research suggest that dysbiosis of the gut microbiota—GM (established role in inflammatory bone loss conditions) is further involved in the severity of COVID-19 disease. In the present review, we thus also highlight the importance of dietary interventions including probiotics (modulating dysbiotic GM) as an adjunct therapeutic alternative in the treatment and management of long-term consequences of COVID-19 on bone health.

Source: Sapra L, Saini C, Garg B, Gupta R, Verma B, Mishra PK, Srivastava RK. Long-term implications of COVID-19 on bone health: pathophysiology and therapeutics. Inflamm Res. 2022 Sep;71(9):1025-1040. doi: 10.1007/s00011-022-01616-9. Epub 2022 Jul 28. PMID: 35900380; PMCID: PMC9330992. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330992/ (Full text)

Risks of digestive diseases in long COVID: Evidence from a large-scale cohort study

Abstract:

Objectives This study aims to evaluate the effect of coronavirus disease 2019 (COVID-19) on the long-term risk of digestive diseases in the general population.

Design Large-scale population-based cohort study based on a prospective cohort.

Setting UK Biobank cohort linked to multiple nationwide electronic health records databases.

Participants The cohort consisted of 112,311 individuals who survived the initial 30 days following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as well as two control groups: a contemporary group (n = 359,671) without any history of COVID-19, and a historical control group (n = 370,979) that predated the COVID-19 outbreak.

Main outcome measures Main outcomes were predefined digestive diseases. Hazard ratios and corresponding 95% confidence intervals (CI) were computed utilizing the Cox regression models after inverse probability weighting.

Results Compared with the contemporary control group, patients with previous COVID-19 infection had higher risks of digestive diseases, including functional gastrointestinal disorders (hazard ratios [HR] 1.95 (95% CI 1.62 to 2.35)); peptic ulcer disease (HR 1.27 (1.04 to 1.56)); gastroesophageal reflux disease (GERD) (HR 1.46 (1.34 to 1.58)); inflammatory bowel diseases (HR 1.40 (1.02 to 1.90)); gallbladder disease (HR 1.28 (1.13 to 1.46)); severe liver disease (HR 1.46 (1.12 to 1.90)); non-alcoholic liver disease (HR 1.33 (1.15 to 1.55)); and pancreatic disease (HR 1.43 (1.17 to 1.74)). The risks of GERD were stepwise increased with severity of the acute phase of COVID-19 infection. The results were consistent when using the historical cohort as the control group.

Conclusions Our study provides important insights into the association between COVID-19 and the long-term risk of digestive system disorders. COVID-19 patients are at a higher risk of developing gastrointestinal disorders, with stepwise increased risk with the severity and persisting even after one year follow-up.

Source: Yuying Ma, Lijun Zhang, Rui Wei, Weiyu Dai, Ruijie Zeng, Dongling Luo, Rui Jiang, Huihuan Wu, Zewei Zhuo, Qi Yang, Jingwei Li, Felix W Leung, Chongyang Duan, Weihong Sha, Hao Chen. Risks of digestive diseases in long COVID: Evidence from a large-scale cohort study. medRxiv 2023.04.25.23289080; doi: https://doi.org/10.1101/2023.04.25.23289080 https://www.medrxiv.org/content/10.1101/2023.04.25.23289080v1.full-text (Full text)

Long-Term Adverse Effects of Mild COVID-19 Disease on Arterial Stiffness, and Systemic and Central Hemodynamics: A Pre-Post Study

Abstract:

COVID-19-associated vascular disease complications are primarily associated with endothelial dysfunction; however, the consequences of disease on vascular structure and function, particularly in the long term (>7 weeks post-infection), remain unexplored. Individual pre- and post-infection changes in arterial stiffness as well as central and systemic hemodynamic parameters were measured in patients diagnosed with mild COVID-19.

As part of in-laboratory observational studies, baseline measurements were taken up to two years before, whereas the post-infection measurements were made 2–3 months after the onset of COVID-19. We used the same measurement protocol throughout the study as well as linear and mixed-effects regression models to analyze the data. Patients (N = 32) were predominantly healthy and young (mean age ± SD: 36.6 ± 12.6). We found that various parameters of arterial stiffness and central hemodynamics—cfPWV, AIx@HR75, and cDBP as well as DBP and MAP—responded to a mild COVID-19 disease.

The magnitude of these responses was dependent on the time since the onset of COVID-19 as well as age (p_{regression_models} ≤ 0.013). In fact, mixed-effects models predicted a clinically significant progression of vascular impairment within the period of 2–3 months following infection (change in cfPWV by +1.4 m/s, +15% in AIx@HR75, approximately +8 mmHg in DBP, cDBP, and MAP).

The results point toward the existence of a widespread and long-lasting pathological process in the vasculature following mild COVID-19 disease, with heterogeneous individual responses, some of which may be triggered by an autoimmune response to COVID-19.

Source: Podrug M, Koren P, Dražić Maras E, Podrug J, Čulić V, Perissiou M, Bruno RM, Mudnić I, Boban M, Jerončić A. Long-Term Adverse Effects of Mild COVID-19 Disease on Arterial Stiffness, and Systemic and Central Hemodynamics: A Pre-Post Study. Journal of Clinical Medicine. 2023; 12(6):2123. https://doi.org/10.3390/jcm12062123 https://www.mdpi.com/2077-0383/12/6/2123 (Full text)

Long- COVID and general health status in hospitalized COVID-19 survivors

Abstract:

Despite advances in clinical research, the long-term effects of COVID-19 on patients are not clear. Many studies revealed persistent long-term signs and symptoms. In a survey study, 259 hospitalized confirmed COVID-19 patients between 18 and 59 years were interviewed. Demographic characteristics and complaints were studied through telephone interviews. Any patient-reported symptoms that continued or developed from 4 weeks up to 12 weeks after the onset of the disease were recorded only if they did not exist prior to infection.

The 12-Item General Health Questionnaire was used for screening and assessing mental symptoms and psychosocial well-being. The mean age of participants was 43.8 ± 9.9 years. About 37% had at least one underlying disease. 92.5% showed ongoing symptoms that the most prevalent complications were hair loss (61.4%), fatigue (54.1%), shortness of breath (40.2%), altered smell (34.4%), and aggression (34.4%), respectively. In terms of factors affecting patients’ complaints, there were significant differences between age, sex, and underlying disease with long-remaining complications. This study shows a high rate of long COVID-19 conditions that should be considered by physicians, policymakers, and managers.

Source: Mohtasham-Amiri, Z., Keihanian, F., Rad, E.H. et al. Long- COVID and general health status in hospitalized COVID-19 survivors. Sci Rep 13, 8116 (2023). https://doi.org/10.1038/s41598-023-35413-z (Full study)

Thromboembolism in the Complications of Long COVID-19

Abstract:

SARS-CoV-2 is a +ssRNA helical coronavirus responsible for the global pandemic caused by coronavirus disease 19 (COVID-19). Classical clinical symptoms from primary COVID-19 when symptomatic include cough, fever, pneumonia or even ARDS; however, they are limited primarily to the respiratory system. Long-COVID-19 sequalae is responsible for many pathologies in almost every organ system and may be present in up to 30% of patients who have developed COVID-19.

Our review focuses on how long-COVID-19 (3 -24 weeks after primary symptoms) may lead to an increased risk for stroke and thromboembolism. Patients who were found to be primarily at risk for thrombotic events included critically ill and immunocompromised patients. Additional risk factors for thromboembolism and stroke included diabetes, hypertension, respiratory and cardiovascular disease, and obesity.

The etiology of how long-COVID-19 leads to a hypercoagulable state are yet to be definitively elucidated. However, anti-phospholipid antibodies and elevated D-dimer are present in many patients who develop thromboembolism. In addition, chronic upregulation and exhaustion of the immune system may lead to a pro-inflammatory and hypercoagulable state, increasing the likelihood for induction of thromboembolism or stroke. ‘

This article provides an up-to-date review on the proposed etiologies for thromboembolism and stroke in patients with long-COVID-19 and to assist health care providers in examining patients who may be at a higher risk for developing these pathologies.

Source: Leilani A Lopes, Devendra K Agrawal. Thromboembolism in the Complications of Long COVID-19. Cardiology and Cardiovascular
Medicine. 7 (2023): 123-128. https://fortunepublish.com/articles/10.26502.fccm.92920317.pdf (Full text)

Cardiovascular Manifestations of the Long COVID Syndrome.

Abstract:

While most coronavirus 2019 (COVID-19) survivors have had complete resolution of symptoms, a significant proportion have suffered from incomplete recovery. Cardiopulmonary symptoms, such as dyspnea, chest pain, and palpitations are responsible for a substantial symptom burden in COVID-19 survivors.

Studies have revealed persistent myocardial injury with late gadolinium enhancement and myocardial scar on cardiac magnetic resonance in a significant proportion of patients. Evidence of myocardial edema, active inflammation, left ventricular dysfunction, and right ventricular dysfunction, is limited to a minority of patients.

Large observational studies of COVID-19 survivors have indicated an increased risk of cardiovascular disease compared to the general population, including the risk of coronary artery disease, cardiomyopathy, and arrhythmias. Management of long COVID is focused on supportive therapy to reduce systemic inflammation. Patients with high cardiovascular risk, namely, those who had cardiovascular complications during acute illness, patients who have new onset cardiopulmonary symptoms in the postinfectious period, and competitive athletes, should be evaluated by a cardiovascular specialist.

Management of cardiovascular sequelae is currently based on general expert guideline recommendations given the lack of evidence specific to long COVID syndrome. In this review, we outline the cardiovascular manifestations of long COVID, the current evidence supporting cardiac abnormalities in the postinfectious period, and the recommended management of these patients.

Source: Lorente-Ros M, Das S, Elias J, Frishman WH, Aronow WS. Cardiovascular Manifestations of the Long COVID Syndrome. Cardiol Rev. 2023 Apr 10. doi: 10.1097/CRD.0000000000000552. Epub ahead of print. PMID: 37071080.

Risk of autoimmune diseases in patients with COVID-19: A retrospective cohort study

Abstract:

Background: There are a growing number of case reports of various autoimmune diseases occurring after COVID-19, yet there is no large-scale population-based evidence to support this potential association. This study provides a closer insight into the association between COVID-19 and autoimmune diseases and reveals discrepancies across sex, age, and race of participants.

Methods: This is a retrospective cohort study based on the TriNetX U.S. Collaborative Network. In the test-negative design, cases were participants with positive polymerase chain reaction (PCR) test results for SARS-CoV-2, while controls were participants who tested negative and were not diagnosed with COVID-19 throughout the follow-up period. Patients with COVID-19 and controls were propensity score-matched (1: 1) for age, sex, race, adverse socioeconomic status, lifestyle-related variables, and comorbidities. The primary endpoint is the incidence of newly recorded autoimmune diseases. Adjusted hazard ratios (aHRs) and 95% confident intervals (CIs) of autoimmune diseases were calculated between propensity score-matched groups with the use of Cox proportional-hazards regression models.

Findings: Between January 1st, 2020 and December 31st, 2021, 3,814,479 participants were included in the study (888,463 cases and 2,926,016 controls). After matching, the COVID-19 cohort exhibited significantly higher risks of rheumatoid arthritis (aHR:2.98, 95% CI:2.78-3.20), ankylosing spondylitis (aHR:3.21, 95% CI:2.50-4.13), systemic lupus erythematosus (aHR:2.99, 95% CI:2.68-3.34), dermatopolymyositis (aHR:1.96, 95% CI:1.47-2.61), systemic sclerosis (aHR:2.58, 95% CI:2.02-3.28), Sjögren’s syndrome (aHR:2.62, 95% CI:2.29-3.00), mixed connective tissue disease (aHR:3.14, 95% CI:2.26-4.36), Behçet’s disease (aHR:2.32, 95% CI:1.38-3.89), polymyalgia rheumatica (aHR:2.90, 95% CI:2.36-3.57), vasculitis (aHR:1.96, 95% CI:1.74-2.20), psoriasis (aHR:2.91, 95% CI:2.67-3.17), inflammatory bowel disease (aHR:1.78, 95%CI:1.72-1.84), celiac disease (aHR:2.68, 95% CI:2.51-2.85), type 1 diabetes mellitus (aHR:2.68, 95%CI:2.51-2.85) and mortality (aHR:1.20, 95% CI:1.16-1.24).

Interpretation: COVID-19 is associated with a different degree of risk for various autoimmune diseases. Given the large sample size and relatively modest effects these findings should be replicated in an independent dataset. Further research is needed to better understand the underlying mechanisms.

Source: Chang R, Yen-Ting Chen T, Wang SI, Hung YM, Chen HY, Wei CJ. Risk of autoimmune diseases in patients with COVID-19: A retrospective cohort study. EClinicalMedicine. 2023 Feb;56:101783. doi: 10.1016/j.eclinm.2022.101783. Epub 2023 Jan 10. PMID: 36643619; PMCID: PMC9830133. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830133/ (Full text)

High risk of autoimmune diseases after COVID-19

The full picture of post-COVID-19 autoimmune diseases and their prevalence is lacking despite numerous case reports and small series. Two studies that use large cohorts now highlight that SARS-CoV-2 infection is linked to a substantially increased risk of developing a diverse spectrum of new-onset autoimmune diseases.

Refers to: Chang, R. et al. Risk of autoimmune diseases in patients with COVID-19: a retrospective cohort study. eClinicalMedicine 56, 101783 (2023).

The triggering of autoimmune conditions by viral infections has been of interest to the scientific community for decades. The COVID-19 pandemic provides a unique opportunity to understand this link and the underlying pathogenesis. SARS-CoV-2 infection leads to a spectrum of symptoms in the host, with respiratory symptoms dominating the clinical picture. SARS-CoV-2 was originally thought to mostly cause respiratory illness, with comparisons being made to common influenza.

However, in a steep learning curve, the spectrum of SARS-CoV-2 infection was observed to range from self-limiting mild infection to critical respiratory distress, with symptoms including fever, cough, myalgia, fatigue and dyspnea¹. Severe COVID-19 cases have demonstrated a substantial inflammatory response with pro-inflammatory cytokines and chemokines that stimulate pulmonary inflammation¹.

As the burden of COVID-19 cases increases worldwide, so does our understanding of the condition. Owing to worldwide vaccination efforts, mortality due to COVID-19 has been decreasing, but we continue to witness considerable morbidity and increased rates of post-COVID-19 conditions and in particular, new-onset autoimmune and inflammatory diseases in individuals who have had COVID-19. The range and incidence of these post-COVID-19 disorders have now been highlighted in two large retrospective cohort studies^2,3.

Source: Sharma, C., Bayry, J. High risk of autoimmune diseases after COVID-19. Nat Rev Rheumatol (2023). https://doi.org/10.1038/s41584-023-00964-y (Full text)

Changes in the State of Vital Systems with Long COVID-19

Abstract:

Long COVID-19 is a chronic disease that continues to be studied. Data on epidemiology and the main symptoms typical for long COVID-19 are presented. Issues related to the pathogenesis of the disease are discussed. At the same time, special attention is paid to the inflammation process (including of the vascular wall endothelium), the state of the immune system (cytokine storm), the hemostasis system (the mechanism for the development of microangiopathy and thrombosis), and oxidative stress. During the analysis, a special place is given to central nervous system disorders (including organic brain damage) and disorders of cognitive functions. In addition, currently known complications from the cardiovascular system and respiratory organs are described. The treatment and rehabilitation of patients with long COVID-19 is not only a medical, but also a significant social problem.

Source: Kuznik, B.I., Shapovalov, K.G. & Chalisova, N.I. Changes in the State of Vital Systems with Long COVID-19. Biol Bull Rev 13, 112–123 (2023). https://doi.org/10.1134/S2079086423020044 (Full text)

Thrombophilia and Immune-Related Genetic Markers in Long COVID

Abstract:

Aiming to evaluate the role of ten functional polymorphisms in long COVID, involved in major inflammatory, immune response and thrombophilia pathways, a cross-sectional sample composed of 199 long COVID (LC) patients and a cohort composed of 79 COVID-19 patients whose follow-up by over six months did not reveal any evidence of long COVID (NLC) were investigated to detect genetic susceptibility to long COVID.

Ten functional polymorphisms located in thrombophilia-related and immune response genes were genotyped by real time PCR. In terms of clinical outcomes, LC patients presented higher prevalence of heart disease as preexistent comorbidity. In general, the proportions of symptoms in acute phase of the disease were higher among LC patients.

The genotype AA of the interferon gamma (IFNG) gene was observed in higher frequency among LC patients (60%; p = 0.033). Moreover, the genotype CC of the methylenetetrahydrofolate reductase (MTHFR) gene was also more frequent among LC patients (49%; p = 0.045). Additionally, the frequencies of LC symptoms were higher among carriers of IFNG genotypes AA than among non-AA genotypes (Z = 5.08; p < 0.0001).

Two polymorphisms were associated with LC in both inflammatory and thrombophilia pathways, thus reinforcing their role in LC. The higher frequencies of acute phase symptoms among LC and higher frequency of underlying comorbidities might suggest that acute disease severity and the triggering of preexisting condition may play a role in LC development.

Source: da Silva R, de Sarges KML, Cantanhede MHD, da Costa FP, dos Santos EF, Rodrigues FBB, de Nazaré do Socorro de Almeida Viana M, de Meira Leite M, da Silva ALS, de Brito MTM, da Silva Torres MK, Queiroz MAF, Vallinoto IMVC, Henriques DF, dos Santos CP, Viana GMR, Quaresma JAS, Falcão LFM, Vallinoto ACR, dos Santos EJM. Thrombophilia and Immune-Related Genetic Markers in Long COVID. Viruses. 2023; 15(4):885. https://doi.org/10.3390/v15040885 https://www.mdpi.com/1999-4915/15/4/885 (Full text)