Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease (COVID-19) triggers the development of numerous pathologies and infection-linked complications and exacerbates existing pathologies in nearly all body systems. Aside from the primarily targeted respiratory organs, adverse SARS-CoV-2 effects were observed in nervous, cardiovascular, gastrointestinal/metabolic, immune, and other systems in COVID-19 survivors. Long-term effects of this viral infection have been recently observed and represent distressing sequelae recognised by the World Health Organisation (WHO) as a distinct clinical entity defined as post-COVID-19 condition. Considering the pandemic is still ongoing, more time is required to confirm post COVID-19 condition diagnosis in the COVID-19 infected cohorts, although many reported post COVID-19 symptoms overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Aims of Review: In this study, COVID-19 clinical presentation and associated post-infection sequelae (post-COVID-19 condition) were reviewed and compared with ME/CFS symptomatology.

Key Scientific Concepts of Review: The onset, progression, and symptom profile of post COVID-19 condition patients have considerable overlap with ME/CFS. Considering the large scope and range of pro-inflammatory effects of this virus, it is reasonable to expect development of post COVID-19 clinical complications in a proportion of the affected population. There are reports of a later debilitating syndrome onset three months post COVID-19 infection (often described as long-COVID-19), marked by the presence of fatigue, headache, cognitive dysfunction, post-exertional malaise, orthostatic intolerance, and dyspnoea. Acute inflammation, oxidative stress, and increased levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), have been reported in SARS-CoV-2 infected patients. Longitudinal monitoring of post COVID-19 patients is warranted to understand the long-term effects of SARS-CoV-2 infection and the pathomechanism of post COVID-19 condition.

Source: Sukocheva OA, Maksoud R, Beeraka NM, Madhunapantula SV, Sinelnikov M, Nikolenko VN, …. and Marshall-Gradisnik S. Analysis of post COVID-19 condition and its overlap with myalgic encephalomyelitis/chronic fatigue syndrome.  Journal of Advanced Research, Available online 26 November 2021. https://www.sciencedirect.com/science/article/pii/S2090123221002320  (Full text)

Mechanisms of coronavirus infectious disease 2019-related neurologic diseases

Abstract:

Purpose of review: As of January 8, 2022, a global pandemic caused by infection with severe acute respiratory syndrome coronavirus (SARS-CoV)-2, a new RNA virus, has resulted in 304,896,785 cases in over 222 countries and regions, with over 5,500,683 deaths (www.worldometers.info/coronavirus/). Reports of neurological and psychiatric symptoms in the context of coronavirus infectious disease 2019 (COVID-19) range from headache, anosmia, and dysgeusia, to depression, fatigue, psychosis, seizures, delirium, suicide, meningitis, encephalitis, inflammatory demyelination, infarction, and acute hemorrhagic necrotizing encephalopathy. Moreover, 30-50% of COVID-19 survivors develop long-lasting neurologic symptoms, including a dysexecutive syndrome, with inattention and disorientation, and/or poor movement coordination. Detection of SARS-CoV-2 RNA within the central nervous system (CNS) of patients is rare, and mechanisms of neurological damage and ongoing neurologic diseases in COVID-19 patients are unknown. However, studies demonstrating viral glycoprotein effects on coagulation and cerebral vasculature, and hypoxia- and cytokine-mediated coagulopathy and CNS immunopathology suggest both virus-specific and neuroimmune responses may be involved. This review explores potential mechanistic insights that could contribute to COVID-19-related neurologic disease.

Recent findings: While the development of neurologic diseases during acute COVID-19 is rarely associated with evidence of viral neuroinvasion, new evidence suggests SARS-CoV-2 Spike (S) protein exhibits direct inflammatory and pro-coagulation effects. This, in conjunction with immune dysregulation resulting in cytokine release syndrome (CRS) may result in acute cerebrovascular or neuroinflammatory diseases. Additionally, CRS-mediated loss of blood-brain barrier integrity in specific brain regions may contribute to the expression of proinflammatory mediators by neural cells that may impact brain function long after resolution of acute infection. Importantly, host co-morbid diseases that affect vascular, pulmonary, or CNS function may contribute to the type of neurologic disease triggered by SARS-COV-2 infection.

Summary: Distinct effects of SARS-CoV-2 S protein and CNS compartment- and region-specific responses to CRS may underlie acute and chronic neuroinflammatory diseases associated with COVID-19.

Source: Klein RS. Mechanisms of coronavirus infectious disease 2019-related neurologic diseases. Curr Opin Neurol. 2022 Mar 11. doi: 10.1097/WCO.0000000000001049. Epub ahead of print. PMID: 35283461. https://pubmed.ncbi.nlm.nih.gov/35283461/

Neurocognitive and psychiatric post-coronavirus disease 2019 conditions: pathogenic insights of brain dysfunction following severe acute respiratory syndrome coronavirus 2 infection

Abstract:

Purpose of review: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), can trigger a myriad of neuropsychiatric manifestations. As a 2-year-old disease (at the writing of this manuscript), its long-term cognitive and neuropsychiatric implications, known as post-COVID-19 conditions, are incompletely recognized and mechanistically obscure.

Recent findings: Fatigue, anxiety, depression, posttraumatic stress disorder, and cognitive dysfunction are reported more frequently in COVID-19 survivors than in matching, non-COVID-19 population. Risk factors are unclear, including comorbidities, age at COVID-19 onset, or disease severity; women, however, have been reported to be at increased risk than men. Although the frequency of these symptoms decreases over time, at least one in five will have persistent cognitive and neuropsychiatric manifestations one year after recovering from COVID-19.

Summary: Neurocognitive and psychiatric post-COVID-19 long-term conditions are frequent and complex multifactorial sequelae. Several acute and chronic factors such as hypoxemia, cerebral thrombotic and inflammatory endothelial damage, and disruption of the blood-brain barrier (leading to parenchymal translocation of pro-inflammatory molecules, cytokines, and cytotoxic T lymphocytes) are involved, leading to microglial activation and astrogliosis. As an evolving topic, evidence derived from prospective studies will expand our understanding of post-COVID-19 these long-term outcomes.

Source: García-Grimshaw M, Sankowski R, Valdés-Ferrer SI. Neurocognitive and psychiatric post-coronavirus disease 2019 conditions: pathogenic insights of brain dysfunction following severe acute respiratory syndrome coronavirus 2 infection. Curr Opin Neurol. 2022 Mar 11. doi: 10.1097/WCO.0000000000001046. Epub ahead of print. PMID: 35283463. https://pubmed.ncbi.nlm.nih.gov/35283463/

On the single and multiple associations of COVID-19 post-acute sequelae: 6-month prospective cohort study

Abstract:

Medical research is progressing to clarify the full spectrum of sub-acute and long-term effects of the post-COVID-19 syndrome. However, most manuscripts published to date only analyze the effects of post-COVID-19 in patients discharged from hospital, which may induce significant bias. Here, we propose a pioneering study to analyze the single and multiple associations between post-COVID-19 characteristics with up to 6-months of follow-up in hospitalized and non-hospitalized COVID-19 patients. The cohort study was conducted from May to October 2020 at the University Hospital Virgen de la Nieves, the leading hospital assigned for patients with COVID-19 in Granada, Spain.

A total of 372 and 217 patients-with 217 and 207 included in the first and second follow-up visits-were referred 2 and 6 months after diagnosing COVID-19, respectively. We find out that post-COVID-19 clinical and mental health impairment symptoms are correlated with patient gender. Logistic adjustments showed strong statistically robust single and multiple associations of demographic, clinical, mental health, X-ray, laboratory indices, and pulmonary function variables. The functional lung tests are good predictors of chest CT imaging abnormalities in elderly patients. Bilateral lung involvement, subpleural reticulum, ground-glass opacity, peripheral lung lesions, and bronchiectasis were the most common findings of the high-resolution computed tomography images. Non-hospitalized patients suffer more severe thromboembolic events and fatigue than those hospitalized.

Source: Jiménez-Rodríguez BM, Gutiérrez-Fernández J, Ramos-Urbina EM, Romero-Ortiz AD, García-Flores PI, Santiago-Puertas MI, Martín-López MJ, López-Milena G, Fabregas R, Morales-García C. On the single and multiple associations of COVID-19 post-acute sequelae: 6-month prospective cohort study. Sci Rep. 2022 Mar 1;12(1):3402. doi: 10.1038/s41598-022-07433-8. PMID: 35233062; PMCID: PMC8888754. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888754/ (Full text)

Number of initial symptoms is more related to long COVID-19 than acute severity of infection: a prospective cohort of hospitalized patients

Abstract:

Objectives: Post–COVID-19 symptoms experienced by many survivors have a further devastating effect. This study aimed to analyze the risk factors associated with long COVID-19 in a prospective cohort of hospitalized patients including those requiring intensive care unit (ICU) transfer, taking into account objective measures of COVID-19 severity.

Methods: Hospitalized patients with confirmed COVID-19 were enrolled. A structured follow-up visit was performed 4 months after hospital admission. Multivariable adjusted regression models were used to analyse the association between parameters at the acute phase and persistent symptoms.

Results: A follow-up visit was performed in 316 patients including 115 (36.4%) discharged from the ICU. Mean age was 64.1 years, and 201 patients (58.3%) were men. Female sex (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.17-3.22; P =.01), hypertension (OR, 2.01; 95% CI, 1.22-3.31; P <.01), and the number of initial symptoms (NIS) (OR, 1.35; 95% CI, 1.17-1.54; P <.001) were significantly associated with long COVID-19. Number of persistent symptoms was significantly associated with NIS (adjusted incidence rate ratio [aIRR], 1.16; 95% CI, 1.11-1.22; P <.001), female sex (aIRR, 1.56; 95% CI 1.29-1.87; P <.001), hypertension (aIRR, 1.23; 95% CI, 1.02-1.50; P =.03), and length of stay in hospital (aIRR, 1.01; 95% CI, 1.005-1.017; P <.001).

Conclusion: Our study suggested that female sex, hypertension, and NIS had a significant impact on persistent symptoms in hospitalized patients in contrast to severity of acute COVID-19 infection.

Source: Adrien CSK, Alexandre C, Marie M, Cédric J, Schmit JL, Jean-Philippe L, Claire A. Number of initial symptoms is more related to long COVID-19 than acute severity of infection: a prospective cohort of hospitalized patients. Int J Infect Dis. 2022 Mar 4;118:220–3. doi: 10.1016/j.ijid.2022.03.006. Epub ahead of print. PMID: 35257903; PMCID: PMC8896858. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8896858/ (Full text)

The Role of Nutrients in Prevention, Treatment and Post-Coronavirus Disease-2019 (COVID-19)

Abstract:

SARS-CoV-2 virus, infecting human cells via its spike protein, causes Coronavirus disease 2019 (COVID-19). COVID-19 is characterized by shortness of breath, fever, and pneumonia and is sometimes fatal. Unfortunately, to date, there is still no definite therapy to treat COVID-19. Therefore, the World Health Organization (WHO) approved only supportive care. During the COVID-19 pandemic, the need to maintain a correct intake of nutrients to support very weakened patients in overcoming disease arose. The literature available on nutrient intake for COVID-19 is mainly focused on prevention. However, the safe intake of micro- and/or macro-nutrients can be useful either for preventing infection and supporting the immune response during COVID-19, as well as in the post-acute phase, i.e., “long COVID”, that is sometimes characterized by the onset of various long lasting and disabling symptoms. The aim of this review is to focus on the role of nutrient intake during all the different phases of the disease, including prevention, the acute phase, and finally long COVID.

Source: Motti ML, Tafuri D, Donini L, Masucci MT, De Falco V, Mazzeo F. The Role of Nutrients in Prevention, Treatment and Post-Coronavirus Disease-2019 (COVID-19). Nutrients. 2022 Feb 26;14(5):1000. doi: 10.3390/nu14051000. PMID: 35267974; PMCID: PMC8912782. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912782/ (Full text)

Serial Changes of Long COVID Symptoms and Clinical Utility of Serum Antibody Titers for Evaluation of Long COVID

Abstract:

Background: Various symptoms persist even after the acute symptoms in about one third of patients with COVID-19. In February 2021, we established an outpatient clinic in a university hospital for patients with long COVID and started medical treatment for sequelae that persisted one month or more after infection.

Methods: To determine the key factors that affect the onset and clinical course of sequelae, a retrospective analysis was performed at Okayama University Hospital (Japan) between February and July 2021. We focused on changes in the numbers of symptoms and the background of the patients during a three-month period from the first outpatient visit. We also examined the relationship with SARS-CoV-2 antibody titers.

Results: Information was obtained from medical records for 65 patients. The symptoms of sequelae were diverse, with more than 20 types. The most frequent symptoms were general malaise, dysosmia, dysgeusia, sleeplessness, and headache. These symptoms improved in about 60% of the patients after 3 months. Patients who required hospitalization and had a poor condition in the acute phase and patients who received oxygen/dexamethasone therapy had higher antibody titers at the time of consultation. Patients with antibody titers ≥200 U/mL showed significantly fewer improvements in long COVID symptoms in 1 month, but they showed improvements at 3 months after the first visit.

Conclusion: Long COVID symptoms were improved at 3 months after the initial visit in more than half of the patients. Serum antibody titers were higher in patients who experienced a severe acute phase, but the serum antibody titers did not seem to be directly related to the long-term persistence of long COVID symptoms.

Source: Sakurada Y, Sunada N, Honda H, Tokumasu K, Otsuka Y, Nakano Y, Hanayama Y, Furukawa M, Hagiya H, Otsuka F. Serial Changes of Long COVID Symptoms and Clinical Utility of Serum Antibody Titers for Evaluation of Long COVID. J Clin Med. 2022 Feb 27;11(5):1309. doi: 10.3390/jcm11051309. PMID: 35268400; PMCID: PMC8911256.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8911256/ (Full text)

The effectiveness of pulmonary rehabilitation for Post-COVID symptoms: A rapid review of the literature

Abstract:

Background: Multi-disciplinary rehabilitation is recommended for individuals with post-acute sequelae of COVID-19 infection (i.e., symptoms 3-4 weeks after acute infection). There are emerging reports of use of pulmonary rehabilitation (PR) in the post-acute stages of COVID-19, however the appropriateness of PR for managing post-COVID symptoms remains unclear. To offer practical guidance with regards to post-COVID PR, a greater understanding of the clinical effectiveness literature is required.

Methods: A rapid review of the published literature was completed. An electronic database search of the literature published between July 1, 2020 and June 1, 2021 was performed in MEDLINE, Pubmed, and EMBASE. Primary studies evaluating the clinical effectiveness of PR for individuals with post-COVID symptoms were included.

Results: Nine studies evaluating the effectiveness of PR were identified; most were small, experimental or quasi-experimental studies, including 1 RCT, and were primarily of low quality. After attending PR, all studies reported improvements in exercise capacity, pulmonary function, and/or quality of life for individuals with post-COVID symptoms who had been hospitalized for their acute COVID-19 infection. Few studies evaluated changes in post-COVID symptom severity or frequency and, of these, improvements in dyspnea, fatigue, anxiety and depression were observed following PR. Further, no studies evaluated non-hospitalized patients or long-term outcomes beyond 3 months after initiating PR.

Conclusions: With limited high-quality evidence, any recommendations or practical guidance for PR programmes for those with post-COVID symptoms should consider factors such as feasibility, current PR capacity, and resource constraints.

Source: Soril LJJ, Damant RW, Lam GY, Smith MP, Weatherald J, Bourbeau J, Hernandez P, Stickland MK. The effectiveness of pulmonary rehabilitation for Post-COVID symptoms: A rapid review of the literature. Respir Med. 2022 Mar 2;195:106782. doi: 10.1016/j.rmed.2022.106782. Epub ahead of print. PMID: 35272262; PMCID: PMC8887973. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887973/ (Full text)

Toward Unbiased Evaluation of Postacute Sequelae of SARS-CoV-2 Infection: Challenges and Solutions for the Long Haul Ahead

Abstract:

The authors argue that postacute SARS-CoV-2 syndrome presents unique challenges in determining risk factors, natural history, and proper management. They call for strategies and actions that are based on rigorous, high-quality evidence.

Source: Wisk LE, Nichol G, Elmore JG. Toward Unbiased Evaluation of Postacute Sequelae of SARS-CoV-2 Infection: Challenges and Solutions for the Long Haul Ahead. Ann Intern Med. 2022 Mar 8:M21-4664. doi: 10.7326/M21-4664. Epub ahead of print. PMID: 35254883; PMCID: PMC8906529. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8906529/ (Full text)

Long COVID and episodic disability: advancing the conceptualisation, measurement and knowledge of episodic disability among people living with Long COVID – protocol for a mixed-methods study

Abstract:

Introduction: As the prevalence of Long COVID increases, there is a critical need for a comprehensive assessment of disability. Our aims are to: (1) characterise disability experiences among people living with Long COVID in Canada, UK, USA and Ireland; and (2) develop a patient-reported outcome measure to assess the presence, severity and episodic nature of disability with Long COVID.

Methods and analysis: In phase 1, we will conduct semistructured interviews with adults living with Long COVID to explore experiences of disability (dimensions, uncertainty, trajectories, influencing contextual factors) and establish an episodic disability (ED) framework in the context of Long COVID (n~10 each country). Using the conceptual framework, we will establish the Long COVID Episodic Disability Questionnaire (EDQ). In phase 2, we will examine the validity (construct, structural) and reliability (internal consistency, test-retest) of the EDQ for use in Long COVID. We will electronically administer the EDQ and four health status criterion measures with adults living with Long COVID, and readminister the EDQ 1 week later (n~170 each country). We will use Rasch analysis to refine the EDQ, and confirm structural and cross-cultural validity. We will calculate Cronbach’s alphas (internal consistency reliability), and intraclass correlation coefficients (test-retest reliability), and examine correlations for hypotheses theorising relationships between EDQ and criterion measure scores (construct validity). Using phase 2 data, we will characterise the profile of disability using structural equation modelling techniques to examine relationships between dimensions of disability and the influence of intrinsic and extrinsic contextual factors. This research involves an academic-clinical-community partnership building on foundational work in ED measurement, Long COVID and rehabilitation.

Ethics and dissemination: This study was approved by the University of Toronto Research Ethics Board. Knowledge translation will occur with community collaborators in the form of presentations and publications in open access peer-reviewed journals and presentations.

Source: O’Brien KK, Brown DA, Bergin C, Erlandson KM, Vera JH, Avery L, Carusone SC, Cheung AM, Goulding S, Harding R, McCorkell L, O’Hara M, Robinson L, Thomson C, Wei H, St Clair-Sullivan N, Torres B, Bannan C, Roche N, Stokes R, Gayle P, Solomon P. Long COVID and episodic disability: advancing the conceptualisation, measurement and knowledge of episodic disability among people living with Long COVID – protocol for a mixed-methods study. BMJ Open. 2022 Mar 7;12(3):e060826. doi: 10.1136/bmjopen-2022-060826. PMID: 35256450; PMCID: PMC8905414.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8905414/ (Full text)