Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments.
TL;DR: In this paper, a review of the literature on long COVID-19 syndrome is presented, which is driven by long-term tissue damage (e.g. lung, brain, and heart) and pathological inflammation (i.e. from viral persistence, immune dysregulation, and autoimmunity).
Abstract: Long COVID or post-COVID-19 syndrome first gained widespread recognition among social support groups and later in scientific and medical communities. This illness is poorly understood as it affects COVID-19 survivors at all levels of disease severity, even younger adults, children, and those not hospitalized. While the precise definition of long COVID may be lacking, the most common symptoms reported in many studies are fatigue and dyspnoea that last for months after acute COVID-19. Other persistent symptoms may include cognitive and mental impairments, chest and joint pains, palpitations, myalgia, smell and taste dysfunctions, cough, headache, and gastrointestinal and cardiac issues. Presently, there is limited literature discussing the possible pathophysiology, risk factors, and treatments in long COVID, which the current review aims to address. In brief, long COVID may be driven by long-term tissue damage (e.g. lung, brain, and heart) and pathological inflammation (e.g. from viral persistence, immune dysregulation, and autoimmunity). The associated risk factors may include female sex, more than five early symptoms, early dyspnoea, prior psychiatric disorders, and specific biomarkers (e.g. D-dimer, CRP, and lymphocyte count), although more research is required to substantiate such risk factors. While preliminary evidence suggests that personalized rehabilitation training may help certain long COVID cases, therapeutic drugs repurposed from other similar conditions, such as myalgic encephalomyelitis or chronic fatigue syndrome, postural orthostatic tachycardia syndrome, and mast cell activation syndrome, also hold potential. In sum, this review hopes to provide the current understanding of what is known about long COVID.
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TL;DR: In this paper , a meta-analysis of proportions was conducted to pool Freeman-Tukey double arcsine transformed proportions using the random-effects restricted maximum-likelihood model to quantify the proportion of individuals experiencing fatigue and cognitive impairment 12 or more weeks following COVID-19 diagnosis.
Abstract: COVID-19 is associated with clinically significant symptoms despite resolution of the acute infection (i.e., post-COVID-19 syndrome). Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome.To quantify the proportion of individuals experiencing fatigue and cognitive impairment 12 or more weeks following COVID-19 diagnosis, and to characterize the inflammatory correlates and functional consequences of post-COVID-19 syndrome.Systematic searches were conducted without language restrictions from database inception to June 8, 2021 on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, and select reference lists.Primary research articles which evaluated individuals at least 12 weeks after confirmed COVID-19 diagnosis and specifically reported on fatigue, cognitive impairment, inflammatory parameters, and/or functional outcomes were selected.Two reviewers independently extracted published summary data and assessed methodological quality and risk of bias. A meta-analysis of proportions was conducted to pool Freeman-Tukey double arcsine transformed proportions using the random-effects restricted maximum-likelihood model.The co-primary outcomes were the proportions of individuals reporting fatigue and cognitive impairment, respectively, 12 or more weeks following COVID-19 infection. The secondary outcomes were inflammatory correlates and functional consequences associated with post-COVID-19 syndrome.The literature search yielded 10,979 studies, and 81 studies were selected for inclusion. The fatigue meta-analysis comprised 68 studies, the cognitive impairment meta-analysis comprised 43 studies, and 48 studies were included in the narrative synthesis. Meta-analysis revealed that the proportion of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis was 0.32 (95% CI, 0.27, 0.37; p < 0.001; n = 25,268; I2 = 99.1%). The proportion of individuals exhibiting cognitive impairment was 0.22 (95% CI, 0.17, 0.28; p < 0.001; n = 13,232; I2 = 98.0). Moreover, narrative synthesis revealed elevations in proinflammatory markers and considerable functional impairment in a subset of individuals.A significant proportion of individuals experience persistent fatigue and/or cognitive impairment following resolution of acute COVID-19. The frequency and debilitating nature of the foregoing symptoms provides the impetus to characterize the underlying neurobiological substrates and how to best treat these phenomena.PROSPERO (CRD42021256965).
369 citations
TL;DR: The COVID-19 Commission report as mentioned in this paper provides a conceptual framework for understanding pandemics and proposes guideposts for strengthening the multilateral system to address global emergencies and to achieve sustainable development.
156 citations
TL;DR: In this article , the authors used data from rounds 3-5 of the REACT-2 study (n = 508,707; September 2020- February 2021) to estimate the prevalence and identify predictors of persistent symptoms lasting 12 weeks or more; and unsupervised learning to cluster individuals by reported symptoms.
Abstract: Abstract Long COVID remains a broadly defined syndrome, with estimates of prevalence and duration varying widely. We use data from rounds 3–5 of the REACT-2 study ( n = 508,707; September 2020 – February 2021), a representative community survey of adults in England, and replication data from round 6 ( n = 97,717; May 2021) to estimate the prevalence and identify predictors of persistent symptoms lasting 12 weeks or more; and unsupervised learning to cluster individuals by reported symptoms. At 12 weeks in rounds 3–5, 37.7% experienced at least one symptom, falling to 21.6% in round 6. Female sex, increasing age, obesity, smoking, vaping, hospitalisation with COVID-19, deprivation, and being a healthcare worker are associated with higher probability of persistent symptoms in rounds 3–5, and Asian ethnicity with lower probability. Clustering analysis identifies a subset of participants with predominantly respiratory symptoms. Managing the long-term sequelae of COVID-19 will remain a major challenge for affected individuals and their families and for health services.
156 citations
TL;DR: A comprehensive review of the putative pathophysiology underlying the persisting symptoms of long COVID found that organ damage from the acute infection phase likely accounts for symptoms, and specific long-lasting inflammatory mechanisms have been proposed, as well.
Abstract: Abstract Background After almost 2 years of fighting against SARS-CoV-2 pandemic, the number of patients enduring persistent symptoms long after acute infection is a matter of concern. This set of symptoms was referred to as “long COVID”, and it was defined more recently as “Post COVID-19 condition” by the World health Organization (WHO). Although studies have revealed that long COVID can manifest whatever the severity of inaugural illness, the underlying pathophysiology is still enigmatic. Aim To conduct a comprehensive review to address the putative pathophysiology underlying the persisting symptoms of long COVID. Method We searched 11 bibliographic databases (Cochrane Library, JBI EBP Database, Medline, Embase, PsycInfo, CINHAL, Ovid Nursing Database, Journals@Ovid, SciLit, EuropePMC, and CoronaCentral). We selected studies that put forward hypotheses on the pathophysiology, as well as those that encompassed long COVID patients in their research investigation. Results A total of 98 articles were included in the systematic review, 54 of which exclusively addressed hypotheses on pathophysiology, while 44 involved COVID patients. Studies that included patients displayed heterogeneity with respect to the severity of initial illness, timing of analysis, or presence of a control group. Although long COVID likely results from long-term organ damage due to acute-phase infection, specific mechanisms following the initial illness could contribute to the later symptoms possibly affecting many organs. As such, autonomic nervous system damage could account for many symptoms without clear evidence of organ damage. Immune dysregulation, auto-immunity, endothelial dysfunction, occult viral persistence, as well as coagulation activation are the main underlying pathophysiological mechanisms so far. Conclusion Evidence on why persistent symptoms occur is still limited, and available studies are heterogeneous. Apart from long-term organ damage, many hints suggest that specific mechanisms following acute illness could be involved in long COVID symptoms. KEY MESSAGES Long-COVID is a multisystem disease that develops regardless of the initial disease severity. Its clinical spectrum comprises a wide range of symptoms. The mechanisms underlying its pathophysiology are still unclear. Although organ damage from the acute infection phase likely accounts for symptoms, specific long-lasting inflammatory mechanisms have been proposed, as well. Existing studies involving Long-COVID patients are highly heterogeneous, as they include patients with various COVID-19 severity levels and different time frame analysis, as well.
147 citations
TL;DR: In this article , the authors analyse the nature, prevalence, and severity of long-term symptoms related to COVID-19, while correcting for symptoms present before SARS-CoV-2 infection and controlling for the symptom dynamics in the population without infection.
139 citations
References
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TL;DR: During the epidemic period of COVID-19, clinicians should suspect severe acute respiratory syndrome coronavirus 2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and lose the chance to treat and prevent further transmission.
Abstract: Importance The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, is serious and has the potential to become an epidemic worldwide. Several studies have described typical clinical manifestations including fever, cough, diarrhea, and fatigue. However, to our knowledge, it has not been reported that patients with COVID-19 had any neurologic manifestations. Objective To study the neurologic manifestations of patients with COVID-19. Design, Setting, and Participants This is a retrospective, observational case series. Data were collected from January 16, 2020, to February 19, 2020, at 3 designated special care centers for COVID-19 (Main District, West Branch, and Tumor Center) of the Union Hospital of Huazhong University of Science and Technology in Wuhan, China. The study included 214 consecutive hospitalized patients with laboratory-confirmed diagnosis of severe acute respiratory syndrome coronavirus 2 infection. Main Outcomes and Measures Clinical data were extracted from electronic medical records, and data of all neurologic symptoms were checked by 2 trained neurologists. Neurologic manifestations fell into 3 categories: central nervous system manifestations (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, and seizure), peripheral nervous system manifestations (taste impairment, smell impairment, vision impairment, and nerve pain), and skeletal muscular injury manifestations. Results Of 214 patients (mean [SD] age, 52.7 [15.5] years; 87 men [40.7%]) with COVID-19, 126 patients (58.9%) had nonsevere infection and 88 patients (41.1%) had severe infection according to their respiratory status. Overall, 78 patients (36.4%) had neurologic manifestations. Compared with patients with nonsevere infection, patients with severe infection were older, had more underlying disorders, especially hypertension, and showed fewer typical symptoms of COVID-19, such as fever and cough. Patients with more severe infection had neurologic manifestations, such as acute cerebrovascular diseases (5 [5.7%] vs 1 [0.8%]), impaired consciousness (13 [14.8%] vs 3 [2.4%]), and skeletal muscle injury (17 [19.3%] vs 6 [4.8%]). Conclusions and Relevance Patients with COVID-19 commonly have neurologic manifestations. During the epidemic period of COVID-19, when seeing patients with neurologic manifestations, clinicians should suspect severe acute respiratory syndrome coronavirus 2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and lose the chance to treat and prevent further transmission.
5,153 citations
TL;DR: A conceptual framework and a set of research guidelines for use in studies of the chronic fatigue syndrome are developed that cover the clinical and laboratory evaluation of persons with unexplained fatigue; the identification of underlying conditions that may explain the presence of chronic fatigue; revised criteria for defining cases of the Chronic fatigue syndrome; and a strategy for dividing the chronic Fatigue syndrome and other unexplained cases of Chronic fatigue into subgroups.
Abstract: The complexities of the chronic fatigue syndrome and the methodologic problems associated with its study indicate the need for a comprehensive, systematic, and integrated approach to the evaluation, classification, and study of persons with this condition and other fatiguing illnesses. We propose a conceptual framework and a set of guidelines that provide such an approach. Our guidelines include recommendations for the clinical evaluation of fatigued persons, a revised case definition of the chronic fatigue syndrome, and a strategy for subgrouping fatigued persons in formal investigations.
4,621 citations
TL;DR: In this small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection.
Abstract: Background Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the dise...
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TL;DR: This case series describes COVID-19 symptoms persisting a mean of 60 days after onset among Italian patients previously discharged from CO VID-19 hospitalization.
Abstract: This case series describes COVID-19 symptoms persisting a mean of 60 days after onset among Italian patients previously discharged from COVID-19 hospitalization.
2,942 citations