Long COVID from rheumatology perspective - a narrative review
TL;DR: In this article, a comprehensive literature review is presented to help rheumatologist to be aware of long COVID manifestations and differentiating features from rheumatic diseases to ensure a timely and correct diagnosis is reached.
Abstract: Long-term sequel of acute COVID-19, commonly referred to as long COVID, has affected millions of patients worldwide. Long COVID patients display persistent or relapsing and remitting symptoms that include fatigue, breathlessness, cough, myalgia, arthralgia, sleep disturbance, cognitive impairment and skin rashes. Due to the shared clinical features, laboratory and imaging findings, long COVID could mimic rheumatic disease posing a diagnostic challenge. Our comprehensive literature review will help rheumatologist to be aware of long COVID manifestations and differentiating features from rheumatic diseases to ensure a timely and correct diagnosis is reached.
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TL;DR: This minireview provides an update of the main findings of NETosis and NETs in immunothrombosis and other COVID-19-related disorders, such as aberrant immunity, neurological disorders, and post CO VID-19 syndromes including lung fibrosis, neurological disorder, tumor progression, and deteriorated chronic illness.
Abstract: Infection with SARS-CoV-2, the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic, causes respiratory problems and multifaceted organ dysfunction. A crucial mechanism of COVID-19 immunopathy is the recruitment and activation of neutrophils at the infection site, which also predicts disease severity and poor outcomes. The release of neutrophil extracellular traps (NETs), occurring during a regulated form of neutrophil cell death known as NETosis, is a key effector function that mediates harmful effects caused by neutrophils. Abundant NETosis and NET generation have been observed in the neutrophils of many COVID-19 patients, leading to unfavorable coagulopathy and immunothrombosis. Moreover, excessive NETosis and NET generation are now more widely recognized as mediators of additional pathophysiological abnormalities following SARS-CoV-2 infection. In this minireview, we introduce subtypes of NET-producing neutrophils (e.g., low-density granulocytes) and explain the biological importance of NETs and the protein cargos of NETs in COVID-19. In addition, we discuss the mechanisms by which SARS-CoV-2 causes NETosis by upregulating viral processes (e.g., viral entry and replication) as well as host pro-NET mechanisms (e.g., proinflammatory mediator release, platelet activation, and autoantibody production). Furthermore, we provide an update of the main findings of NETosis and NETs in immunothrombosis and other COVID-19-related disorders, such as aberrant immunity, neurological disorders, and post COVID-19 syndromes including lung fibrosis, neurological disorder, tumor progression, and deteriorated chronic illness. Finally, we address potential prospective COVID-19 treatment strategies that target dysregulated NETosis and NET formation via inhibition of NETosis and promotion of NET degradation, respectively.
59 citations
TL;DR: In this article , the authors describe clinical and laboratory features of post-COVID manifestations accompanied by the reactivation of herpes virus infections (CMV, EBV, HHV6).
Abstract: The global spread of SARS-CoV-2 points to unrivaled mutational variation of the virus, contributing to a variety of post-COVID sequelae in immunocompromised subjects and high mortality. Numerous studies have reported the reactivation of "sluggish" herpes virus infections in COVID-19, which exaggerate the course of the disease and complicate with lasting post-COVID manifestations CMV, EBV, HHV6). This study aimed to describe clinical and laboratory features of post-COVID manifestations accompanied by the reactivation of herpes virus infections (CMV, EBV, HHV6). 88 patients were recruited for this study, including subjects with reactivation of herpes viruses, 68 (72.3%) (main group) and 20 (27.7%) subjects without detectable DNA of herpesviruses (control group): 46 (52.3%) female and 42 (47.7%) male; median age was 41.4 ± 6.7 years. Patients with post-COVID manifestations presented with reactivation of EBV in 42.6%, HHV6 in 25.0%, and EBV plus HHV6 in 32.4%. Compared with controls, patients with herpes virus infections presented with more frequent slight fever temperature, headache, psycho-neurological disorders, pulmonary abnormalities and myalgia (p < 0.01), activation of liver enzymes, elevated CRP and D-dimer, and suppressed cellular immune response (p ≤ 0.05). Preliminary results indicate a likely involvement of reactivated herpes virus infections, primarily EBV infections in severe COVID-19 and the formation of the post-COVID syndrome. Patients with the post-COVID syndrome and reactivation of EBV and HHV6 infections are at high risk of developing various pathologies, including rheumatologic diseases.
32 citations
TL;DR: In this article , the authors argue that I-R injury also underpins elements of the pathology of a variety of chronic, inflammatory diseases, including rheumatoid arthritis, ME/CFS and, most proximally, Long COVID.
Abstract: Ischaemia–reperfusion (I–R) injury, initiated via bursts of reactive oxygen species produced during the reoxygenation phase following hypoxia, is well known in a variety of acute circumstances. We argue here that I–R injury also underpins elements of the pathology of a variety of chronic, inflammatory diseases, including rheumatoid arthritis, ME/CFS and, our chief focus and most proximally, Long COVID. Ischaemia may be initiated via fibrin amyloid microclot blockage of capillaries, for instance as exercise is started; reperfusion is a necessary corollary when it finishes. We rehearse the mechanistic evidence for these occurrences here, in terms of their manifestation as oxidative stress, hyperinflammation, mast cell activation, the production of marker metabolites and related activities. Such microclot-based phenomena can explain both the breathlessness/fatigue and the post-exertional malaise that may be observed in these conditions, as well as many other observables. The recognition of these processes implies, mechanistically, that therapeutic benefit is potentially to be had from antioxidants, from anti-inflammatories, from iron chelators, and via suitable, safe fibrinolytics, and/or anti-clotting agents. We review the considerable existing evidence that is consistent with this, and with the biochemical mechanisms involved.
16 citations
TL;DR: In this article , a review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein-Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity.
Abstract: A novel syndrome called long-haul COVID or long COVID is increasingly recognized in a significant percentage of individuals within a few months after infection with SARS-CoV-2. This disorder is characterized by a wide range of persisting, returning or even new but related symptoms that involve different tissues and organs, including respiratory, cardiac, vascular, gastrointestinal, musculo-skeletal, neurological, endocrine and systemic. Some overlapping symptomatologies exist between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Very much like with long ME/CFS, infections with herpes family viruses, immune dysregulation, and the persistence of inflammation have been reported as the most common pattern for the development of long COVID. This review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein–Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity. Based on these factors, we propose diagnostic strategies such as the measurement of IgG and IgM antibodies against SARS-CoV-2, EBV, HHV-6, viral superantigens, gut microbiota, and biomarkers of autoimmunity to better understand and manage this multi-factorial disorder that continues to affect millions of people in the world.
9 citations
01 Nov 2022
TL;DR: The most frequently reported symptoms associated with Long COVID include chronic fatigue with post exertional features, neurocognitive dysfunction, breathlessness, and somatic pain this article , which can range in severity from mild to severely debilitating, with resultant loss of quality of life and productivity.
Abstract: As of this writing, it is estimated that there have been nearly 600 million cases of coronavirus disease 2019 (COVID-19) around the world with over six million deaths. While shocking, these figures do not fully illustrate the morbidity associated with this disease. It is also estimated that between 10% and 30% of those who survive COVID-19 develop persistent symptoms after the acute infection has passed. These individuals, who most often experienced initial infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) considered mild to moderate in severity, often display a broad array of symptoms. Collectively, this disorder or syndrome is now referred to as Long COVID (among other designations), and it represents a national/international health crisis. The most frequently reported symptoms associated with Long COVID include chronic fatigue with post exertional features, neurocognitive dysfunction, breathlessness, and somatic pain. Long COVID can range in severity from mild to severely debilitating, with resultant loss of quality of life and productivity. For now, there are many unanswered questions surrounding Long COVID: how can it be best defined, what is needed for accurate diagnosis, what is causing it, and how should it be best managed. How rheumatologists will engage in the Long COVID pandemic is another question; at the minimum, we will be called upon to evaluate and manage our own patients with immune-mediated inflammatory diseases who have developed it. This review focuses on addressing the disease essentials, providing both declarative and procedural knowledge to prepare rheumatologists for how to address Long COVID: understanding its origins, its current case definitions, epidemiology, pathobiology and clinical manifestations. Finally, it will provide an outline on how to clinically approach patients with possible Long COVID and initiate treatment and/or guide them on how to best manage it.
8 citations
References
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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
TL;DR: In this article, the authors describe the long-term health consequences of patients with COVID-19 who have been discharged from hospital and investigate the associated risk factors, in particular disease severity.
2,933 citations
TL;DR: The patient who has a delayed recovery from an episode of covid-19 that was managed in the community or in a standard hospital ward is referred to, which can be divided into those who may have serious sequelae and those with a non-specific clinical picture, often dominated by fatigue and breathlessness.
Abstract: ### What you need to know
Post-acute covid-19 (“long covid”) seems to be a multisystem disease, sometimes occurring after a relatively mild acute illness.1 Clinical management requires a whole-patient perspective.2 This article, intended for primary care clinicians, relates to the patient who has a delayed recovery from an episode of covid-19 that was managed in the community or in a standard hospital ward. Broadly, such patients can be divided into those who may have serious sequelae (such as thromboembolic complications) and those with a non-specific clinical picture, often dominated by fatigue and breathlessness. The specialist rehabilitation needs of a third group, covid-19 patients whose acute illness required intensive care, have been covered elsewhere.3
In the absence of agreed definitions, for the purposes of this article we define post-acute covid-19 as extending beyond three weeks from the onset of first symptoms and chronic covid-19 as extending beyond 12 weeks. Since many people were not tested, and false negative tests are common,4 we suggest that a positive test for covid-19 is not a prerequisite for diagnosis.
### How common is it?
Around 10% of patients who have tested positive for SARS-CoV-2 virus remain unwell beyond three weeks, and a smaller proportion for months (see box 1).7 This is based on the UK COVID Symptom Study, in which people enter their ongoing symptoms on a smartphone app. This percentage is lower than that cited in many published observational …
1,045 citations
TL;DR: There is currently very limited information on the nature and prevalence of post‐COVID‐19 symptoms after hospital discharge.
Abstract: BACKGROUND: There is currently very limited information on the nature and prevalence of post-COVID-19 symptoms after hospital discharge. METHODS: A purposive sample of 100 survivors discharged from a large University hospital were assessed 4 to 8 weeks after discharge by a multidisciplinary team of rehabilitation professionals using a specialist telephone screening tool designed to capture symptoms and impact on daily life. EQ-5D-5L telephone version was also completed. RESULTS: Participants were between 29 and 71 days (mean 48 days) postdischarge from hospital. Thirty-two participants required treatment in intensive care unit (ICU group) and 68 were managed in hospital wards without needing ICU care (ward group). New illness-related fatigue was the most common reported symptom by 72% participants in ICU group and 60.3% in ward group. The next most common symptoms were breathlessness (65.6% in ICU group and 42.6% in ward group) and psychological distress (46.9% in ICU group and 23.5% in ward group). There was a clinically significant drop in EQ5D in 68.8% in ICU group and in 45.6% in ward group. CONCLUSIONS: This is the first study from the United Kingdom reporting on postdischarge symptoms. We recommend planning rehabilitation services to manage these symptoms appropriately and maximize the functional return of COVID-19 survivors.
912 citations
TL;DR: The temporal changes of the diverse CT manifestations followed a specific pattern, which might indicate the progression and recovery of the illness.
Abstract: Background CT may play a central role in the diagnosis and management of coronavirus disease 2019 (COVID-19) pneumonia. Purpose To perform a longitudinal study to analyze the serial CT findings over time in patients with COVID-19 pneumonia. Materials and Methods During January 16 to February 17, 2020, 90 patients (33 men, 57 women; mean age, 45 years) with COVID-19 pneumonia were prospectively enrolled and followed up until being discharged, death, or the end of the study. A total of 366 CT scans were acquired and reviewed by two groups of radiologists for the patterns and distribution of lung abnormalities, total CT scores, and number of zones involved. Those features were analyzed for temporal change. Results CT scores and number of zones involved progressed rapidly, peaked during illness days 6-11 (median CT score, 5; median number of zones involved, five), and were followed by persistence of high levels. The predominant pattern of abnormalities after symptom onset was ground-glass opacity (35 of 78 scans [45%] to 49 of 79 scans [62%] in different periods). The percentage of mixed pattern peaked on illness days 12-17 (30 of 78 scans [38%]) and became the second most predominant pattern thereafter. Pure ground-glass opacity was the most prevalent subtype of ground-glass opacity after symptom onset (20 of 50 scans [40%] to 20 of 28 scans [71%]). The percentage of ground-glass opacity with irregular linear opacity peaked on illness days 6-11 (14 of 50 scans [28%]) and became the second most prevalent subtype thereafter. The distribution of lesions was predominantly bilateral and subpleural. Sixty-six of the 70 patients discharged (94%) had residual disease on final CT scans (median CT score, 4; median number of zones involved, four), with ground-glass opacity (42 of 70 patients [60%]) and pure ground-glass opacity (31 of 42 patients [74%]) the most common pattern and subtype. Conclusion The extent of lung abnormalities at CT peaked during illness days 6-11. The temporal changes of the diverse CT manifestations followed a specific pattern, which might indicate the progression and recovery of the illness. © RSNA, 2020 Online supplemental material is available for this article.
742 citations