Long-haul COVID: heed the lessons from other infection-triggered illnesses

According to the Johns Hopkins Coronavirus Resource Center, more than 115 million people worldwide have been infected with SARS-CoV-2 during the COVID-19 pandemic, with extensive implications for morbidity and mortality. Description of long-term effects of COVID-19 are apparing in the medical literature; the first large cohort study with 6-months’ follow-up has been published, and more data are sure to follow. A small number of studies point not only to persistent imaging and testing abnormalities across several organ systems in the postacute period, but to a high frequency of patient-reported symptoms such as fatigue, insomnia, anxiety and depression, autonomic disturbances, cognitive difficulties, pain, and others. The presence of patient support groups, and the rapid expansion of clinics to manage or treat these symptoms, validate further their existence and impact.
Although the frequency, severity, and potentially the etiology of persistent symptoms can vary, sequelae after COVID-19 appears poised to join the range of other postinfectious syndromes described in the field of infectious diseases.

These often share a common symptom phenotype, which might also meet case definitions for myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, or post-treatment Lyme disease. We hope that researchers and clinicians will draw on these other conditions as they continue to advance scientific understanding of so-called long-haul or persistent COVID-19. We would also argue that there are important lessons to learn and pitfalls to avoid; our specific area of clinical care and research (post-treatment Lyme disease) has remained a fiercely contentious condition for more than 30 years.

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Source: John N Aucott, Alison W Rebman. Long-haul COVID: heed the lessons from other infection-triggered illnesses. The Lancet, CORRESPONDENCE| VOLUME 397, ISSUE 10278, P967-968, MARCH 13, 2021 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00446-3/fulltext (Full text) 

Beyond COVID-19 and SARS-CoV-2, cardiovascular outcomes of “long covid” from a pathological perspective – a look back and road ahead

Abstract:

With the decrease in severity of COVID-19 there is a sense of relief in the general population. However, there has been an increased incidence of cardiovascular and other organ complications post-infection, which have raised concerns about long COVID. The term “long COVID” was first used by Perego on social media to denote the persistence of symptoms weeks or months after initial SARS-CoV-2 infection and the term ‘long haulers’ was first described by Watson and by Yong to identify post-COVID conditions.

There has been an increased incidence of sudden cardiac death and MI post-COVID-19 in healthy individuals, sports persons and prominent movie stars. Potential mechanisms contributing to the pathophysiology of post-acute COVID-19 may include 1) Damage to tissues and cells that are important for blood flow, so clotting of blood is increased. 2) Persistence of fragments of virus or its sub-particles/ protein material in a wide range of body sites and, 3) an immune system gone haywire.

As the majority of countries across the globe are easing coronavirus precautionary measures, there is an urgent need by health care organizations and policymakers worldwide to generate awareness by educating the public at large, about the ill effects of long-COVID and varied types of post-acute sequelae of COVID-19.

Source: Aden D, Zaheer S, Kumar R, Raj S, Khan T, Varshney S. Beyond COVID-19 and SARS-CoV-2, cardiovascular outcomes of “long covid” from a pathological perspective – a look back and road ahead. Pathol Res Pract. 2022 Sep 29;239:154144. doi: 10.1016/j.prp.2022.154144. Epub ahead of print. PMID: 36242969; PMCID: PMC9519512.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9519512/ (Full text)

Long-COVID in people with intellectual disabilities: A call for research of a neglected area

Abstract:

Background: Long-COVID (also known as post-coronavirus-19 syndrome) is a term used to describe symptoms that people experience following their recovery from the COVID-19 virus. The severity of long-COVID is well recognised, with healthcare providers commissioning services to diagnose and treat those affected, as well as funded research into the condition.

Methods: We performed a systematic search for relevant articles but were unable to find any research on long-COVID in people with intellectual disabilities. Due to the lack of data, we have only been able to make extrapolations from what is known about the condition within the general population.

Findings: We provide an overview of long-COVID and its potential relevance to people with an intellectual disability. We have focused specifically on symptoms or signs, prevalence, risk factors and treatments of the condition in this group, highlighting areas for clinical practice and future research from a psychosocial perspective. We raise serious questions about our current understanding and the availability of the evidence-based to inform treatments tailored towards this population.

Conclusion: This is the first report that we are aware of on the topic of long-COVID in people with an intellectual disability. The lack of research is preventing us from gaining a greater understanding of how the condition impacts people with an intellectual disability.

Source: Rawlings GH, Beail N. Long-COVID in people with intellectual disabilities: A call for research of a neglected area. Br J Learn Disabil. 2022 Aug 29:10.1111/bld.12499. doi: 10.1111/bld.12499. Epub ahead of print. PMID: 36247098; PMCID: PMC9538317. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9538317/  (Full text)

Negative correlation between ACE2 gene expression levels and loss of taste in a cohort of COVID-19 hospitalized patients: New clues to long-term cognitive disorders

Abstract:

In early 2020, one of the most prevalent symptoms of SARS-CoV-2 infection was the loss of smell (anosmia), found in 60-70% of all cases. Anosmia used to occur early, concomitantly with other symptoms, and often persisted after recovery for an extended period, sometimes for months. In addition to smell disturbance, COVID-19 has also been associated with loss of taste (ageusia). The latest research suggests that SARS-CoV-2 could spread from the respiratory system to the brain through receptors in sustentacular cells localized to the olfactory epithelium. The virus invades human cells via the obligatory receptor, angiotensin-converting enzyme II (ACE2), and a priming protease, TMPRSS2, facilitating viral penetration. There is an abundant expression of both ACE2 and TMPRSS2 in sustentacular cells.

In this study, we evaluated 102 COVID-19 hospitalized patients, of which 17.60% presented anosmia and 9.80% ageusia. ACE1, ACE2, and TMPRSS2 gene expression levels in nasopharyngeal tissue were obtained by RT-qPCR and measured using ΔCT analysis. ACE1 Alu287bp association was also evaluated. Logistic regression models were generated to estimate the effects of variables on ageusia and anosmia.

Association of ACE2 expression levels with ageusia. was observed (OR: 1.35; 95% CI: 1.098-1.775); however, no association was observed between TMPRSS2 and ACE1 expression levels and ageusia. No association was observed among the three genes and anosmia, and the Alu287bp polymorphism was not associated with any of the outcomes.

Lastly, we discuss whetherthere is a bridge linking these initial symptoms, including molecular factors, to long-term COVID-19 health consequences such as cognitive dysfunctions.

Source: Braga-Paz I, Ferreira de Araújo JL, Alves HJ, de Ávila RE, Resende GG, Teixeira MM, de Aguiar RS, de Souza RP, Bahia D. Negative correlation between ACE2 gene expression levels and loss of taste in a cohort of COVID-19 hospitalized patients: New clues to long-term cognitive disorders. Front Cell Infect Microbiol. 2022 Sep 29;12:905757. doi: 10.3389/fcimb.2022.905757. PMID: 36250059; PMCID: PMC9556632. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9556632/ (Full text)

Long COVID: An inevitable sequela of SARS-CoV-2 infection

Abstract:

At present, there are more than 560 million confirmed cases of the coronavirus disease 2019 (COVID-19) worldwide. Although more than 98% of patients with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection can survive acute COVID, a significant portion of survivors can develop residual health problems, which is termed as long COVID. Although severe COVID-19 is generally associated with a high risk of long COVID, patients with asymptomatic or mild disease can also show long COVID.

The definition of long COVID is inconsistent and its clinical manifestations are protean. In addition to general symptoms, such as fatigue, long COVID can affect many organ systems, including the respiratory, neurological, psychosocial, cardiovascular, gastrointestinal, and metabolic systems. Moreover, patients with long COVID may experience exercise intolerance and impaired daily function and quality of life. Long COVID may be caused by SARS-CoV-2 direct injury or its associated immune/inflammatory response.

Assessment of patients with long COVID requires comprehensive evaluation, including history taking, physical examination, laboratory tests, radiography, and functional tests. However, there is no known effective treatment for long COVID. Based on the limited evidence, vaccines may help to prevent the development of long COVID. As long COVID is a new clinical entity that is constantly evolving, there are still many unknowns, and further investigation is warranted to enhance our understanding of this disease.

Source: Chih-Cheng Lai, Chi-Kuei Hsu, Muh-Yong Yen, Ping-Ing Lee, Wen-Chien Ko, Po-Ren Hsueh. Long COVID: An inevitable sequela of SARS CoV-2 infection. Journal of Microbiology, Immunology and Infection, 2022, ISSN 1684-1182,
https://doi.org/10.1016/j.jmii.2022.10.003 (Full text)

Headaches and Dizziness as Disabling, Persistent Symptoms in Patients with Long COVID-A National Multicentre Study

Abstract:

Background: Currently, about 15% of coronavirus disease-19 (COVID-19) patients are affected by Long COVID worldwide; however, this condition has not yet been sufficiently studied. The aim of this study was to identify the impact of symptom persistence as well as clinical and socio-demographic variables in a cohort of people with Long COVID.

Methods: We conducted a descriptive cross-sectional study of a sample of adult patients from different Spanish regions presenting with Long COVID. Data collection was conducted between April and July 2021. Functional status and dependency were assessed.

Results: A multivariate linear regression was performed, and the model was statistically significant (F (7; 114) = 8.79; p < 0.001), according to the overall ALDQ score. The variables with a statistically significant effect on the degree of dependence were age (p = 0.014), time since diagnosis (p = 0.02), headaches (p = 0.031), and dizziness (p = 0.039). Functional status post-COVID showed a positive and significant relationship with the percentage of dependence (p < 0.001).

Conclusions: People affected by Long COVID showed moderate dependency status and limitations in functionality. Those with neurological symptoms, such as dizziness and headaches, as well as older age, showed a higher degree of dependency. Improvements in dependency status occurred with increasing time since diagnosis.

Source: Rodríguez-Pérez MP, Sánchez-Herrera-Baeza P, Rodríguez-Ledo P, Serrada-Tejeda S, García-Bravo C, Pérez-de-Heredia-Torres M. Headaches and Dizziness as Disabling, Persistent Symptoms in Patients with Long COVID-A National Multicentre Study. J Clin Med. 2022 Oct 6;11(19):5904. doi: 10.3390/jcm11195904. PMID: 36233769; PMCID: PMC9572453. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9572453/ (Full text)

SARS-CoV-2, long COVID, prion disease and neurodegeneration

Introduction:

On the last day of the year 2019 a novel Betacoronavirus (2019-nCov), now known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and causing the highly transmissible and lethal pneumonia COVID-19 was first reported in Wuhan, Hubei Province in Central China (Huang et al., ; Fu et al., ; Lu and Sun, ). Since then ongoing research and long-term studies of the sequelae of SARS-CoV-2 infection have indicated that post-infection, recovery from COVID-19 and/or COVID-19 aftermath is associated with long-term physiological and neurological deficits known generically as “long COVID” (Roy et al., ; Ahmad et al., ; Baazaoui and Iqbal, ). Multiple independent epidemiological and clinical studies further indicate that SARS-CoV-2 infection and “long COVID” strongly correlate with the onset of progressive neurological disturbances that include Alzheimer’s disease (AD), prion disease (PrD) and other neurodegenerative disorders. These are apparent: (i) especially in aged and/or senile COVID-19 patients; (ii) in patients experiencing overlapping or inter-current illnesses that include heart disease, diabetes, hypertension, neuropsychiatric and other age-related neurological disorders; and (iii) in those COVID-19 patients who have experienced a particularly virulent and/or a near fatal episode of SARS-CoV-2 infection (Farheen et al., ; Flud et al., ; Fu et al., ). Conversely, increasing numbers of epidemiological studies suggest that elderly people with neurological deficits commonly observed in AD are highly vulnerable to SARS-CoV-2 infection, and especially the development of more severe forms of COVID-19 disease (Chiricosta et al., ; Hsu et al., ; Fu et al., ). The recent finding that the SARS-CoV-2 “S1” spike protein essential for viral infectivity contains prion-like domains associated with immune-evasion and the promotion of protein aggregation and aggregate “seeding” is particularly intriguing (Baazaoui and Iqbal, ; Bernardini et al., ; Tetz and Tetz, ). Based on these and other very recent findings this “Opinion” paper will: (i) address our current understanding of the emerging role of SARS-CoV-2 infection with “long COVID” with special reference to AD and PrD; (ii) will review the latest findings of the SARS-CoV-2 “S1” spike protein and its preferred interaction with the ubiquitous angiotensin converting enzyme-2 (ACE2) receptor (ACE2R); and (iii) will highlight the interplay of the molecular biology and neuropathology of SARS-CoV-2 with the unusual and immune-evasive character of prion neurobiology, AD and PrD.

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Source: Zhao Y, Jaber VR, Lukiw WJ. SARS-CoV-2, long COVID, prion disease and neurodegeneration. Front Neurosci. 2022 Sep 27;16:1002770. doi: 10.3389/fnins.2022.1002770. PMID: 36238082; PMCID: PMC9551214.  Zhao Y, Jaber VR, Lukiw WJ. SARS-CoV-2, long COVID, prion disease and neurodegeneration. Front Neurosci. 2022 Sep 27;16:1002770. doi: 10.3389/fnins.2022.1002770. PMID: 36238082; PMCID: PMC9551214. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9551214/ (Full text)

Post-COVID syndrome, inflammation, and diabetes

Abstract:

The raging COVID-19 pandemic is in its third year of global impact. The SARS CoV 2 virus has a high rate of spread, protean manifestations, and a high morbidity and mortality in individuals with predisposing risk factors. The pathophysiologic mechanisms involve a heightened systemic inflammatory state, cardiometabolic derangements, and varying degrees of glucose intolerance. The latter can be evident as significant hyperglycemia leading to new-onset diabetes or worsening of preexisting disease.

Unfortunately, the clinical course beyond the acute phase of the illness may persist in the form of a variety of symptoms that together form the so-called “Long COVID” or “Post-COVID Syndrome”. It is thought that a chronic, low-grade inflammatory and immunologic state persists during this phase, which may last for weeks or months. Although numerous insights have been gained into COVID-related hyperglycemia and diabetes, its prediction, course, and management remain to be fully elucidated.

Source: Rizvi AA, Kathuria A, Al Mahmeed W, Al-Rasadi K, Al-Alawi K, Banach M, Banerjee Y, Ceriello A, Cesur M, Cosentino F, Galia M, Goh SY, Janez A, Kalra S, Kempler P, Lessan N, Lotufo P, Papanas N, Santos RD, Stoian AP, Toth PP, Viswanathan V, Rizzo M; CArdiometabolic Panel of International experts on Syndemic COvid-19 (CAPISCO). Post-COVID syndrome, inflammation, and diabetes. J Diabetes Complications. 2022 Oct 6;36(11):108336. doi: 10.1016/j.jdiacomp.2022.108336. Epub ahead of print. PMID: 36228563; PMCID: PMC9534783. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9534783/ (Full text)

Persistence of Neutrophil extracellular traps and anti-cardiolipin auto-antibodies in post-acute phase COVID-19 patients

Abstract:

This exploratory prospective study based on 279 individuals showed that plasma levels of neutrophil elastase, myeloperoxidase and circulating DNA of nuclear and mitochondrial origins in non-severe (NS), severe (S) and post-acute phase (PAP) COVID-19 patients were statistically different as compared to the levels in healthy individuals, and revealed the high diagnostic power of these markers in respect to the disease severity. The diagnostic power of NE, MPO, and cir-nDNA as determined by the Area Under Receiver Operating Curves (AUROC) was 0.95, 097 and 0.64; 0.99, 1.0 and 0.82; and 0.94, 1.0, and 0.93, in NS, S and PAP patient subgroups, respectively. In addition, a significant fraction of NS, S as well as of PAP patients exhibited aCL IgM/IgG and anti-B2GP IgM/IgG positivity.

We first demonstrate persistence of these NETs (Neutrophil extracellular traps) markers in PAP patients and consequently of sustained innate immune response imbalance, and a prolonged low-level pro-thrombotic potential activity highlighting the need to monitor these markers in all COVID-19 PAP individuals, to investigate post-acute COVID-19 pathogenesis following intensive care, and to better identify which medical resources will ensure complete patient recovery.

Source: Pisareva E, Badiou S, Mihalovičová L, Mirandola A, Pastor B, Kudriavstev A, Berger M, Roubille C, Fesler P, Klouche K, Cristol JP, Thierry AR. Persistence of Neutrophil extracellular traps and anti-cardiolipin auto-antibodies in post-acute phase COVID-19 patients. J Med Virol. 2022 Oct 13. doi: 10.1002/jmv.28209. Epub ahead of print. PMID: 36226380. https://pubmed.ncbi.nlm.nih.gov/36226380/

Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study

Abstract:

With increasing numbers infected by SARS-CoV-2, understanding long-COVID is essential to inform health and social care support. A Scottish population cohort of 33,281 laboratory-confirmed SARS-CoV-2 infections and 62,957 never-infected individuals were followed-up via 6, 12 and 18-month questionnaires and linkage to hospitalization and death records. Of the 31,486 symptomatic infections,1,856 (6%) had not recovered and 13,350 (42%) only partially. No recovery was associated with hospitalized infection, age, female sex, deprivation, respiratory disease, depression and multimorbidity.

Previous symptomatic infection was associated with poorer quality of life, impairment across all daily activities and 24 persistent symptoms including breathlessness (OR 3.43, 95% CI 3.29-3.58), palpitations (OR 2.51, OR 2.36-2.66), chest pain (OR 2.09, 95% CI 1.96-2.23), and confusion (OR 2.92, 95% CI 2.78-3.07). Asymptomatic infection was not associated with adverse outcomes. Vaccination was associated with reduced risk of seven symptoms. Here we describe the nature of long-COVID and the factors associated with it.

Source: Hastie CE, Lowe DJ, McAuley A, Winter AJ, Mills NL, Black C, Scott JT, O’Donnell CA, Blane DN, Browne S, Ibbotson TR, Pell JP. Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study. Nat Commun. 2022 Oct 12;13(1):5663. doi: 10.1038/s41467-022-33415-5. PMID: 36224173; PMCID: PMC9556711. https://www.nature.com/articles/s41467-022-33415-5 (Full text)