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)

Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults: A Systematic Review and Meta-analysis

Abstract

Importance: Reduced exercise capacity is commonly reported among individuals with COVID-19 symptoms more than 3 months after SARS-CoV-2 infection (long COVID-19 [LC]). Cardiopulmonary exercise testing (CPET) is the criterion standard to measure exercise capacity and identify patterns of exertional intolerance.

Objectives: To estimate the difference in exercise capacity among individuals with and without LC symptoms and characterize physiological patterns of limitations to elucidate possible mechanisms of LC.

Data sources: A search of PubMed, EMBASE, Web of Science, preprint servers, conference abstracts, and cited references was performed on December 20, 2021, and again on May 24, 2022. A preprint search of medrxiv.org, biorxiv.org, and researchsquare.com was performed on June 9, 2022.

Study selection: Studies of adults with SARS-CoV-2 infection more than 3 months earlier that included CPET-measured peak oxygen consumption (V̇o2) were screened independently by 2 blinded reviewers; 72 (2%) were selected for full-text review, and 35 (1%) met the inclusion criteria. An additional 3 studies were identified from preprint servers.

Data extraction and synthesis: Data extraction was performed by 2 independent reviewers according to the PRISMA reporting guideline. Data were pooled using random-effects models.

Main outcomes and measures: Difference in peak V̇o2 (in mL/kg/min) among individuals with and without persistent COVID-19 symptoms more than 3 months after SARS-CoV-2 infection.

Results: A total of 38 studies were identified that performed CPET on 2160 individuals 3 to 18 months after SARS-CoV-2 infection, including 1228 with symptoms consistent with LC. Most studies were case series of individuals with LC or cross-sectional assessments within posthospitalization cohorts. Based on a meta-analysis of 9 studies including 464 individuals with LC symptoms and 359 without symptoms, the mean peak V̇o2 was -4.9 (95% CI, -6.4 to -3.4) mL/kg/min among those with symptoms with a low degree of certainty. Deconditioning and peripheral limitations (abnormal oxygen extraction) were common, but dysfunctional breathing and chronotropic incompetence were also described. The existing literature was limited by small sample sizes, selection bias, confounding, and varying symptom definitions and CPET interpretations, resulting in high risk of bias and heterogeneity.

Conclusions and relevance: The findings of this systematic review and meta-analysis study suggest that exercise capacity was reduced more than 3 months after SARS-CoV-2 infection among individuals with symptoms consistent with LC compared with individuals without LC symptoms, with low confidence. Potential mechanisms for exertional intolerance other than deconditioning include altered autonomic function (eg, chronotropic incompetence, dysfunctional breathing), endothelial dysfunction, and muscular or mitochondrial pathology.

Source: Durstenfeld MS, Sun K, Tahir P, Peluso MJ, Deeks SG, Aras MA, Grandis DJ, Long CS, Beatty A, Hsue PY. Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults: A Systematic Review and Meta-analysis. JAMA Netw Open. 2022 Oct 3;5(10):e2236057. doi: 10.1001/jamanetworkopen.2022.36057. PMID: 36223120. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2797203 (Full text)

Long-Haul COVID Patients: Prevalence of POTS Are Reduced but Cerebral Blood Flow Abnormalities Remain Abnormal with Longer Disease Duration

Abstract:

Background: Postural orthostatic tachycardia syndrome (POTS) has been described early after the onset of the COVID-19 infection, but also orthostatic hypotension (OH). In the present study, we hypothesized that orthostatic intolerance decreases over time.
Methods: In 29 long-haul COVID-19 (LHC) patients, a tilt test was performed, including measurements of cerebral blood flow (CBF) by extracranial Doppler. The time interval between the onset of infection and the tilt test varied between 3 and 28 months.
Results: In the first 12 months after the infection, 71% of the LHC patients showed POTS and after 24 months none of them. In the first 12 months, 29% of patients had a normal heart rate and blood pressure response (normHRBP) and after 24 months 75% (distribution of POTS, OH, and a normHRBP over time: p < 0.0001). Linear regression showed that, over time, there was a decrease in the abnormal CBF during the tilt (p = 0.024) but remained abnormal.
Conclusion: In LHC patients, hemodynamic abnormalities of a tilt test change over time. Patients studied early after the onset of the disease mainly exhibit POTS, but patients studied later in the time course mainly show a normHRBP or OH. In addition, the abnormal CBF reduction improves over time, but CBF remains abnormal.
Source: Campen CMCv, Visser FC. Long-Haul COVID Patients: Prevalence of POTS Are Reduced but Cerebral Blood Flow Abnormalities Remain Abnormal with Longer Disease Duration. Healthcare. 2022; 10(10):2105. https://doi.org/10.3390/healthcare10102105 https://www.mdpi.com/2227-9032/10/10/2105/htm (Full text)

Orthostatic Intolerance in Long-Haul COVID after SARS-CoV-2: A Case-Control Comparison with Post-EBV and Insidious-Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

Background: As complaints of long-haul COVID patients are similar to those of ME/CFS patients and as orthostatic intolerance (OI) plays an important role in the COVID infection symptomatology, we compared 14 long-haul COVID patients with 14 ME/CFS patients with a post-viral Ebstein-Barr (EBV) onset and 14 ME/CFS patients with an insidious onset of the disease.
Methods: In all patients, OI analysis by history taking and OI assessed during a tilt test, as well as cerebral blood flow measurements by extracranial Doppler, and cardiac index measurements by suprasternal Doppler during the tilt test were obtained in all patients.
Results: Except for disease duration no differences were found in clinical characteristics. The prevalence of POTS was higher in the long-haul patients (100%) than in post-EBV (43%) and in insidious-onset (50%) patients (p = 0.0002). No differences between the three groups were present in the prevalence of OI, heart rate and blood pressure changes, changes in cerebral blood flow or in cardiac index during the tilt test.
Conclusion: OI symptomatology and objective abnormalities of OI (abnormal cerebral blood flow and cardiac index reduction during tilt testing) are comparable to those in ME/CFS patients. It indicates that long-haul COVID is essentially the same disease as ME/CFS.
Source: van Campen CMC, Visser FC. Orthostatic Intolerance in Long-Haul COVID after SARS-CoV-2: A Case-Control Comparison with Post-EBV and Insidious-Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Healthcare. 2022; 10(10):2058. https://doi.org/10.3390/healthcare10102058 (Full text)

Experiences of carers of youth, adult children and spouses with ME/CFS

Abstract:

Objectives: The debilitating nature of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) means that family members often take on a caring role. This study compared the experiences of people caring for three groups: youth, young adults, spouses.

Methods: An opportunistic sample of 36 carers completed an online survey of open-ended questions asking about their experiences. Thematic analysis was used to consider the three sets of responses separately and Thematic Comparison was used to identify points of connection and disconnection across the sets.

Results: The themes identified were very similar to those identified in past studies. Two super-ordinate themes were identified: “Lack of knowledge and understanding” and “Holistic Impact”. Though most sub-ordinate themes were evident across all three groups, important differences were found. The sub-ordinate themes “Caring Blindly”, “Emotional and physical health cost”, and “Impact on the whole family” were more evident amongst carers of youth while the theme “Worry for the future” was more evident from carers of young adults and spouses.

Discussion: Differences seemed to be related to both the time since diagnosis and the life stage. A longitudinal study would help to understand how carer experiences change over the life course of caring for someone with ME/CFS.

Source: Baken DM, Ross KJ, Hodges LD, Batten L. Experiences of carers of youth, adult children and spouses with ME/CFS. Chronic Illn. 2022 Oct 18:17423953221121696. doi: 10.1177/17423953221121696. Epub ahead of print. PMID: 36259126. https://pubmed.ncbi.nlm.nih.gov/36259126/

The Hindi Version of International Consensus Criteria: A Cross-cultural Adaptation and Validation Study for Myalgic Encephalomyelitis in Post-COVID Patients

Abstract: 

Context: Fatigue is the most prominent feature of long COVID. With the increasing burden of long COVID cases post-acute phase of illness after recurrent waves of the pandemic, understanding its pathophysiology is of paramount importance.

Such fatigue and post-viral illness could be associated with features of neuroimmune exhaustion and thus be a part of a larger syndrome such as myalgic encephalomyelitis (ME).

Identifying the proportion of patients having ME from those experiencing fatigue would bring us one step closer to understanding the pathophysiology. International consensus criteria (ICC) originally published in English (ICC-E) is a valid and reliable tool for identifying cases of ME. However, a validated Hindi version of ICC-E is not available.

Aims: To develop and validate an equivalent version of ICC-E in the native Hindi language (ICC-H) to suit Indian patients and health care workers even at peripheries and to make conducting large scales surveys more feasible.

Subjects and methods: Once permission from the ethics board was granted, guidelines given by MAPI Research Trust were followed and ICC-H was developed from ICC-E, in the following steps: (a) translation to Hindi, (b) back translation, (c) comparison between the translated and back-translated version performed by experts, and (d) pre-pilot test in the intended population. The ICC-H was applied to 53 bilingual individuals knowing both Hindi and English.

Statistical analysis used: The distribution of Hindi and English questionnaires was analyzed using the Chi-square test and Spearman’s correlation coefficient was used for correlation between answers of each question.

Results: The score of individual items and its global score was highly correlated with each other (p<0.001). The scores of individual components and global scores of ICC-H at baseline and original ICC-E after 4 weeks did not differ significantly.

Conclusion: This study shows that the ICC-H is a valid and reliable instrument for the assessment of ME. ICC-H can be used for Hindi speaking population for identifying cases of ME.

Source: Shah M, Kakar A, Gogia A. The Hindi Version of International Consensus Criteria: A Cross-cultural Adaptation and Validation Study for Myalgic Encephalomyelitis in Post-COVID Patients. J Assoc Physicians India 2022;70(10):59–63. https://www.japi.org/x2d4b494/the-hindi-version-of-international-consensus-criteria-a-cross-cultural-adaptation-and-validation-study-for-myalgic-encephalomyelitis-in-post-covid-patients  https://www.researchgate.net/profile/Atul-Gogia/publication/364241915_Postgraduate_Student_2_Vice_Chairman_and_Senior_Consultant_The_Hindi_Version_of_International_Consensus_Criteria_A_Cross-cultural_Adaptation_and_Validation_Study_for_Myalgic_Encephalomyelitis_in_Post-/links/63405e8aff870c55ce0adebf/Postgraduate-Student-2-Vice-Chairman-and-Senior-Consultant-The-Hindi-Version-of-International-Consensus-Criteria-A-Cross-cultural-Adaptation-and-Validation-Study-for-Myalgic-Encephalomyelitis-in-Post.pdf (Full text available as PDF file)