Tag: long Covid

Disturbances in sleep, circadian rhythms and daytime functioning in relation to coronavirus infection and Long-COVID – A multinational ICOSS study

Abstract:

This protocol paper describes the second survey produced by the International Covid Sleep Study (ICOSS) group with the aim to examine the associations between SARS-CoV-2 infection and sleep, sleepiness, and circadian problems as potential predisposing factors for more severe COVID-19 disease profile and for development of Long-COVID in the general population. The survey consists of 47 questions on sleep, daytime sleepiness, circadian rhythm, health, mental wellbeing, life habits, and socioeconomic situation before and during the pandemic, and conditional questions to those reporting having had coronavirus infection, being vaccinated, or suffering from particular sleep symptoms or sleep disorders. Surveys will be administered online between May and November 2021 in Austria, Brazil, Bulgaria, Canada, China, Croatia, Finland, France, Germany, Israel, Italy, Japan, Norway, Portugal, Sweden and USA. Data collected by the survey will give valuable information on the open questions regarding COVID-19 disease risk factors, symptomatology and evolution of Long-COVID, and on other long-term consequences related to the pandemic.

Source: Merikanto I, Dauvilliers Y, Chung F, Holzinger B, De Gennaro L, Wing YK, Korman M, Partinen M; 2nd ICOSS members. Disturbances in sleep, circadian rhythms and daytime functioning in relation to coronavirus infection and Long-COVID – A multinational ICOSS study. J Sleep Res. 2021 Dec 28:e13542. doi: 10.1111/jsr.13542. Epub ahead of print. PMID: 34964184. https://pubmed.ncbi.nlm.nih.gov/34964184/

Multisystem Involvement in Post-acute Sequelae of COVID-19 (PASC)

Abstract:

Objective: To describe cerebrovascular, neuropathic and autonomic features of post-acute sequelae of COVID-19 (PASC).

Methods: This retrospective study evaluated consecutive patients with chronic fatigue, brain fog and orthostatic intolerance consistent with PASC. Controls included postural tachycardia syndrome patients (POTS) and healthy participants. Analyzed data included surveys and autonomic (Valsalva maneuver, deep breathing, sudomotor and tilt tests), cerebrovascular (cerebral blood flow velocity (CBFv) monitoring in middle cerebral artery), respiratory (capnography monitoring) and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/autoimmune markers.

Results: Nine PASC patients were evaluated 0.7±0.3 years after a mild COVID-19 infection, treated as home observations. Autonomic, pain, brain fog, fatigue and dyspnea surveys were abnormal in PASC and POTS (n=10), compared to controls (n=15). Tilt table test reproduced the majority of PASC symptoms. Orthostatic CBFv declined in PASC (-20.0±13.4%) and POTS (-20.3±15.1%), compared to controls (-3.0±7.5%,p=0.001) and was independent of end-tidal carbon dioxide in PASC, but caused by hyperventilation in POTS. Reduced orthostatic CBFv in PASC included both subjects without (n=6) and with (n=3) orthostatic tachycardia. Dysautonomia was frequent (100% in both PASC and POTS) but was milder in PASC (p=0.013). PASC and POTS cohorts diverged in frequency of small fiber neuropathy (89% vs. 60%) but not in inflammatory markers (67% vs. 70%). Supine and orthostatic hypocapnia was observed in PASC.

Interpretation: PASC following mild COVID-19 infection is associated with multisystem involvement including: 1) cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction; 2) small fiber neuropathy and related dysautonomia; 3) respiratory dysregulation; 4) chronic inflammation.

Source: Novak P, Mukerji SS, Alabsi HS, Systrom D, Marciano SP, Felsenstein D, Mullally WJ, Pilgrim DM. Multisystem Involvement in Post-acute Sequelae of COVID-19 (PASC). Ann Neurol. 2021 Dec 24. doi: 10.1002/ana.26286. Epub ahead of print. PMID: 34952975. https://pubmed.ncbi.nlm.nih.gov/34952975/

Biomedical Perspectives of Acute and Chronic Neurological and Neuropsychiatric Sequelae of COVID-19

Abstract:

The incidence of infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent for coronavirus disease 2019 (COVID-19), has dramatically escalated following the initial outbreak in China in late 2019, resulting in a global pandemic with millions of deaths. Although the majority of infected patients survive, and the rapid advent and deployment of vaccines have afforded increased immunity against SARS-CoV-2, long term sequelae of SARS-CoV-2 infection have become increasingly recognized. These include, but are not limited to, chronic pulmonary disease, cardiovascular disorders, and proinflammatory-associated neurological dysfunction that may lead to psychological and neurocognitive impairment. A major component of cognitive dysfunction is operationally categorized as “brain fog” which comprises difficulty with concentration, forgetfulness, confusion, depression, and fatigue.

Multiple parameters associated with long-term neuropsychiatric sequelae of SARS-CoV-2 infection have been detailed in clinical studies. Empirically elucidated mechanisms associated with the neuropsychiatric manifestations of COVID-19 are by nature complex, but broad based working models have focused on mitochondrial dysregulation leading to systemic reductions of metabolic activity and cellular bioenergetics within CNS structures. Multiple factors underlying the expression of brain fog may facilitate future pathogenic insults leading to repetitive cycles of viral and bacterial propagation. Interestingly, diverse neurocognitive sequelae associated with COVID-19 are not dissimilar from those observed in other historical pandemics, thereby providing a broad and integrative perspective on potential common mechanisms of CNS dysfunction subsequent to viral infection. Poor mental health status may be reciprocally linked to compromised immune processes and enhanced susceptibility to infection by diverse pathogens.

By extrapolation, we contend that COVID-19 may potentiate the severity of neurological/neurocognitive deficits in patients afflicted by well-studied neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Accordingly, the prevention, diagnosis, and management of sustained neuropsychiatric manifestations of COVID-19 are pivotal health care directives and provide a compelling rationale for careful monitoring of infected patients, as early mitigation efforts may reduce short- and long-term complications.

Source: Stefano GB, Büttiker P, Weissenberger S, Ptacek R, Wang F, Esch T, Bilfinger TV, Kream RM. Biomedical Perspectives of Acute and Chronic Neurological and Neuropsychiatric Sequelae of COVID-19. Curr Neuropharmacol. 2021 Dec 23. doi: 10.2174/1570159X20666211223130228. Epub ahead of print. PMID: 34951387. https://pubmed.ncbi.nlm.nih.gov/34951387/

Year-long COVID-19 infection reveals within-host evolution of SARS-CoV-2 in a patient with B cell depletion

Abstract:

B-cell depleting therapies may lead to prolonged disease and viral shedding in individuals infected with SARS-CoV-2 and this viral persistence raises concern for viral evolution. We report on the sequencing of early and late samples from a 335-day infection in an immunocompromised patient. The virus accumulated a unique deletion in the amino-terminal domain of the spike protein, and complete deletion of ORF7b and ORF8, the first report of its kind in an immunocompromised patient. Overall, the unique viral mutations found in this study highlight the importance of analyzing viral evolution in protracted SARS-CoV-2 infection, especially in immunosuppressed hosts.

Source: Nussenblatt V, Roder AE, Das S, de Wit E, Youn JH, Banakis S, Mushegian A, Mederos C, Wang W, Chung M, Pérez-Pérez L, Palmore T, Brudno JN, Kochenderfer JN, Ghedin E. Year-long COVID-19 infection reveals within-host evolution of SARS-CoV-2 in a patient with B cell depletion. J Infect Dis. 2021 Dec 23:jiab622. doi: 10.1093/infdis/jiab622. Epub ahead of print. PMID: 34940844. https://pubmed.ncbi.nlm.nih.gov/34940844/

Levocetirizine and montelukast in the COVID-19 treatment paradigm

Abstract:

Levocetirizine, a third-generation antihistamine, and montelukast, a leukotriene receptor antagonist, exhibit remarkable synergistic anti-inflammatory activity across a spectrum of signaling proteins, cell adhesion molecules, and leukocytes. By targeting cellular protein activity, they are uniquely positioned to treat the symptoms of COVID-19. Clinical data to date with an associated six-month follow-up, suggests the combination therapy may prevent the progression of the disease from mild to moderate to severe, as well as prevent/treat many of the aspects of ‘Long COVID,’ thereby cost effectively reducing both morbidity and mortality. To investigate patient outcomes, 53 consecutive COVID-19 test (+) cases (ages 3-90) from a well-established, single-center practice in Boston, Massachusetts, between March – November 2020, were treated with levocetirizine and montelukast in addition to then existing protocols [2]. The data set was retrospectively reviewed.

Thirty-four cases were considered mild (64%), 17 moderate (32%), and 2 (4%) severe. Several patients presented with significant comorbidities (obesity: n = 22, 41%; diabetes: n = 10, 19%; hypertension: n = 24, 45%). Among the cohort there were no exclusions, no intubations, and no deaths. The pilot study in Massachusetts encompassed the first COVID-19 wave which peaked on April 23, 2020 as well as the ascending portion of the second wave in the fall. During this period the average weekly COVID-19 case mortality rate (confirmed deaths/confirmed cases) varied considerably between 1 and 7.5% [37]. FDA has approved a multicenter, randomized, placebo-controlled, Phase 2 clinical trial design, replete with electronic diaries and laboratory metrics to explore scientific questions not addressed herein.

Source: May BC, Gallivan KH. Levocetirizine and montelukast in the COVID-19 treatment paradigm. Int Immunopharmacol. 2021 Dec 15;103:108412. doi: 10.1016/j.intimp.2021.108412. Epub ahead of print. PMID: 34942461; PMCID: PMC8673734. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673734/ (Full text)

Intravenous immunoglobulin as an important adjunct in the prevention and therapy of coronavirus 2019 disease

Abstract:

The coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenged globally with its morbidity and mortality. A small percentage of affected patients (20%) progress into the second stage of the disease clinically presenting with severe or fatal involvement of lung, heart and vascular system, all contributing to multiple-organ failure. The so-called ‘cytokines storm’ is considered the pathogenic basis of severe disease and it is a target for treatment with corticosteroids, immunotherapies and intravenous immunoglobulin (IVIg).

We provide an overview of the role of IVIg in the therapy of adult patients with COVID-19 disease. After discussing the possible underlying mechanisms of IVIg immunomodulation in COVID-19 disease, we review the studies in which IVIg was employed. Considering the latest evidence that show a link between new coronavirus and autoimmunity, we also discuss the use of IVIg in COVID-19 and anti-SARS-CoV-2 vaccination related autoimmune diseases and the post-COVID-19 syndrome.

The benefit of high-dose IVIg is evident in almost all studies with a rapid response, a reduction in mortality and improved pulmonary function in critically ill COVID-19 patients. It seems that an early administration of IVIg is crucial for a successful outcome. Studies’ limitations are represented by the small number of patients, the lack of control groups in some and the heterogeneity of included patients. IVIg treatment can reduce the stay in ICU and the demand for mechanical ventilation, thus contributing to attenuate the burden of the disease.

Source: Danieli MG, Piga MA, Paladini A, Longhi E, Mezzanotte C, Moroncini G, Shoenfeld Y. Intravenous immunoglobulin as an important adjunct in the prevention and therapy of coronavirus 2019 disease. Scand J Immunol. 2021 Nov;94(5):e13101. doi: 10.1111/sji.13101. Epub 2021 Sep 16. PMID: 34940980; PMCID: PMC8646640. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8646640/ (Full text)

Physical, cognitive and mental health impacts of COVID-19 following hospitalisation – a multi-centre prospective cohort study

Abstract:

Background The impact of COVID-19 on physical and mental health, and employment following hospitalisation is poorly understood.

Methods PHOSP-COVID is a multi-centre, UK, observational study of adults discharged from hospital with a clinical diagnosis of COVID-19 involving an assessment between two- and seven-months later including detailed symptom, physiological and biochemical testing. Multivariable logistic regression was performed for patient-perceived recovery with age, sex, ethnicity, body mass index (BMI), co-morbidities, and severity of acute illness as co-variates. Cluster analysis was performed using outcomes for breathlessness, fatigue, mental health, cognition and physical function.

Findings We report findings of 1077 patients discharged in 2020, from the assessment undertaken a median 5 [IQR4 to 6] months later: 36% female, mean age 58 [SD 13] years, 69% white ethnicity, 27% mechanical ventilation, and 50% had at least two co-morbidities. At follow-up only 29% felt fully recovered, 20% had a new disability, and 19% experienced a health-related change in occupation. Factors associated with failure to recover were female, middle-age, white ethnicity, two or more co-morbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial and weakly related to acute severity. Four clusters were identified with different severities of mental and physical health impairment: 1) Very severe (17%), 2) Severe (21%), 3) Moderate with cognitive impairment (17%), 4) Mild (46%), with 3%, 7%, 36% and 43% feeling fully recovered, respectively. Persistent systemic inflammation determined by C-reactive protein was related to cluster severity, but not acute illness severity.

Interpretation We identified factors related to recovery from a hospital admission with COVID-19 and four different phenotypes relating to the severity of physical, mental, and cognitive health five months later. The implications for clinical care include the potential to stratify care and the need for a pro-active approach with wide-access to COVID-19 holistic clinical services.

Source: Sigfrid, Louise, et al. “Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol.” medRxiv (2021).  https://www.medrxiv.org/content/10.1101/2021.03.22.21254057v1.full-text (Full text)

Long covid in adults discharged from UK hospitals after covid-19: a prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol

Abstract:

Background: This study sought to establish the long-term effects of Covid-19 following hospitalisation.

Methods: 327 hospitalised participants, with SARS-CoV-2 infection were recruited into a prospective multicentre cohort study at least 3 months post-discharge. The primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, disability (Washington group short scale), breathlessness (MRC Dyspnoea scale) and quality of life (EQ5D-5L).

Findings: 55% of participants reported not feeling fully recovered. 93% reported persistent symptoms, with fatigue the most common (83%), followed by breathlessness (54%). 47% reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24% of participants. The EQ5D-5L summary index was significantly worse following acute illness (median difference 0.1 points on a scale of 0 to 1, IQR: -0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age.

Interpretation: Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present in young, previously healthy working age adults, and were most common in younger females.

Source: Sigfrid L, Drake TM, Pauley E, Jesudason EC, Olliaro P, Lim WS, Gillesen A, Berry C, Lowe DJ, McPeake J, Lone N, Munblit D, Cevik M, Casey A, Bannister P, Russell CD, Goodwin L, Ho A, Turtle L, O’Hara ME, Hastie C, Donohue C, Spencer RG, Donegan C, Gummery A, Harrison J, Hardwick HE, Hastie CE, Carson G, Merson L, Baillie JK, Openshaw P, Harrison EM, Docherty AB, Semple MG, Scott JT; ISARIC4C investigators. Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. Lancet Reg Health Eur. 2021 Sep;8:100186. doi: 10.1016/j.lanepe.2021.100186. Epub 2021 Aug 6. PMID: 34386785; PMCID: PMC8343377. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343377/ (Full text)

Covid-19: Middle aged women face greater risk of debilitating long term symptoms

Middle aged women have a higher risk of experiencing a range of debilitating ongoing symptoms, such as fatigue, breathlessness, muscle pain, anxiety, depression, and “brain fog” after hospital treatment for covid-19, suggest the findings of two unpublished studies available as preprints.

Seven in 10 patients admitted to hospital with covid-19 reported “long covid” symptoms an average of five months after discharge in the larger PHOSP-COVID study, and symptoms were more prevalent in women aged 40-60.1 White ethnicity, two or more comorbidities at admission, and receiving invasive ventilation while in hospital increased the risk, but severity of acute covid-19 disease did not seem to affect the likelihood of experiencing long covid symptoms.

Only 29% of the 1077 patients studied felt fully recovered when followed up, on average five months after discharge. Over a quarter had clinically significant symptoms of anxiety and depression, 12% had symptoms of post-traumatic stress disorder, 17% had at least mild cognitive impairment, 46% had lower physical performance than age and sex matched controls, and 20% had a new disability.

Before hospital admission 68% of patients had worked full time, but 18% of these had not returned to work and 19% had had to change their way of working because of longlasting effects.

The researchers grouped patients into four clusters according to the severity of their physical and mental symptoms post-covid: very severe (17% of patients), severe (21%), moderate with cognitive impairment (17%), and mild (46%).

Rachael Evans, National Institute for Health Research clinical scientist at the University of Leicester and a study author, said, “The symptoms are very real, but they don’t have a straightforward relationship with heart and lung damage, or certainly heart and lung damage can’t explain all the symptoms.”

Immune response

A smaller second study, from the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC), found that women under 50 were five times less likely to report feeling recovered, twice as likely to report worse fatigue, seven times more likely to become more breathless, and more likely to have greater disability than men of the same age who had been admitted to hospital with covid-19.2 Disability usually affected memory, mobility, communication, vision, or hearing. More than half of the 327 patients assessed in this study did not feel fully recovered when followed up on average seven months later, and persistent symptoms were reported by 93.3%, with fatigue and breathlessness the most common.

Chris Brightling, professor of respiratory medicine at the University of Leicester and a PHOSP-COVID study researcher, speculated that sex based differences in the immune response may be responsible for the higher prevalence of long covid symptoms in women, noting that autoimmune diseases were more prevalent in women than in men at age 40-60.

“Maybe there’s a difference in the immune response acutely, such that men are more likely to have a more severe condition at the time of the infection,” he told a press conference at the Science Media Centre on 24 March. “It may be that the immune response is different in women, so you then have a continued inflammatory reaction that then leads to a higher likelihood of having long covid.”

Higher levels of C reactive protein, a marker of systemic inflammation, were seen in patients in the most severe long covid symptoms. Brightling said that a number of immune and chronic inflammatory conditions can also cause elevated C reactive protein.

About 450 000 people have been admitted to hospital with covid-19 in the UK, so a “very large” proportion of these would potentially be affected by long covid, he said, adding, “Clearly there’s an even larger number of people that have had covid in the community, and a portion of those will also have long covid.”

Source: Torjesen I. Covid-19: Middle aged women face greater risk of debilitating long term symptoms BMJ 2021; 372 :n829 doi:10.1136/bmj.n829 https://www.bmj.com/content/372/bmj.n829 (Full text)

Clinical characteristics with inflammation profiling of long-covid and association with one-year recovery following hospitalisation in the UK: a prospective observational study.

Summary:

Background: There are currently no effective pharmacological or non-pharmacological interventions for Long-COVID. To identify potential therapeutic targets, we focussed on previously described four recovery clusters five months after hospital discharge, their underlying inflammatory profiles and relationship with clinical outcomes at one year.

Methods: PHOSP-COVID is a prospective longitudinal cohort study, recruiting adults hospitalised with COVID-19 across the UK. Recovery was assessed using patient reported outcomes measures (PROMs), physical performance, and organ function at five-months and one-year after hospital discharge. Hierarchical logistic regression modelling was performed for patient-perceived recovery at one-year. Cluster analysis was performed using clustering large applications (CLARA) k-medoids approach using clinical outcomes at five-months. Inflammatory protein profiling from plasma at the five-month visit was performed.

Findings: 2320 participants have been assessed at five months after discharge and 807 participants have completed both five-month and one-year visits. Of these, 35·6% were female, mean age 58·7 (SD 12·5) years, and 27·8% received invasive mechanical ventilation (IMV). The proportion of patients reporting full recovery was unchanged between five months 501/1965 (25·5%) and one year 232/804 (28·9%). Factors associated with being less likely to report full recovery at one year were: female sex OR 0·68 (95% CI 0·46-0·99), obesity OR 0·50 (95%CI 0·34-0·74) and IMV OR 0·42 (95%CI 0·23-0·76).

Cluster analysis (n=1636) corroborated the previously reported four clusters: ‘very severe’, ‘severe’, ‘moderate/cognitive’, ‘mild’ relating to the severity of physical, mental health and cognitive impairments at five months in a larger sample. There was elevation of inflammatory mediators of tissue damage and repair in both the ‘very severe’ and the ‘moderate/cognitive’ clusters compared to the ‘mild’ cluster including interleukin-6 which was elevated in both comparisons. Overall, there was a substantial deficit in median (IQR) EQ5D-5L utility index from pre-COVID (retrospective assessment) 0·88 (0·74-1·00), five months 0·74 (0·60-0·88) to one year: 0·74 (0·59-0·88), with minimal improvements across all outcome measures at one-year after discharge in the whole cohort and within each of the four clusters.

Interpretation: The sequelae of a hospital admission with COVID-19 remain substantial one year after discharge across a range of health domains with the minority in our cohort feeling fully recovered. Patient perceived health-related quality of life remains reduced at one year compared to pre-hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.

Source: Rachael A Evans, Olivia C Leavy, Matthew Richardson, Omer Elneima, Hamish J C McAuley, Aarti Shikotra, Amisha Singapuri, Marco Sereno et al. Clinical characteristics with inflammation profiling of long-covid and association with one-year recovery following hospitalisation in the UK: a prospective observational study. medRxiv 2021.12.13.21267471; doi: https://doi.org/10.1101/2021.12.13.21267471 https://www.medrxiv.org/content/10.1101/2021.12.13.21267471v1.full-text (Full Text)