Tag: covid-19

Studying severe long COVID to understand post-infectious disorders beyond COVID-19

To the Editor — As the COVID Human Genetic Effort consortium (https://www.covidhge.com/), we have studied genetic and immunological determinants of life-threatening COVID-19 pneumonia1, multisystem inflammatory syndrome (MIS-C)2, resistance to SARS-CoV-2 infection3 and ‘COVID toes’4, and here we present our efforts to investigate post-acute COVID-19 syndrome, or ‘long COVID’.

Most people infected with SARS-CoV-2 experience a mild to moderate acute infection, while ~10% develop hypoxemic pneumonia and 3% develop critical illness, which are outcomes associated with older age and male sex. Inborn errors of type I interferon immunity involving the viral sensors TLR7 or TLR3 can explain critical disease in 1–5% of people less than 60 years of age, whereas neutralizing autoantibodies to the type I interferons IFN-α, IFN-β and IFN-ω are seen in 15–20% of people over 70 years of age1, which highlights the importance of type I interferon immunity for protective immunity against acute SARS-CoV-2 infection in the respiratory tract.

Although hypoxemic pneumonia typically occurs 2 weeks after infection, a small fraction of children and young adults develop MIS-C at about 4 weeks after infection. This disorder overlaps Kawasaki disease and superantigen-mediated toxic shock syndrome. Immunological analyses have revealed hyperinflammatory immune responses, distinct from those of acute COVID-19 and Kawasaki disease5, and activation of T cells, possibly by a SARS-CoV-2 superantigen6. There is massive expansion of T cells expressing the T cell receptor (TCR) β-chain variable region TRBV11-2 in combination with variable TCR α-chains and broadly reactive autoantibodies2. Intriguingly, the delayed presentation of MIS-C after infection is at odds with other superantigen-mediated disorders, which might be explained by viral persistence specifically in the intestine and repeated superantigen-mediated activation through a leaky gut. Viral persistence has been proposed to be associated with the degree of activation of the immune system during acute infection with SARS-CoV-27.

Signs and symptoms after SARS-CoV-2 infection have been reported to also persist even longer in some children and adults. The World Health Organization defines the ‘post COVID’ condition as one that “occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis” (https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1). Long COVID spans from very mild to severely debilitating disease with objective organ damage, but sometimes the distinction between recovery from post–intensive care unit syndrome and ongoing pathology is not clearly defined or reported in studies.

Interestingly, an acute multi-organ phenotype encompassing multiple neurological, neuropsychological–neurocognitive, cardiopulmonary, gastrointestinal and dermatological complaints during acute COVID-19 correlates with longer persistence of signs and symptoms8.

The World Health Organization’s definition of long COVID is vague, which leads to concerns that a variety of conditions, including psychosomatic complaints, become intermixed with more severe, post-infectious organ dysfunction. To maximize our chances of identifying the human genetic immunological determinants of disease, we will focus our efforts on the most severe cases of long COVID available through our international network of collaborators and clinics. We will include patients with over 3 months of persistent signs and symptoms after PCR-verified SARS-CoV-2 infection. We will also limit our studies to patients with severe organ damage or dysfunction that can be objectively verified by imaging and physiological or biochemical–molecular tests (Fig. 1a). Finally, to distinguish these patients with severe long COVID from patients with post–critical illness syndromes, we will include only patients whose persistent organ dysfunction cannot be explained by the severity of the preceding SARS-CoV-2 infection or by the treatments or medical interventions experienced.

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Source: Brodin P, Casari G, Townsend L, O’Farrelly C, Tancevski I, Löffler-Ragg J, Mogensen TH, Casanova JL; COVID Human Genetic Effort. Studying severe long COVID to understand post-infectious disorders beyond COVID-19. Nat Med. 2022 Apr 5. doi: 10.1038/s41591-022-01766-7. Epub ahead of print. PMID: 35383311. https://www.nature.com/articles/s41591-022-01766-7 (Full article)

Long COVID and long chain fatty acids (LCFAs): Psychoneuroimmunity implication of omega-3 LCFAs in delayed consequences of COVID-19

Abstract:

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the lasting pandemic of coronavirus disease 2019 (COVID-19) and the post-acute phase sequelae of heterogeneous negative impacts in multiple systems known as the “long COVID.” The mechanisms of neuropsychiatric complications of long COVID are multifactorial, including long-term tissue damages from direct CNS viral involvement, unresolved systemic inflammation and oxidative stress, maladaptation of the renin-angiotensin-aldosterone system and coagulation system, dysregulated immunity, the dysfunction of neurotransmitters and hypothalamus–pituitaryadrenal (HPA) axis, and the psychosocial stress imposed by societal changes in response to this pandemic. The strength of safety, well-acceptance, and accumulating scientific evidence has now afforded nutritional medicine a place in the mainstream of neuropsychiatric intervention and prophylaxis.

Long chain omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) might have favorable effects on immunity, inflammation, oxidative stress and psychoneuroimmunity at different stages of SARS-CoV-2 infection. Omega-3 PUFAs, particularly EPA, have shown effects in treating mood and neurocognitive disorders by reducing pro-inflammatory cytokines, altering the HPA axis, and modulating neurotransmission via lipid rafts. In addition, omega-3 PUFAs and their metabolites, including specialized pro-resolvin mediators, accelerate the process of cleansing chronic inflammation and restoring tissue homeostasis, and therefore offer a promising strategy for Long COVID. In this article, we explore in a systematic review the putative molecular mechanisms by which omega-3 PUFAs and their metabolites counteract the negative effects of long COVID on the brain, behavior, and immunity.

Source: Yang CP, Chang CM, Yang CC, Pariante CM, Su KP. Long COVID and long chain fatty acids (LCFAs): Psychoneuroimmunity implication of omega-3 LCFAs in delayed consequences of COVID-19. Brain Behav Immun. 2022 Apr 4;103:19-27. doi: 10.1016/j.bbi.2022.04.001. Epub ahead of print. PMID: 35390469; PMCID: PMC8977215. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8977215/ (Full text)

Reducing fatigue-related symptoms in Long COVID-19: a preliminary report of a lymphatic drainage intervention

Abstract:

In the early days of the first global wave of the COVID-19 pandemic, the potential for a postviral syndrome to manifest following COVID-19 infection was first recognized. Here, we present an analysis of a case series of the first 20 patients’ data collected in clinical practice to evaluate the potential of a possible alternative treatment for Long COVID.

Methods: Face-to-face treatment sessions with Perrin technique practitioners occurred weekly involving effleurage/other manual articulatory techniques. The individuals being treated also undertook daily self-massage along with gentle mobility exercises. Patients recorded symptom severity using the self-report 54-item profile of fatigue-related states (PFRS) before and after treatment.

Results: The mean age of male patients was 41.8 years (range, 29-53 years), and for female patients, 39.3 years (range, 28-50 years). None of the participants had a prior diagnosis of chronic fatigue syndrome, and all were new attendees to the clinics at the time of initial assessment. The average number of treatment sessions was 9.7 in men and 9.4 in women. The reduction in PFRS scores was 45% in men and 52% in women. The highest subscale scores on average were for fatigue, with the lowest for somatic symptoms. All subscale scores showed, on average, a similar reduction of approximately 50% postintervention, with the reduction in score relating to a decrease in the severity of symptoms.

Conclusion: Our findings suggest that a specific manual lymphatic drainage intervention may help to reduce fatigue symptoms related to Long COVID. Perhaps preventing acute symptoms through early intervention.

Source: H Heald A, Perrin R, Walther A, Stedman M, Hann M, Mukherjee A, Riste L. Reducing fatigue-related symptoms in Long COVID-19: a preliminary report of a lymphatic drainage intervention. Cardiovasc Endocrinol Metab. 2022 Apr 12;11(2):e0261. doi: 10.1097/XCE.0000000000000261. PMID: 35441129; PMCID: PMC9010124. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010124/ (Full text)

COVCOG 2: Cognitive and Memory Deficits in Long COVID: A Second Publication From the COVID and Cognition Study

Abstract:

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been often characterized as a respiratory disease. However, it is increasingly being understood as an infection that impacts multiple systems, and many patients report neurological symptoms. Indeed, there is accumulating evidence for neural damage in some individuals, with recent studies suggesting loss of gray matter in multiple regions, particularly in the left hemisphere. There are several mechanisms by which the COVID-19 infection may lead to neurological symptoms and structural and functional changes in the brain, and cognitive problems are one of the most commonly reported symptoms in those experiencing Long COVID – the chronic illness following the COVID-19 infection that affects between 10 and 25% of patients. However, there is yet little research testing cognition in Long COVID.

The COVID and Cognition Study is a cross-sectional/longitudinal study aiming to understand cognitive problems in Long COVID. The first paper from the study explored the characteristics of our sample of 181 individuals who had experienced the COVID-19 infection, and 185 who had not, and the factors that predicted ongoing symptoms and self-reported cognitive deficits.

In this second paper from the study, we assess this sample on tests of memory, language, and executive function. We hypothesize that performance on “objective” cognitive tests will reflect self-reported cognitive symptoms. We further hypothesize that some symptom profiles may be more predictive of cognitive performance than others, perhaps giving some information about the mechanism. We found a consistent pattern of memory deficits in those that had experienced the COVID-19 infection, with deficits increasing with the severity of self-reported ongoing symptoms. Fatigue/Mixed symptoms during the initial illness and ongoing neurological symptoms were predictive of cognitive performance.

Source: Guo P, Benito Ballesteros A, Yeung SP, Liu R, Saha A, Curtis L, Kaser M, Haggard MP, Cheke LG. COVCOG 2: Cognitive and Memory Deficits in Long COVID: A Second Publication From the COVID and Cognition Study. Front Aging Neurosci. 2022 Mar 17;14:804937. doi: 10.3389/fnagi.2022.804937. PMID: 35370620; PMCID: PMC8967943. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967943/ (Full study)

COVCOG 1: Factors Predicting Physical, Neurological and Cognitive Symptoms in Long COVID in a Community Sample. A First Publication From the COVID and Cognition Study

Abstract:

Since its first emergence in December 2019, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has evolved into a global pandemic. Whilst often considered a respiratory disease, a large proportion of COVID-19 patients report neurological symptoms, and there is accumulating evidence for neural damage in some individuals, with recent studies suggesting loss of gray matter in multiple regions, particularly in the left hemisphere.

There are a number of mechanisms by which COVID-19 infection may lead to neurological symptoms and structural and functional changes in the brain, and it is reasonable to expect that many of these may translate into cognitive problems. Indeed, cognitive problems are one of the most commonly reported symptoms in those experiencing “Long COVID”-the chronic illness following COVID-19 infection that affects between 10 and 25% of patients. The COVID and Cognition Study is a part cross-sectional, part longitudinal, study documenting and aiming to understand the cognitive problems in Long COVID. In this first paper from the study, we document the characteristics of our sample of 181 individuals who had experienced COVID-19 infection, and 185 who had not.

We explore which factors may be predictive of ongoing symptoms and their severity, as well as conducting an in-depth analysis of symptom profiles. Finally, we explore which factors predict the presence and severity of cognitive symptoms, both throughout the ongoing illness and at the time of testing. The main finding from this first analysis is that that severity of initial illness is a significant predictor of the presence and severity of ongoing symptoms, and that some symptoms during the initial illness-particularly limb weakness-may be more common in those that have more severe ongoing symptoms. Symptom profiles can be well described in terms of 5 or 6 factors, reflecting the variety of this highly heterogenous condition experienced by the individual. Specifically, we found that neurological/psychiatric and fatigue/mixed symptoms during the initial illness, and that neurological, gastrointestinal, and cardiopulmonary/fatigue symptoms during the ongoing illness, predicted experience of cognitive symptoms.

Source: Guo P, Benito Ballesteros A, Yeung SP, Liu R, Saha A, Curtis L, Kaser M, Haggard MP, Cheke LG. COVCOG 1: Factors Predicting Physical, Neurological and Cognitive Symptoms in Long COVID in a Community Sample. A First Publication From the COVID and Cognition Study. Front Aging Neurosci. 2022 Mar 17;14:804922. doi: 10.3389/fnagi.2022.804922. PMID: 35370617; PMCID: PMC8968323. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968323/ (Full text)

Obesity and lipid metabolism disorders determine the risk for development of long COVID syndrome: a cross-sectional study from 50,402 COVID-19 patients

Abstract:

Purpose: Metabolic disorders have been identified as major risk factors for severe acute courses of COVID-19. With decreasing numbers of infections in many countries, the long COVID syndrome (LCS) represents the next major challenge in pandemic management, warranting the precise definition of risk factors for LCS development.

Methods: We identified 50,402 COVID-19 patients in the Disease Analyzer database (IQVIA) featuring data from 1056 general practices in Germany. Multivariate logistic regression analysis was used to identify risk factors for the development of LCS.

Results: Of the 50,402 COVID-19 patients included into this analysis, 1,708 (3.4%) were diagnosed with LCS. In a multivariate regression analysis, we identified lipid metabolism disorders (OR 1.46, 95% CI 1.28-1.65, p < 0.001) and obesity (OR 1.25, 95% CI 1.08-1.44, p = 0.003) as strong risk factors for the development of LCS. Besides these metabolic factors, patients’ age between 46 and 60 years (compared to age ≤ 30, (OR 1.81 95% CI 1.54-2.13, p < 0.001), female sex (OR 1.33, 95% CI 1.20-1.47, p < 0.001) as well as pre-existing asthma (OR 1.67, 95% CI 1.39-2.00, p < 0.001) and depression (OR 1.27, 95% CI 1.09-1.47, p = < 0.002) in women, and cancer (OR 1.4, 95% CI 1.09-1.95, p = < 0.012) in men were associated with an increased likelihood of developing LCS.

Conclusion: Lipid metabolism disorders and obesity represent age-independent risk factors for the development of LCS, suggesting that metabolic alterations determine the risk for unfavorable disease courses along all phases of COVID-19.

Source: Loosen SH, Jensen BO, Tanislav C, Luedde T, Roderburg C, Kostev K. Obesity and lipid metabolism disorders determine the risk for development of long COVID syndrome: a cross-sectional study from 50,402 COVID-19 patients. Infection. 2022 Mar 30:1–6. doi: 10.1007/s15010-022-01784-0. Epub ahead of print. PMID: 35355237; PMCID: PMC8966865. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8966865/ (Full text)

Long COVID (post-COVID-19 condition) in children: a modified Delphi process

Abstract:

Objective: The aim of this study was to derive a research definition for ‘Long COVID (post-COVID-19 condition)’ in children and young people (CYP) to allow comparisons between research studies.

Design: A three-phase online Delphi process was used, followed by a consensus meeting. Participants were presented with 49 statements in each phase and scored them from 1 to 9 based on how important they were for inclusion in the research definition of Long COVID in CYP. The consensus meeting was held to achieve representation across the stakeholder groups. Statements agreed at the consensus meeting were reviewed by participants in the Patient and Public Involvement (PPI) Research Advisory Group.

Setting: The study was conducted remotely using online surveys and a virtual consensus meeting.

Participants: 120 people with relevant expertise were divided into three panels according to their area of expertise: Service Delivery, Research (or combination of research and service delivery) and Lived Experience. The PPI Research Advisory group consisted of CYP aged 11-17 years.

Main outcome measures: Consensus was defined using existing guidelines. If consensus was achieved in two or more panels or was on the border between one and two panels, those statements were discussed and voted on at the consensus meeting.

Results: Ten statements were taken forward for discussion in the consensus meeting and five statements met threshold to be included in the research definition of Long COVID among CYP. The research definition, aligned to the clinical case definition of the WHO, is proposed as follows: Post-COVID-19 condition occurs in young people with a history of confirmed SARS-CoV-2 infection, with at least one persisting physical symptom for a minimum duration of 12 weeks after initial testing that cannot be explained by an alternative diagnosis. The symptoms have an impact on everyday functioning, may continue or develop after COVID infection, and may fluctuate or relapse over time. The positive COVID-19 test referred to in this definition can be a lateral flow antigen test, a PCR test or an antibody test.

Conclusions: This is the first research definition of Long COVID (post-COVID-19 condition) in CYP and complements the clinical case definition in adults proposed by the WHO.

Source: Stephenson T, Allin B, Nugawela MD, Rojas N, Dalrymple E, Pinto Pereira S, Soni M, Knight M, Cheung EY, Heyman I; CLoCk Consortium, Shafran R. Long COVID (post-COVID-19 condition) in children: a modified Delphi process. Arch Dis Child. 2022 Apr 1:archdischild-2021-323624. doi: 10.1136/archdischild-2021-323624. Epub ahead of print. PMID: 35365499; PMCID: PMC8983414. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8983414/ (Full text)

Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates

Abstract:

Neurological manifestations are a significant complication of coronavirus disease (COVID-19), but underlying mechanisms aren’t well understood. The development of animal models that recapitulate the neuropathological findings of autopsied brain tissue from patients who died from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are critical for elucidating the neuropathogenesis of infection and disease.

Here, we show neuroinflammation, microhemorrhages, brain hypoxia, and neuropathology that is consistent with hypoxic-ischemic injury in SARS-CoV-2 infected non-human primates (NHPs), including evidence of neuron degeneration and apoptosis. Importantly, this is seen among infected animals that do not develop severe respiratory disease, which may provide insight into neurological symptoms associated with “long COVID”. Sparse virus is detected in brain endothelial cells but does not associate with the severity of central nervous system (CNS) injury.

We anticipate our findings will advance our current understanding of the neuropathogenesis of SARS-CoV-2 infection and demonstrate SARS-CoV-2 infected NHPs are a highly relevant animal model for investigating COVID-19 neuropathogenesis among human subjects.

Source: Rutkai I, Mayer MG, Hellmers LM, Ning B, Huang Z, Monjure CJ, Coyne C, Silvestri R, Golden N, Hensley K, Chandler K, Lehmicke G, Bix GJ, Maness NJ, Russell-Lodrigue K, Hu TY, Roy CJ, Blair RV, Bohm R, Doyle-Meyers LA, Rappaport J, Fischer T. Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates. Nat Commun. 2022 Apr 1;13(1):1745. doi: 10.1038/s41467-022-29440-z. PMID: 35365631. https://www.nature.com/articles/s41467-022-29440-z (Full text)

Histopathology of Persistent Long COVID Toe: A Case Report

Abstract:

During the 2020 coronavirus (SARS-CoV-2) pandemic, several cutaneous lesions were identified, including: pseudo-chilblain, vesicular, urticarial, maculopapular, and livedo/necrosis. A 59-year-old obese man with probable COVID-19 developed painful cyanosis with histopathologic capillary thrombosis of toes, and the cyanosis persisted for nearly 22 months. Shortly after initial exposure to family members with documented SARS-CoV-2, he developed upper respiratory symptoms, yet his anti-SARS-CoV-2 antibody and nasal swab RT-PCR tests were repeatedly negative. Two family members were hospitalized and one of them succumbed with documented SARS-CoV-2 pneumonia within ten days of exposure. Biopsy of the distal toe 16 weeks after initial exposure demonstrated papillary dermal capillary thrombosis with endothelial swelling, telangiectasia, and peri-eccrine lymphocytic infiltrates resembling pernio. Overall, this is the first case of biopsy of “long COVID toe” following presumed SARS-Cov-2 exposure, with demonstration of thrombotic vasculopathy, toe cyanosis, and pernio-like pathology.

Source: Nirenberg MS, Requena L, Santonja C, Smith GT, McClain SA. Histopathology of Persistent Long COVID Toe: A Case Report. J Cutan Pathol. 2022 Apr 2. doi: 10.1111/cup.14240. Epub ahead of print. PMID: 35366017.  https://pubmed.ncbi.nlm.nih.gov/35366017/

Dietary Recommendations for Post-COVID-19 Syndrome

Abstract:

At the beginning of the coronavirus disease (COVID-19) pandemic, global efforts focused on containing the spread of the virus and avoiding contagion. Currently, it is evident that health professionals should deal with the overall health status of COVID-19 survivors. Indeed, novel findings have identified post-COVID-19 syndrome, which is characterized by malnutrition, loss of fat-free mass, and low-grade inflammation. In addition, the recovery might be complicated by persistent functional impairment (i.e., fatigue and muscle weakness, dysphagia, appetite loss, and taste/smell alterations) as well as psychological distress.

Therefore, the appropriate evaluation of nutritional status (assessment of dietary intake, anthropometrics, and body composition) is one of the pillars in the management of these patients. On the other hand, personalized dietary recommendations represent the best strategy to ensure recovery. Therefore, this review aimed to collect available evidence on the role of nutrients and their supplementation in post-COVID-19 syndrome to provide a practical guideline to nutritionists to tailor dietary interventions for patients recovering from COVID-19 infections.

Source: Barrea L, Grant WB, Frias-Toral E, Vetrani C, Verde L, de Alteriis G, Docimo A, Savastano S, Colao A, Muscogiuri G. Dietary Recommendations for Post-COVID-19 Syndrome. Nutrients. 2022 Mar 20;14(6):1305. doi: 10.3390/nu14061305. PMID: 35334962; PMCID: PMC8954128. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8954128/(Full text)