Tag: covid-19

Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID

Abstract:

Background: COVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID).

Methods: We assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalization and up to 9 months of convalescence following COVID-19, respiratory syncytial virus (RSV) or influenza A (flu). Progressive fibrosing interstitial lung disease (PFILD) patients were included a positive control for severe, ongoing lung injury.

Results: Monocyte alterations in acute COVID-19 patients included aberrant expression of leucocyte migration molecules, continuing into convalescence (n=142) and corresponding to specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of chemokine receptor CXCR6 (p<0.0001) and adhesion molecule PSGL-1 (p<0.01), alongside preferential migration of monocytes towards CXCR6 ligand CXCL16 (p<0.05) which is abundantly expressed in the lung. Monocyte CXCR6 and lung CXCL16 were heightened in PFILD patients (p<0.001) confirming a role for the CXCR6-CXCL16 axis in ongoing lung injury. Conversely, monocytes from long COVID patients with ongoing fatigue exhibited sustained reduction of the prostaglandin-generating enzyme COX-2 (p<0.01) and CXCR2 expression (p<0.05). These monocyte changes were not present in RSV or flu convalescence.

Conclusions: Our data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.

Source: Scott NA, Pearmain L, Knight SB, Brand O, Morgan DJ, Jagger C, Harbach S, Khan S, Shuwa HA, Franklin M, Kästele V, Williams T, Prise I, McClure FA, Hackney P, Smith L, Menon M, Konkel JE, Lawless C, Wilson J, Mathioudakis AG, Stanel SC, Ustianowski A, Lindergard G, Brij S, Diar Bakerly N, Dark P, Brightling C, Rivera-Ortega P, Lord GM, Horsley A; CIRCO; Piper Hanley K, Felton T, Simpson A, Grainger JR, Hussell T, Mann ER. Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID. Eur Respir J. 2023 Mar 15:2202226. doi: 10.1183/13993003.02226-2022. Epub ahead of print. PMID: 36922030. https://erj.ersjournals.com/content/early/2023/02/23/13993003.02226-2022 (Full article available as PDF file)

Demographic And Clinical Factors Associated With Long COVID

Abstract:

Risk factors for postacute sequelae of SARS-CoV-2 infection (“long COVID”) in community-dwelling populations remain poorly understood. Large-scale data, follow-up, comparison groups, and a consensus definition of long COVID are often lacking. Using data from the OptumLabs Data Warehouse on a nationwide sample of commercial and Medicare Advantage enrollees from the period January 2019 through March 2022, we examined demographic and clinical factors associated with long COVID, using two definitions of people who suffer symptoms long after they were first diagnosed with COVID-19 (“long haulers”).

We identified 8,329 long haulers using the narrow definition (diagnosis code), 207,537 long haulers using the broad definition (symptom based), and 600,161 non–long haulers (comparison group).

On average, long haulers were older and more likely female, with more comorbidities. Among narrow-definition long haulers, the leading risk factors for long COVID included hypertension, chronic lung disease, obesity, diabetes, and depression. Their time between initial COVID-19 diagnosis and diagnosis of long COVID averaged 250 days, with racial and ethnic differences. Broad-definition long haulers exhibited similar risk factors. Distinguishing long COVID from the progression of underlying conditions can be challenging, but further study may advance the evidence base related to the identification, causes, and consequences of long COVID.

Source: Song Z, Giuriato M. Demographic And Clinical Factors Associated With Long COVID. Health Aff (Millwood). 2023 Mar;42(3):433-442. doi: 10.1377/hlthaff.2022.00991. PMID: 36877912. https://pubmed.ncbi.nlm.nih.gov/36877912/

Post-exertional malaise among people with long COVID compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Background: Long COVID describes a condition with symptoms that linger for months to years following acute COVID-19. Many of these Long COVID symptoms are like those experienced by patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Objective: We wanted to determine if people with Long COVID experienced post-exertional malaise (PEM), the hallmark symptom of ME/CFS, and if so, how it compared to PEM experienced by patients with ME/CFS.

Methods: A questionnaire that asked about the domains of PEM including triggers, experience, recovery, and prevention was administered to 80 people seeking care for Long COVID at Bateman Horne Center. Their responses were compared to responses about PEM given by 151 patients with ME/CFS using chi-square tests of independence.

Results: All but one Long COVID respondent reported having PEM. There were many significant differences in the types of PEM triggers, symptoms experienced during PEM, and ways to recover and prevent PEM between Long COVID and ME/CFS. Similarities between Long COVID and ME/CFS included low and medium physical and cognitive exertion to trigger PEM, symptoms of fatigue, pain, immune reaction, neurologic, orthostatic intolerance, and gastrointestinal symptoms during PEM, rest to recover from PEM, and pacing to prevent PEM.

Conclusion: People with Long COVID experience PEM. There were significant differences in PEM experienced by people with Long COVID compared to patients with ME/CFS. This may be due to the newness of Long COVID, not knowing what exertional intolerance is or how to manage it.

Source: Vernon SD, Hartle M, Sullivan K, Bell J, Abbaszadeh S, Unutmaz D, Bateman L. Post-exertional malaise among people with long COVID compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Work. 2023 Mar 7. doi: 10.3233/WOR-220581. Epub ahead of print. PMID: 36911963. https://content.iospress.com/articles/work/wor220581 (Full text)

Predictors of impaired functioning among long COVID patients

Abstract:

Background: There is limited information on what acute factors predict more long-term symptoms from COVID-19.

Objective: Our objective was to conduct an exploratory factor analysis of self-reported symptoms at two time points of Long COVID-19.

Methods: Data from patients with Long COVID-19 were collected at the initial two weeks of contracting SARS CoV-2 and the most recent two weeks, with a mean duration of 21.7 weeks between the two-time points. At time point 2, participants also complete the Coronavirus Impact Scale (CIS), measuring how the COVID-19 pandemic affected various dimensions of their lives (e.g., routine, access to medical care, social/family support, etc.).

Results: At time 1, a three-factor model emerged consisting of Cognitive Dysfunction, Autonomic Dysfunction and Gastrointestinal Dysfunction. The analysis of time 2 resulted in a three-factor model consisting of cognitive dysfunction, autonomic dysfunction, and post-exertional malaise. Using factor scores from time 1, the Autonomic Dysfunction and the Gastrointestinal Dysfunction factor scores significantly predicted the CIS summary score at time two. In addition, the same two factor scores at time 1 predicted the occurrence of myalgic encephalomyelitis/chronic fatigue syndrome at time 2.

Conclusion: As Cognitive and Autonomic Dysfunction emerged as factors for both time points, suggesting health care workers might want to pay particular attention to these factors that might be related to later symptoms and difficulties with returning to pre-illness family life and work functioning.

Source: Jason LA, Dorri JA. Predictors of impaired functioning among long COVID patients. Work. 2023 Mar 8. doi: 10.3233/WOR-220428. Epub ahead of print. PMID: 36911958. https://content.iospress.com/articles/work/wor220428 (Full text)

Prevalence and risk factor for long COVID in children and adolescents: A meta-analysis and systematic review

Abstract:

Background: Millions of COVID-19 pediatric survivors are facing the risk of long COVID after recovery from acute COVID-19. The primary objective of this study was to systematically review the available literature and determine the pooled prevalence of, and risk factors for long COVID among the pediatric survivors.

Methods: Studies that assessed the prevalence of, or risk factors associated with long COVID among pediatric COVID-19 survivors were systematically searched in PubMed, Embase, Cochrane Library, medRxiv and bioRxiv up to December 11th, 2022. Random effects model was performed to estimate the pooled prevalence of long COVID among pediatric COVID-19 patients. Subgroup analyses and meta-regression on the estimated prevalence of long COVID were performed by stratification with follow-up duration, mean age, sex ratio, percentage of multisystem inflammatory syndrome, hospitalization rate at baseline, and percentage of severe illness.

Results: Based on 40 studies with 12,424 individuals, the pooled prevalence of any long COVID was 23.36% ([95% CI 15.27-32.53]). The generalized symptom (19.57%, [95% CI 9.85-31.52]) was reported most commonly, followed by respiratory (14.76%, [95% CI 7.22-24.27]), neurologic (13.51%, [95% CI 6.52-22.40]), and psychiatric (12.30%, [95% CI 5.38-21.37]). Dyspnoea (22.75%, [95% CI 9.38-39.54]), fatigue (20.22%, [95% CI 9.19-34.09]), and headache (15.88%, [95% CI 6.85-27.57]) were most widely reported specific symptoms. The prevalence of any symptom during 3-6, 6-12, and >12 months were 26.41% ([95% CI 14.33-40.59]), 20.64% ([95% CI 17.06-24.46]), and 14.89% ([95% CI 6.09-26.51]), respectively. Individuals with aged over ten years, multisystem inflammatory syndrome, or had severe clinical symptoms exhibited higher prevalence of long COVID in multi-systems. Factors such as older age, female, poor physical or mental health, or had severe infection or more symptoms were more likely to have long COVID in pediatric survivors.

Conclusions: Nearly one quarter of pediatric survivors suffered multisystem long COVID, even at 1 year after infection. Ongoing monitoring, comprehensive prevention and intervention is warranted for pediatric survivors, especially for individuals with high risk factors.

Source: Zheng YB, Zeng N, Yuan K, Tian SS, Yang YB, Gao N, Chen X, Zhang AY, Kondratiuk AL, Shi PP, Zhang F, Sun J, Yue JL, Lin X, Shi L, Lalvani A, Shi J, Bao YP, Lu L. Prevalence and risk factor for long COVID in children and adolescents: A meta-analysis and systematic review. J Infect Public Health. 2023 Mar 7. doi: 10.1016/j.jiph.2023.03.005. Epub ahead of print. PMCID: PMC9990879. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9990879/ (Full text)

Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics

Abstract:

The development of long-term symptoms of coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed “long COVID” or post-acute sequela of COVID-19 (PASC), can implicate persistent neurological complications in up to one third of patients and present as fatigue, “brain fog”, headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, and peripheral neuropathy. Pathogenic mechanisms of these symptoms of long COVID remain largely unclear; however, several hypotheses implicate both nervous system and systemic pathogenic mechanisms such as SARS-CoV2 viral persistence and neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, and endotheliopathy.
Outside of the CNS, SARS-CoV-2 can invade the support and stem cells of the olfactory epithelium leading to persistent alterations to olfactory function. SARS-CoV-2 infection may induce abnormalities in innate and adaptive immunity including monocyte expansion, T-cell exhaustion, and prolonged cytokine release, which may cause neuroinflammatory responses and microglia activation, white matter abnormalities, and microvascular changes. Additionally, microvascular clot formation can occlude capillaries and endotheliopathy, due to SARS-CoV-2 protease activity and complement activation, can contribute to hypoxic neuronal injury and blood–brain barrier dysfunction, respectively.
Current therapeutics target pathological mechanisms by employing antivirals, decreasing inflammation, and promoting olfactory epithelium regeneration. Thus, from laboratory evidence and clinical trials in the literature, we sought to synthesize the pathophysiological pathways underlying neurological symptoms of long COVID and potential therapeutics.
Source: Leng A, Shah M, Ahmad SA, Premraj L, Wildi K, Li Bassi G, Pardo CA, Choi A, Cho S-M. Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics. Cells. 2023; 12(5):816. https://doi.org/10.3390/cells12050816 (Full text)

“Long COVID”: the current state of the problem. Review of foreign scientific and medical publications

Abstract:

Not all the patients who are diagnosed with COVID-19 can completely recover; some of them experience miscellaneous persistent symptoms that subsequently wax or wane.  As the COVID-19 pandemic continues, the number of people with long-term symptoms is rapidly increasing, adding to the burden on healthcare and society. The prevalence of the consequences of COVID-19 varies between studies, with some reporting that more than half of hospitalized patients have prolonged symptoms for at least 6 months after acute SARS-CoV-2 infection, and others for more than 12 months. The overall prevalence of residual symptoms in patients infected with SARS-CoV-2 is currently estimated to be 10–30%.

This clinical syndrome is commonly referred to as post-acute COVID syndrome (PACS) or long COVID. This multifactorial syndrome is characterised by a variety of debilitating symptoms, including fatigue, brain fog, postural hypotension with tachycardia, and post-exertional malaise. Many of the observations of post COVID-19 condition, including changes in immune, cardiovascular, gastrointestinal, nervous and autonomic systems, are shared with the symptoms described in myalgic encephalitis/chronic fatigue syndrome (ME/CFS) patients.

Comprehensive longitudinal symptom monitoring is required to confirm of diagnosis, uncover the mechanisms of post-COVID-19-associated ME/CFS, and develop prevention and treatment measures. Current absence of the effective treatment reflects the unclear causes of the post COVID-19 conditions which cannot be targeted properly until the mechanism is established and confirmed.

The multisystem aspects of long COVID remain poorly understood. The COVID-19 pandemic has exposed a significant gap in knowledge about the post-acute consequences of infectious diseases and the need for a unified nomenclature and classification of post-COVID conditions, diagnostic criteria, and reliable assessments of these disorders. Unraveling the complex biology of PACS relies on the identification of biomarkers in plasma and tissue samples taken from individuals infected with SARS-CoV-2 that will allow classification of the phenotypes of patients who develop PACS.

For the full treatment of patients with post-COVID syndrome, multidisciplinary therapy and rehabilitation are required. Understanding the physiological mechanisms underlying the long-term clinical manifestations of COVID-19 and the post-COVID-19 state is vital to the development of appropriate effective therapies.

Source: Golota A.S., Vologzhanin D.A., Kamilova T.A., Sсherbak S.G., Makarenko S.V. “Long COVID”: the current state of the problem. Review of foreign scientific and medical publications // Physical and rehabilitation medicine, medical rehabilitation. – 2023. – Vol. 5. – N. 1. doi: 10.36425/rehab121733 (Full text available in Russian)

Symptomatic Characteristics of Hypozincemia Detected in Long COVID Patients

Abstract:

Objectives: The aim of this study was to determine the characteristics of hypozincemia in long COVID patients.
Methods: This study was a single-center retrospective observational study for outpatients who visited the long COVID clinic established in a university hospital during the period from 15 February 2021 to 28 February 2022. Characteristics of patients with a serum zinc concentration lower than 70 μg/dL (10.7 μmol/L) were compared with characteristics of patients with normozincemia.
Results: In a total of 194 patients with long COVID after excluding 32 patients, hypozincemia was detected in 43 patients (22.2%) including 16 male patients (37.2%) and 27 female patients (62.8%). Among various parameters including the background characteristics of the patients and medical histories, the patients with hypozincemia were significantly older than the patients with normozincemia (median age: 50 vs. 39 years). A significant negative correlation was found between serum zinc concentrations and age in male patients (R = −0.39; p < 0.01) but not in female patients. In addition, there was no significant correlation between serum zinc levels and inflammatory markers. General fatigue was the most frequent symptom in both male patients with hypozincemia (9 out of 16: 56.3%) and female patients with hypozincemia (8 out of 27: 29.6%). Patients with severe hypozincemia (serum zinc level lower than 60 μg/dL) had major complaints of dysosmia and dysgeusia, which were more frequent complaints than general fatigue.
Conclusions: The most frequent symptom in long COVID patients with hypozincemia was general fatigue. Serum zinc levels should be measured in long COVID patients with general fatigue, particularly in male patients.
Source: Matsuda Y, Tokumasu K, Otsuka Y, Sunada N, Honda H, Sakurada Y, Nakano Y, Hasegawa T, Obika M, Ueda K, Otsuka F. Symptomatic Characteristics of Hypozincemia Detected in Long COVID Patients. Journal of Clinical Medicine. 2023; 12(5):2062. https://doi.org/10.3390/jcm12052062 https://www.mdpi.com/2077-0383/12/5/2062 (Full text)

The role of immune activation and antigen persistence in acute and long COVID

Abstract:

In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered the global coronavirus disease 2019 (COVID-19) pandemic. Although most infections cause a self-limited syndrome comparable to other upper respiratory viral pathogens, a portion of individuals develop severe illness leading to substantial morbidity and mortality. Furthermore, an estimated 10%-20% of SARS-CoV-2 infections are followed by post-acute sequelae of COVID-19 (PASC), or long COVID.

Long COVID is associated with a wide variety of clinical manifestations including cardiopulmonary complications, persistent fatigue, and neurocognitive dysfunction. Severe acute COVID-19 is associated with hyperactivation and increased inflammation, which may be an underlying cause of long COVID in a subset of individuals. However, the immunologic mechanisms driving long COVID development are still under investigation.

Early in the pandemic, our group and others observed immune dysregulation persisted into convalescence after acute COVID-19. We subsequently observed persistent immune dysregulation in a cohort of individuals experiencing long COVID. We demonstrated increased SARS-CoV-2-specific CD4+ and CD8+ T-cell responses and antibody affinity in patients experiencing long COVID symptoms. These data suggest a portion of long COVID symptoms may be due to chronic immune activation and the presence of persistent SARS-CoV-2 antigen.

This review summarizes the COVID-19 literature to date detailing acute COVID-19 and convalescence and how these observations relate to the development of long COVID. In addition, we discuss recent findings in support of persistent antigen and the evidence that this phenomenon contributes to local and systemic inflammation and the heterogeneous nature of clinical manifestations seen in long COVID.

Source: Opsteen S, Files JK, Fram T, Erdmann N. The role of immune activation and antigen persistence in acute and long COVID. J Investig Med. 2023 Mar 6:10815589231158041. doi: 10.1177/10815589231158041. Epub ahead of print. PMID: 36879504; PMCID: PMC9996119. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9996119/ (Full text)

Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course

Abstract:

Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes.

Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration.

Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.

Source: Muri J, Cecchinato V, Cavalli A, Shanbhag AA, Matkovic M, Biggiogero M, Maida PA, Moritz J, Toscano C, Ghovehoud E, Furlan R, Barbic F, Voza A, De Nadai G, Cervia C, Zurbuchen Y, Taeschler P, Murray LA, Danelon-Sargenti G, Moro S, Gong T, Piffaretti P, Bianchini F, Crivelli V, Podešvová L, Pedotti M, Jarrossay D, Sgrignani J, Thelen S, Uhr M, Bernasconi E, Rauch A, Manzo A, Ciurea A, Rocchi MBL, Varani L, Moser B, Bottazzi B, Thelen M, Fallon BA, Boyman O, Mantovani A, Garzoni C, Franzetti-Pellanda A, Uguccioni M, Robbiani DF. Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course. Nat Immunol. 2023 Mar 6. doi: 10.1038/s41590-023-01445-w. Epub ahead of print. PMID: 36879067. https://www.nature.com/articles/s41590-023-01445-w (Full text)