Tag: long covid immunology

Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study

Abstract:

Growing evidence links COVID-19 with acute and long-term neurological dysfunction. However, the pathophysiological mechanisms resulting in central nervous system involvement remain unclear, posing both diagnostic and therapeutic challenges. Here we show outcomes of a cross-sectional clinical study (NCT04472013) including clinical and imaging data and corresponding multidimensional characterization of immune mediators in the cerebrospinal fluid (CSF) and plasma of patients belonging to different Neuro-COVID severity classes.

The most prominent signs of severe Neuro-COVID are blood-brain barrier (BBB) impairment, elevated microglia activation markers and a polyclonal B cell response targeting self-antigens and non-self-antigens. COVID-19 patients show decreased regional brain volumes associating with specific CSF parameters, however, COVID-19 patients characterized by plasma cytokine storm are presenting with a non-inflammatory CSF profile. Post-acute COVID-19 syndrome strongly associates with a distinctive set of CSF and plasma mediators. Collectively, we identify several potentially actionable targets to prevent or intervene with the neurological consequences of SARS-CoV-2 infection.

Source: Etter MM, Martins TA, Kulsvehagen L, Pössnecker E, Duchemin W, Hogan S, Sanabria-Diaz G, Müller J, Chiappini A, Rychen J, Eberhard N, Guzman R, Mariani L, Melie-Garcia L, Keller E, Jelcic I, Pargger H, Siegemund M, Kuhle J, Oechtering J, Eich C, Tzankov A, Matter MS, Uzun S, Yaldizli Ö, Lieb JM, Psychogios MN, Leuzinger K, Hirsch HH, Granziera C, Pröbstel AK, Hutter G. Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study. Nat Commun. 2022 Nov 9;13(1):6777. doi: 10.1038/s41467-022-34068-0. PMID: 36351919; PMCID: PMC9645766.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9645766/ (Full text)

Clinical and laboratory predictors of long-COVID in children: a single center retrospective study

Abstract:

Objective: The majority of children experience a mild course of acute Coronavirus Disease 2019 (COVID-19). Only few studies have looked at long-term recovery from COVID-19 infection in children. The purpose of this study was to identify the predictors of long-COVID by performing a thorough analysis of the clinical, laboratory, and demographic characteristics of children with COVID-19.

Patients and methods: Between August and October 2021, data were obtained retrospectively from the medical records of 251 children diagnosed with COVID-19 at a tertiary single-center hospital. The prognostic effects of admission-related factors were compared between patients who experienced long-lasting symptoms and those who did not.

Results: Long-COVID symptoms were noted in 12.4% of patients. Joint pain (7.6%), lumbago (4.8%), and headache (3.2%) were the most common symptoms. The mean onset of long-COVID symptoms was 1.35±0.49 months. The onset of long-COVID symptoms was 4 weeks after initial diagnosis in 64.5% of patients and 4-8 weeks later in 35.5% of the patients. The mean duration of long-COVID symptoms was 5.32±2.51 months. Children with long-COVID had higher leukocytes, neutrophils, monocytes, basophils, platelets, and D-dimer when compared with patients without long-COVID (p < 0.001). Leukocytes, neutrophils, monocytes, platelets, and D-dimer had the highest AUC in the ROC analysis (0.694, 0.658, 0.681, 0.667, and 0.612, respectively) and were statistically significant.

Conclusions: Despite the majority of children with COVID-19 having mild or asymptomatic acute disease, the majority of long-COVID symptoms were associated with functional impairment between 1 and 9 months after the start of the infection. Increased leukocytes, monocytes, neutrophils, platelets, and D-dimer appear to be the most powerful laboratory predictors for long-COVID and monitoring these predictors may assist clinicians to identify and follow-up patients with higher risk for long-COVID.

Source: Güven D, Buluş AD. Clinical and laboratory predictors of long-COVID in children: a single center retrospective study. Eur Rev Med Pharmacol Sci. 2022 Oct;26(20):7695-7704. doi: 10.26355/eurrev_202210_30046. PMID: 36314341.  https://www.europeanreview.org/article/30046 (Full text)

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

Abstract:

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

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

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

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

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/

Kynurenine serves as useful biomarker in acute, Long- and Post-COVID-19 diagnostics

Abstract:

Introduction: In patients with SARS-CoV-2, innate immunity is playing a central role, depicted by hyperinflammation and longer lasting inflammatory response. Reliable inflammatory markers that cover both acute and long-lasting COVID-19 monitoring are still lacking. Thus, we investigated one specific inflammatory marker involved as one key player of the immune system, kynurenine (Kyn), and its use for diagnosis/detection of the Long-/Post-COVID syndrome in comparison to currently used markers in both serum and saliva samples.

Material and methods: The study compromised in total 151 inpatients with a SARS-CoV-2 infection hospitalized between 03/2020 and 09/2021. The group NC (normal controls) included blood bank donors (n=302, 144f/158m, mean age 47.1 ± 18.3 years (range 18-75)). Two further groups were generated based on Group A (n=85, 27f/58m, mean age 63.1 ± 18.3 years (range 19-90), acute admission to the hospital) and Group B (n=66, 22f/44m, mean age 66.6 ± 17.6 years (range 17-90), admitted either for weaning or for rehabilitation period due to Long-COVID symptoms/syndrome). Plasma concentrations of Kyn, C-Reactive Protein (CRP) and interleukin-6 (IL-6) were measured on admission. In Group B we determined Kyn 4 weeks after the negative PCR-test. In a subset of patients (n=11) concentrations of Kyn and CRP were measured in sera and saliva two, three and four months after dismission. We identified 12 patients with Post-COVID symptoms >20 weeks with still significant elevated Kyn-levels.

Results: Mean values for NC used as reference were 2.79 ± 0.61 µM, range 1.2-4.1 µM. On admission, patients showed significantly higher concentrations of Kyn compared to NC (p-values < 0.001). Kyn significantly correlated with IL-6 peak-values (r=0.411; p-values <0.001) and CRP (r=0.488, p-values<0.001). Kyn values in Group B (Long-/Post-COVID) showed still significant higher values (8.77 ± 1.72 µM, range 5.5-16.6 µM), whereas CRP values in Group B were in the normal range.

Conclusion: Serum and saliva Kyn are reflecting the acute and long-term pathophysiology of the SARS-CoV-2 disease concerning the innate immune response and thus may serve a useful biomarker for diagnosis and monitoring both Long- and Post-COVID syndrome and its therapy.

Source: Bizjak DA, Stangl M, Börner N, Bösch F, Durner J, Drunin G, Buhl JL, Abendroth D. Kynurenine serves as useful biomarker in acute, Long- and Post-COVID-19 diagnostics. Front Immunol. 2022 Sep 23;13:1004545. doi: 10.3389/fimmu.2022.1004545. PMID: 36211365; PMCID: PMC9537769. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9537769/ (Full text)

Plasma cytokine levels reveal deficiencies in IL-8 and gamma interferon in Long-COVID

Abstract:

Up to half of individuals who contract SARS-CoV-2 develop symptoms of long-COVID approximately three months after initial infection. These symptoms are highly variable, and the mechanisms inducing them are yet to be understood.

We compared plasma cytokine levels from individuals with long-COVID to healthy individuals and found that those with long-COVID had 100% reductions in circulating levels of interferon gamma (IFNγ) and interleukin-8 (IL-8). Additionally, we found significant reductions in levels of IL-6, IL-2, IL-17, IL-13, and IL-4 in individuals with long-COVID.

We propose immune exhaustion as the driver of long-COVID, with the complete absence of IFNγ and IL-8 preventing the lungs and other organs from healing after acute infection, and reducing the ability to fight off subsequent infections, both contributing to the myriad of symptoms suffered by those with long-COVID.

Source: Williams ESCP, Martins TB, Hill HR, Coiras M, Shah KS, Planelles V, Spivak AM. Plasma cytokine levels reveal deficiencies in IL-8 and gamma interferon in Long-COVID. medRxiv [Preprint]. 2022 Oct 5:2022.10.03.22280661. doi: 10.1101/2022.10.03.22280661. PMID: 36238724; PMCID: PMC9558442. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9558442/ (Full text)

Increased levels of inflammatory molecules in blood of Long COVID patients point to thrombotic endotheliitis

Abstract:

The prevailing hypotheses for the persistent symptoms of Long COVID have been narrowed down to immune dysregulation and autoantibodies, widespread organ damage, viral persistence, and fibrinaloid microclots (entrapping numerous inflammatory molecules) together with platelet hyperactivation. Here we demonstrate significantly increased concentrations of Von Willebrand Factor, platelet factor 4, serum amyloid A, alpha-2-antiplasmin E-selectin, and platelet endothelial cell adhesion molecule-1, in the soluble part of the blood.

It was noteworthy that the mean level of alpha-2-antiplasmin exceeded the upper limit of the laboratory reference range in Long COVID patients, and the other 5 were significantly elevated in Long COVID patients as compared to the controls. This is alarming if we take into consideration that a significant amount of the total burden of these inflammatory molecules has previously been shown to be entrapped inside fibrinolysis-resistant microclots (thus decreasing the apparent level of the soluble molecules). We also determined that by individually adding E-selectin and PECAM-1 to healthy blood, these molecules may indeed be involved in protein-protein interactions with plasma proteins (contributing to microclot formation) and platelet hyperactivation. This investigation was performed as a laboratory model investigation and the final exposure concentration of these molecules was chosen to mimic concentrations found in Long COVID.

We conclude that presence of microclotting, together with relatively high levels of six inflammatory molecules known to be key drivers of endothelial and clotting pathology, points to thrombotic endotheliitis as a key pathological process in Long COVID. This has implications for the choice of appropriate therapeutic options in Long COVID.

Source: Simone Turner, Caitlin Naidoo, Thomas Usher, Arneaux Kruger, Chantelle Venter, Gert J Laubscher, M Asad Khan, Douglas B Kell, Etheresia Pretorius. Increased levels of inflammatory molecules in blood of Long COVID patients point to thrombotic endotheliitis. medRxiv 2022.10.13.22281055; doi: https://doi.org/10.1101/2022.10.13.22281055 (Full text available as PDF file)

Neurogenesis is disrupted in human hippocampal progenitor cells upon exposure to serum samples from hospitalized COVID-19 patients with neurological symptoms

Abstract:

Coronavirus disease 2019 (COVID-19), represents an enormous new threat to our healthcare system and particularly to the health of older adults. Although the respiratory symptoms of COVID-19 are well recognized, the neurological manifestations, and their underlying cellular and molecular mechanisms, have not been extensively studied yet. Our study is the first one to test the direct effect of serum from hospitalised COVID-19 patients on human hippocampal neurogenesis using a unique in vitro experimental assay with human hippocampal progenitor cells (HPC0A07/03 C). We identify the different molecular pathways activated by serum from COVID-19 patients with and without neurological symptoms (i.e., delirium), and their effects on neuronal proliferation, neurogenesis, and apoptosis.

We collected serum sample twice, at time of hospital admission and approximately 5 days after hospitalization. We found that treatment with serum samples from COVID-19 patients with delirium (n = 18) decreased cell proliferation and neurogenesis, and increases apoptosis, when compared with serum samples of sex- and age-matched COVID-19 patients without delirium (n = 18). This effect was due to a higher concentration of interleukin 6 (IL6) in serum samples of patients with delirium (mean ± SD: 229.9 ± 79.1 pg/ml, vs. 32.5 ± 9.5 pg/ml in patients without delirium).

Indeed, treatment of cells with an antibody against IL6 prevented the decreased cell proliferation and neurogenesis and the increased apoptosis. Moreover, increased concentration of IL6 in serum samples from delirium patients stimulated the hippocampal cells to produce IL12 and IL13, and treatment with an antibody against IL12 or IL13 also prevented the decreased cell proliferation and neurogenesis, and the increased apoptosis. Interestingly, treatment with the compounds commonly administered to acute COVID-19 patients (the Janus kinase inhibitors, baricitinib, ruxolitinib and tofacitinib) were able to restore normal cell viability, proliferation and neurogenesis by targeting the effects of IL12 and IL13.

Overall, our results show that serum from COVID-19 patients with delirium can negatively affect hippocampal-dependent neurogenic processes, and that this effect is mediated by IL6-induced production of the downstream inflammatory cytokines IL12 and IL13, which are ultimately responsible for the detrimental cellular outcomes.

Source: Borsini, A., Merrick, B., Edgeworth, J. et al. Neurogenesis is disrupted in human hippocampal progenitor cells upon exposure to serum samples from hospitalized COVID-19 patients with neurological symptoms. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01741-1  (Full text)

Molecular Mimicry between SARS-CoV-2 and Human Endocrinocytes: A Prerequisite of Post-COVID-19 Endocrine Autoimmunity?

Abstract:

Molecular mimicry between human and microbial/viral/parasite peptides is common and has long been associated with the etiology of autoimmune disorders provoked by exogenous pathogens. A growing body of evidence accumulated in recent years suggests a strong correlation between SARS-CoV-2 infection and autoimmunity. The article analyzes the immunogenic potential of the peptides shared between the SARS-CoV-2 spike glycoprotein (S-protein) and antigens of human endocrinocytes involved in most common autoimmune endocrinopathies.

A total of 14 pentapeptides shared by the SARS-CoV-2 S-protein, thyroid, pituitary, adrenal cortex autoantigens and beta-cells of the islets of Langerhans were identified, all of them belong to the immunoreactive epitopes of SARS-CoV-2. The discussion of the findings relates the results to the clinical correlates of COVID-19-associated autoimmune endocrinopathies. The most common of these illnesses is an autoimmune thyroid disease, so the majority of shared pentapeptides belong to the marker autoantigens of this disease.

The most important in pathogenesis of severe COVID-19, according to the authors, may be autoimmunity against adrenals because their adequate response prevents excessive systemic action of the inflammatory mediators causing cytokine storm and hemodynamic shock. A critique of the antigenic mimicry concept is given with an assertion that peptide sharing is not a guarantee but only a prerequisite for provoking autoimmunity based on the molecular mimicry. The latter event occurs in carriers of certain HLA haplotypes and when a shared peptide is only used in antigen processing.

Source: Churilov LP, Normatov MG, Utekhin VJ. Molecular Mimicry between SARS-CoV-2 and Human Endocrinocytes: A Prerequisite of Post-COVID-19 Endocrine Autoimmunity? Pathophysiology. 2022 Aug 25;29(3):486-494. doi: 10.3390/pathophysiology29030039. PMID: 36136066; PMCID: PMC9504401. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9504401/ (Full text)

Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long-COVID symptoms

Abstract:

Background: Autoimmunity has been reported in patients with severe COVID-19. We investigated whether antinuclear/extractable-nuclear antibodies (ANAs) were present up to a year after infection, and if they were associated with the development of clinically relevant Post-Acute Sequalae of COVID-19 (PASC) symptoms.

Methods: A rapid assessment line immunoassay was used to measure circulating levels of ANA/ENAs in 106 convalescent COVID-19 patients with varying acute phase severities at 3, 6, and 12 months post-recovery. Patient-reported fatigue, cough, and dyspnea were recorded at each timepoint. Multivariable logistic regression model and receiver-operating curves (ROC) were used to test the association of autoantibodies with patient-reported outcomes and pro-inflammatory cytokines.

Results: Compared to age- and sex-matched healthy controls (n=22) and those who had other respiratory infections (n=34), patients with COVID-19 had higher detectable ANAs at 3 months post-recovery (p<0.001). The mean number of ANA autoreactivities per individual decreased from 3 to 12 months (3.99 to 1.55) with persistent positive titers associated with fatigue, dyspnea, and cough severity. Antibodies to U1-snRNP and anti-SS-B/La were both positively associated with persistent symptoms of fatigue (p<0.028, AUC=0.86) and dyspnea (p<0.003, AUC=0.81). Pro-inflammatory cytokines such as tumour necrosis factor alpha (TNFα) and C-reactive protein predicted the elevated ANAs at 12 months. TNFα, D-dimer, and IL-1β had the strongest association with symptoms at 12 months. Regression analysis showed TNFα predicted fatigue (β=4.65, p=0.004) and general symptomaticity (β=2.40, p=0.03) at 12 months.

Interpretation: Persistently positive ANAs at 12 months post-COVID are associated with persisting symptoms and inflammation (TNFα) in a subset of COVID-19 survivors. This finding indicates the need for further investigation into the role of autoimmunity in PASC.

Source: Son K, Jamil R, Chowdhury A, Mukherjee M, Venegas C, Miyasaki K, Zhang K, Patel Z, Salter B, Yuen ACY, Lau KS, Cowbrough B, Radford K, Huang C, Kjarsgaard M, Dvorkin-Gheva A, Smith J, Li QZ, Waserman S, Ryerson CJ, Nair P, Ho T, Balakrishnan N, Nazy I, Bowdish DM, Svenningsen S, Carlsten C, Mukherjee M. Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long-COVID symptoms. Eur Respir J. 2022 Sep 22:2200970. doi: 10.1183/13993003.00970-2022. Epub ahead of print. PMID: 36137590. https://pubmed.ncbi.nlm.nih.gov/36137590/