Tag: long covid immunology

Spontaneous, persistent, T cell-dependent IFN-γ release in patients who progress to Long Covid

Abstract:

After acute infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a proportion of patients experience persistent symptoms beyond 12 weeks, termed Long Covid. Understanding the mechanisms that cause this debilitating disease and identifying biomarkers for diagnostic, therapeutic, and monitoring purposes are urgently required.

We detected persistently high levels of interferon-γ (IFN-γ) from peripheral blood mononuclear cells of patients with Long Covid using highly sensitive FluoroSpot assays. This IFN-γ release was seen in the absence of ex vivo peptide stimulation and remains persistently elevated in patients with Long Covid, unlike the resolution seen in patients recovering from acute SARS-CoV-2 infection. The IFN-γ release was CD8+ T cell-mediated and dependent on antigen presentation by CD14+ cells.

Longitudinal follow-up of our study cohort showed that symptom improvement and resolution correlated with a decrease in IFN-γ production to baseline levels. Our study highlights a potential mechanism underlying Long Covid, enabling the search for biomarkers and therapeutics in patients with Long Covid.

Source: Krishna BA, Lim EY, Metaxaki M, Jackson S, Mactavous L; NIHR BioResource; Lyons PA, Doffinger R, Bradley JR, Smith KGC, Sinclair J, Matheson NJ, Lehner PJ, Sithole N, Wills MR. Spontaneous, persistent, T cell-dependent IFN-γ release in patients who progress to Long Covid. Sci Adv. 2024 Feb 23;10(8):eadi9379. doi: 10.1126/sciadv.adi9379. Epub 2024 Feb 21. PMID: 38381822; PMCID: PMC10881041. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10881041/ (Full text)

A pilot study on the immune cell proteome of long COVID patients shows changes to physiological pathways similar to those in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ~ 10% develop the chronic post-viral debilitating condition, long COVID (LC). Although LC is a heterogeneous condition, about half of cases have typical post-viral fatigue with onset and symptoms that are very similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A key question is whether these conditions are closely related. ME/CFS is a post-stressor fatigue condition that arises from multiple triggers.

To investigate the pathophysiology of LC, a pilot study of patients (n = 6) and healthy controls (n = 5) has used quantitative proteomics to discover changes in peripheral blood mononuclear cell (PBMC) proteins. A principal component analysis separated all long COVID patients from healthy controls. Analysis of 3131 proteins identified 162 proteins differentially regulated, of which 37 were related to immune functions, and 21 to mitochondrial functions.

Markov cluster analysis identified clusters involved in immune system processes, and two aspects of gene expression-spliceosome and transcription. These results were compared with an earlier dataset of 346 differentially regulated proteins in PBMC’s from ME/CFS patients (n = 9) analysed by the same methodology. There were overlapping protein clusters and enriched molecular pathways particularly in immune functions, suggesting the two conditions have similar immune pathophysiology as a prominent feature, and mitochondrial functions involved in energy production were affected in both conditions.

Source: Peppercorn, K., Edgar, C.D., Kleffmann, T. et al. A pilot study on the immune cell proteome of long COVID patients shows changes to physiological pathways similar to those in myalgic encephalomyelitis/chronic fatigue syndrome. Sci Rep 13, 22068 (2023). https://doi.org/10.1038/s41598-023-49402-9 https://www.nature.com/articles/s41598-023-49402-9 (Full text)

Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment

Abstract:

Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood–brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog.

Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.

Source: Greene, C., Connolly, R., Brennan, D. et al. Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci (2024). https://doi.org/10.1038/s41593-024-01576-9 https://www.nature.com/articles/s41593-024-01576-9 (Full text)

Unraveling Links between Chronic Inflammation and Long COVID: Workshop Report

As COVID-19 continues, an increasing number of patients develop long COVID symptoms varying in severity that last for weeks, months, or longer. Symptoms commonly include lingering loss of smell and taste, hearing loss, extreme fatigue, and “brain fog.” Still, persistent cardiovascular and respiratory problems, muscle weakness, and neurologic issues have also been documented. A major problem is the lack of clear guidelines for diagnosing long COVID. Although some studies suggest that long COVID is due to prolonged inflammation after SARS-CoV-2 infection, the underlying mechanisms remain unclear.

The broad range of COVID-19’s bodily effects and responses after initial viral infection are also poorly understood. This workshop brought together multidisciplinary experts to showcase and discuss the latest research on long COVID and chronic inflammation that might be associated with the persistent sequelae following COVID-19 infection.

Source: Pushpa Tandon, Natalie D. Abrams, Leela Rani Avula, Danielle M. Carrick, Preethi Chander, Rao L. Divi, Johanna T. Dwyer, Gallya Gannot, Nataliya Gordiyenko, Qian Liu, Kyung Moon, Mercy PrabhuDas, Anju Singh, Mulualem E. Tilahun, Merriline M. Satyamitra, Chiayeng Wang, Ronald Warren, Christina H. Liu; Unraveling Links between Chronic Inflammation and Long COVID: Workshop Report. J Immunol 15 February 2024; 212 (4): 505–512. https://doi.org/10.4049/jimmunol.2300804 https://journals.aai.org/jimmunol/article/212/4/505/266648 (Full text)

High Prevalence of Long COVID in Common Variable Immunodeficiency: An Italian Multicentric Study

Abstract:

The long-term effects of SARS-CoV-2 infection represent a relevant global health problem. Long COVID (LC) is defined as a complex of signs and symptoms developed during or after SARS-CoV-2 infection and lasting > 12 weeks. In common variable immunodeficiency (CVID) patients, we previously reported higher risk of hospitalization and death during SARS-CoV-2 infection, as well as prolonged swab positivity and frequent reinfections.

The aim of the present study was to assess the risk of LC in an Italian cohort of CVID patients. We used a translated version of the survey proposed by Centers for Disease Control and Prevention (CDC) to collect data on LC. In the enrolled cohort of 175 CVID patients, we found a high prevalence of LC (65.7%). The most frequent LC symptoms were fatigue (75.7%), arthralgia/myalgia (48.7%), and dyspnea (41.7%). The majority of patients (60%) experienced prolonged symptoms, for at least 6 months after infection.

In a multivariate analysis, the presence of complicated phenotype (OR 2.44, 95% CI 1.88-5.03; p = 0.015), obesity (OR 11.17, 95% CI 1.37-90.95; p = 0.024), and female sex (OR 2.06, 95% CI 1.09-3.89; p = 0.024) significantly correlated with the development of LC.

In conclusion, in this multicenter observational cohort study, we demonstrated that CVID patients present an increased prevalence of LC when compared to the general population. Improved awareness on the risk of LC in CVID patients could optimize management of this new and alarming complication of SARS-CoV-2 infection.

Source: Villa A, Milito C, Deiana CM, Gambier RF, Punziano A, Buso H, Bez P, Lagnese G, Garzi G, Costanzo G, Giannuzzi G, Pagnozzi C, Dalm VASH, Spadaro G, Rattazzi M, Cinetto F, Firinu D. High Prevalence of Long COVID in Common Variable Immunodeficiency: An Italian Multicentric Study. J Clin Immunol. 2024 Feb 6;44(2):59. doi: 10.1007/s10875-024-01656-2. PMID: 38319477; PMCID: PMC10847195. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10847195/ (Full text)

Restrained memory CD8+ T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID

Abstract:

During the COVID-19 pandemic it was widely described that certain individuals infected by SARS-CoV-2 experience persistent disease signs and symptoms, Long COVID, which in some cases is very severe with life changing consequences. To maximize our chances of identifying the underpinnings of this illness, we have focused on 121 of the most severe cases from >1000 patients screened in specialized clinics in Sweden and Belgium. We restricted this study to subjects with objective measures of organ damage or dysfunction, >3 months following a verified, but mild-to-moderate SARS-CoV-2 infection.

By performing systems-level immunological testing and comparisons to controls fully convalescent following a similar mild/moderate COVID-19 episode, we identify elevated serological responses to SARS-CoV-2 in severe Long COVID suggestive of chronic antigen stimulation. Persistent viral reservoirs have been proposed in Long COVID and using multiple orthogonal methods for detection of SARS-CoV-2 RNA and protein in plasma we identify a subset of patients with detectable antigens, but with minimal overlap across assays, and no correlation to symptoms or immune measurements.

Elevated serologic responses to SARS-CoV-2 on the other hand were inversely correlated with clonally expanded memory CD8+ T cells, indicating that restrained clonal expansion enables viral persistence, chronic antigen exposure and elevated IgG responses, even if antigen-detection in blood is not universally possible.

Source: Lucie Rodriguez, Ziyang Tan, Tadepally Lakshmikanth, Jun Wang, Hugo Barcenilla, Zoe Swank, Fanglei Zuo, Hassan Abolhassani, Ana Jimena Pavlovitch-Bedzyk, Chunlin Wang, Laura Gonzalez, Constantin Habimana Mugabo, Anette Johnsson, Yang Chen, Anna James, Jaromir Mikes, Linn Kleberg, Christopher Sundling, Mikael Björnson, Malin Nygren Bonnier, Marcus Ståhlberg, Michael Runold, Sophia Björkander, Erik Melén, Isabelle Meyts, Johan Van Weyenbergh, Qian-Pan Hammarström, Mark M Davis, David R. Walt, Nils Landegren, COVID Human Genetic Effort, Alessandro Aiuti, Giorgio Casari, Jean-Laurent Casanova, Marc Jamoulle, Judith Bruchfeld, Petter Brodin. Restrained memory CD8+ T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID. medRxiv 2024.02.11.24302636; doi: https://doi.org/10.1101/2024.02.11.24302636 https://www.medrxiv.org/content/10.1101/2024.02.11.24302636v1.full-text (Full text)

Early immune factors associated with the development of post-acute sequelae of SARS-CoV-2 infection in hospitalized and non-hospitalized individuals

Abstract:

Background: Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to post-acute sequelae of SARS-CoV-2 (PASC) that can persist for weeks to years following initial viral infection. Clinical manifestations of PASC are heterogeneous and often involve multiple organs. While many hypotheses have been made on the mechanisms of PASC and its associated symptoms, the acute biological drivers of PASC are still unknown.

Methods: We enrolled 494 patients with COVID-19 at their initial presentation to a hospital or clinic and followed them longitudinally to determine their development of PASC. From 341 patients, we conducted multi-omic profiling on peripheral blood samples collected shortly after study enrollment to investigate early immune signatures associated with the development of PASC.

Results: During the first week of COVID-19, we observed a large number of differences in the immune profile of individuals who were hospitalized for COVID-19 compared to those individuals with COVID-19 who were not hospitalized. Differences between individuals who did or did not later develop PASC were, in comparison, more limited, but included significant differences in autoantibodies and in epigenetic and transcriptional signatures in double-negative 1 B cells, in particular.

Conclusions: We found that early immune indicators of incident PASC were nuanced, with significant molecular signals manifesting predominantly in double-negative B cells, compared with the robust differences associated with hospitalization during acute COVID-19. The emerging acute differences in B cell phenotypes, especially in double-negative 1 B cells, in PASC patients highlight a potentially important role of these cells in the development of PASC.

Source: Leung JM, Wu MJ, Kheradpour P, Chen C, Drake KA, Tong G, Ridaura VK, Zisser HC, Conrad WA, Hudson N, Allen J, Welberry C, Parsy-Kowalska C, Macdonald I, Tapson VF, Moy JN, deFilippi CR, Rosas IO, Basit M, Krishnan JA, Parthasarathy S, Prabhakar BS, Salvatore M, Kim CC. Early immune factors associated with the development of post-acute sequelae of SARS-CoV-2 infection in hospitalized and non-hospitalized individuals. Front Immunol. 2024 Jan 22;15:1348041. doi: 10.3389/fimmu.2024.1348041. PMID: 38318183; PMCID: PMC10838987. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10838987/ (Full text)

Role of Ferroptosis in the Progression of COVID-19 and the Development of Long COVID

Abstract:

Objectives: To examine the role of ferroptosis on the pathogenesis and progression of COVID-19.

Materials and methods: A total of 127 patients who were hospitalized for COVID-19 were categorized into two groups according to the intensity of oxygen therapy (high-flow or low-flow). Clinical characteristics, laboratory parameters, plasma markers, and peripheral blood mononuclear cell (PBMC) markers were measured at baseline and one or two weeks after treatment. Telephone follow-up was performed 3 months after discharge to assess long COVID.

Results: Patients receiving high-flow oxygen therapy had greater levels of neutrophils; D-dimer; C reactive protein; procalcitonin; plasma protein levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), IL-17, and acyl-CoA synthetase long-chain family member 4 (ACSL4); and PBMC mRNA level of TNF-α; but had lower levels of lymphocytes and plasma glutathione peroxidase 4 (GPX4). There were negative correlations of plasma GPX4 and cystine/glutamate transporter-11 (SLC7A11) with TNF-α, IL-6, and IL-17, and positive correlations of ACSL4 with inflammatory markers in plasma and PBMCs. The plasma levels of TNF-α, IL-6, IL-17, and ACSL4 were significantly lower after treatment than at baseline, but there were higher post-treatment levels of lymphocytes, GPX4, and SLC7A11. Patients with long COVID had a lower baseline level of plasma SLC7A11.

Conclusion: Ferroptosis is activated during the progression of COVID-19, and a low baseline level of a ferroptosis marker (SLC7A11) may indicate an increased risk for long COVID-19. Ferroptosis has potential as a clinical indicator of long COVID and as a therapeutic target.

Source: Zhao W, Wang S, Han Y, Zhang H, Cao J, Dong S, Li D, Lei M, Liu C, Gao Y. Role of Ferroptosis in the Progression of COVID-19 and the Development of Long COVID. Curr Med Chem. 2024 Jan 3. doi: 10.2174/0109298673281662231208102354. Epub ahead of print. PMID: 38310391. https://pubmed.ncbi.nlm.nih.gov/38310391/

Haematological sequelae in the post-acute phase of symptomatic SARS-CoV-2 infection

Abstract:

Many patients surviving SARS-CoV-2 infection suffer from long-term symptoms (long COVID or post COVID) such as shortness of breath, fatigue, loss of taste or smell and cognitive deterioration. However, few data are available concerning blood cell counts and haematological parameters during the post-COVID period.

We analysed haematological data from 83 patients previously admitted to the internal medicine unit of our institution because of symptomatic SARS-CoV-2 infection; all data were obtained within 1-12 months from disease onset. A control group of 70 apparently healthy, age- and sex-matched COVID-19 negative individuals was assessed for comparison. Blood cell counts improved in the post-COVID period, but 81% of patients had persistent abnormalities, compared with 50% in the control group, p < 0.001.

Most common haematological findings included anaemia (40%), reduced lymphocyte (43%) or eosinophil counts (38%) and low IgM memory B cells and correlated with advanced age, number of chronic comorbidities, female gender, altered renal function, reduced baseline Hb and procalcitonin concentrations and increased RDW. Data on lymphocytes and IgM memory B cells show that impaired immune responses may persist for up to one year in the post-COVID period, possibly contributing to long-term symptoms, especially in female patients.

Source: Bergamaschi G, Barteselli C, Calabretta F, Lenti MV, Merli S, Rossi CM, Di Sabatino A. Haematological sequelae in the post-acute phase of symptomatic SARS-CoV-2 infection. Intern Emerg Med. 2024 Jan;19(1):125-133. doi: 10.1007/s11739-023-03459-6. Epub 2023 Nov 24. PMID: 38001354. https://pubmed.ncbi.nlm.nih.gov/38001354/

Decreased risk of COVID-19 and long COVID in patients with psoriasis receiving IL-23 inhibitor: A cross-sectional cohort study from China

Abstract:

Background: Although clinical trials and real-world data suggest that the risk of COVID-19 and its complications is not exacerbated in patients with psoriasis treated by biological agents, the evidence for this is still limited.

Objectives: We aimed to assess the outcomes of COVID-19 among Chinese patients with psoriasis treated by IL-23 inhibitor, and to compare these variables in patients receiving other therapies.

Methods: A cross-sectional cohort study was conducted to compare psoriasis treatment with IL-23 inhibitor to other treatment methods. All the patients received a questionnaire that contained questions about their psoriasis treatment, COVID-19 symptoms, and related risk factors. The prevalence of COVID-19 was calculated, and logistic regression analyses were performed to determine the association between treatment method and COVID-19 risk. The symptoms of COVID-19 and long COVID were described for each treatment group.

Results: Between December 2022 and February 2023, 732 patients with psoriasis were included in the final analysis. 549 patients had a SARS-CoV-2 infection during the study period. Our results showed that individuals who worked outdoors had a decreased risk of COVID-19, as did those who had other allergic disease. With regard to the effect of the treatment regimens, IL-23 inhibitor treatment was associated with a decreased risk of COVID-19 compared to almost all the other treatments except acitretin. Fever was the most common symptom, but the maximum temperature and duration of fever were comparable among the treatment groups. Patients treated with IL-23 inhibitor were more likely to be asymptomatic after recovery compared to patients treated with methotrexate, narrow-bound ultra violet B, or TNF-α inhibitor.

Conclusions: IL-23 inhibitor treatment may lower the risk of COVID-19 and long COVID. Thus, IL-23 inhibitor treatment might be beneficial and positively considered for patients with psoriasis who require systemic treatment during periods when there is a surge in COVID-19 cases.

Source: Hu Y, Huang D, Jiang Y, Yu Q, Lu J, Ding Y, Shi Y. Decreased risk of COVID-19 and long COVID in patients with psoriasis receiving IL-23 inhibitor: A cross-sectional cohort study from China. Heliyon. 2024 Jan 9;10(2):e24096. doi: 10.1016/j.heliyon.2024.e24096. PMID: 38293509; PMCID: PMC10826651. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10826651/ (Full text)