Tag: covid immunology

Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study

Abstract:

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities.

During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.

Source: Ozonoff, A., Jayavelu, N.D., Liu, S. et al. Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study. Nat Commun 15, 216 (2024). https://doi.org/10.1038/s41467-023-44090-5 https://www.nature.com/articles/s41467-023-44090-5 (Full text)

SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels

Abstract:

COVID-19 patients present higher risk for myocardial infarction (MI), acute coronary syndrome, and stroke for up to 1 year after SARS-CoV-2 infection. While the systemic inflammatory response to SARS-CoV-2 infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques to locally promote inflammation remains unknown. Here, we report that SARS-CoV-2 viral RNA (vRNA) is detectable and replicates in coronary atherosclerotic lesions taken at autopsy from patients with severe COVID-19. SARS-CoV-2 localizes to plaque macrophages and shows a stronger tropism for arterial lesions compared to corresponding perivascular fat, correlating with the degree of macrophage infiltration.

In vitro infection of human primary macrophages highlights that SARS-CoV-2 entry is increased in cholesterol-loaded macrophages (foam cells) and is dependent, in part, on neuropilin-1 (NRP-1). Furthermore, although viral replication is abortive, SARS-CoV-2 induces a robust inflammatory response that includes interleukins IL-6 and IL-1β, key cytokines known to trigger ischemic cardiovascular events. SARS-CoV-2 infection of human atherosclerotic vascular explants recapitulates the immune response seen in cultured macrophages, including pro-atherogenic cytokine secretion.

Collectively, our data establish that SARS-CoV-2 infects macrophages in coronary atherosclerotic lesions, resulting in plaque inflammation that may promote acute CV complications and long-term risk for CV events.

Source: Eberhardt N, Noval MG, Kaur R, Sajja S, Amadori L, Das D, Cilhoroz B, Stewart O, Fernandez DM, Shamailova R, Guillen AV, Jangra S, Schotsaert M, Gildea M, Newman JD, Faries P, Maldonado T, Rockman C, Rapkiewicz A, Stapleford KA, Narula N, Moore KJ, Giannarelli C. SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels. bioRxiv [Preprint]. 2023 Aug 15:2023.08.14.553245. doi: 10.1101/2023.08.14.553245. PMID: 37645908; PMCID: PMC10461985. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10461985/ (Full text)

Risk of autoimmune diseases following COVID-19 and the potential protective effect from vaccination: a population-based cohort study

Summary:

Background: Case reports suggest that SARS-CoV-2 infection could lead to immune dysregulation and trigger autoimmunity while COVID-19 vaccination is effective against severe COVID-19 outcomes. We aim to examine the association between COVID-19 and development of autoimmune diseases (ADs), and the potential protective effect of COVID-19 vaccination on such an association.

Methods: A retrospective cohort study was conducted in Hong Kong between 1 April 2020 and 15 November 2022. COVID-19 was confirmed by positive polymerase chain reaction or rapid antigen test. Cox proportional hazard regression with inverse probability of treatment weighting was applied to estimate the risk of incident ADs following COVID-19. COVID-19 vaccinated population was compared against COVID-19 unvaccinated population to examine the protective effect of COVID-19 vaccination on new ADs.

Findings: The study included 1,028,721 COVID-19 and 3,168,467 non-COVID individuals. Compared with non-COVID controls, patients with COVID-19 presented an increased risk of developing pernicious anaemia [adjusted Hazard Ratio (aHR): 1.72; 95% Confidence Interval (CI): 1.12–2.64]; spondyloarthritis [aHR: 1.32 (95% CI: 1.03–1.69)]; rheumatoid arthritis [aHR: 1.29 (95% CI: 1.09–1.54)]; other autoimmune arthritis [aHR: 1.43 (95% CI: 1.33–1.54)]; psoriasis [aHR: 1.42 (95% CI: 1.13–1.78)]; pemphigoid [aHR: 2.39 (95% CI: 1.83–3.11)]; Graves’ disease [aHR: 1.30 (95% CI: 1.10–1.54)]; anti-phospholipid antibody syndrome [aHR: 2.12 (95% CI: 1.47–3.05)]; immune mediated thrombocytopenia [aHR: 2.1 (95% CI: 1.82–2.43)]; multiple sclerosis [aHR: 2.66 (95% CI: 1.17–6.05)]; vasculitis [aHR: 1.46 (95% CI: 1.04–2.04)]. Among COVID-19 patients, completion of two doses of COVID-19 vaccine shows a decreased risk of pemphigoid, Graves’ disease, anti-phospholipid antibody syndrome, immune-mediated thrombocytopenia, systemic lupus erythematosus and other autoimmune arthritis.

Interpretation: Our findings suggested that COVID-19 is associated with an increased risk of developing various ADs and the risk could be attenuated by COVID-19 vaccination. Future studies investigating pathology and mechanisms would be valuable to interpreting our findings.

Source: Kuan Peng, Xue Li, Deliang Yang, Shirley C.W. Chan, Jiayi Zhou, Eric Y.F. Wan, et al. Risk of autoimmune diseases following COVID-19 and the potential protective effect from vaccination: a population-based cohort study. The Lancet, VOLUME 63, 102154, SEPTEMBER 2023 https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00331-0/fulltext (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)

Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome

Abstract:

The duration and severity of COVID-19 are related to age, comorbidities, and cytokine synthesis. This study evaluated the impact of these factors on patients with clinical presentations of COVID-19 in a Brazilian cohort.

A total of 317 patients diagnosed with COVID-19 were included; cases were distributed according to clinical status as severe (n=91), moderate (n=56) and mild (n=170). Of these patients, 92 had acute COVID-19 at sample collection, 90 had already recovered from COVID-19 without sequelae, and 135 had sequelae (long COVID syndrome).

In the acute COVID-19 group, patients with the severe form had higher IL-6 levels (p=0.0260). In the post-COVID-19 group, there was no significant difference in cytokine levels between groups with different clinical conditions. In the acute COVID-19 group, younger patients had higher levels of TNF-α, and patients without comorbidities had higher levels of TNF-α, IL-4 and IL-2 (p<0.05). In contrast, patients over age 60 with comorbidities had higher levels of IL-6. In the post-COVID-19 group, subjects with long COVID-19 had higher levels of IL-17 and IL-2 (p<0.05), and subjects without sequelae had higher levels of IL-10, IL-6 and IL- 4 (p<0.05).

Our results suggest that advanced age, comorbidities and elevated serum IL-6 levels are associated with severe COVID-19 and are good markers to differentiate severe from mild cases. Furthermore, high serum levels of IL-17 and IL-2 and low levels of IL-4 and IL-10 appear to constitute a cytokine profile of long COVID-19, and these markers are potential targets for COVID-19 treatment and prevention strategies.

Source: Queiroz MAF, Neves PFMD, Lima SS, Lopes JDC, Torres MKDS, Vallinoto IMVC, Bichara CDA, Dos Santos EF, de Brito MTFM, da Silva ALS, Leite MM, da Costa FP, Viana MNDSA, Rodrigues FBB, de Sarges KML, Cantanhede MHD, da Silva R, Bichara CNC, van den Berg AVS, Veríssimo AOL, Carvalho MDS, Henriques DF, Dos Santos CP, Nunes JAL, Costa IB, Viana GMR, Carneiro FRO, Palacios VRDCM, Quaresma JAS, Brasil-Costa I, Dos Santos EJM, Falcão LFM, Vallinoto ACR. Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome. Front Cell Infect Microbiol. 2022 Jun 30;12:922422. doi: 10.3389/fcimb.2022.922422. PMID: 35846757; PMCID: PMC9279918. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279918/ (Full text)

Detecting anti-SARS-CoV-2 antibodies in urine samples: A noninvasive and sensitive way to assay COVID-19 immune conversion

Abstract:

Serum-based ELISA (enzyme-linked immunosorbent assay) has been widely used to detect anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. However, to date, no study has investigated patient urine as a biological sample to detect SARS-CoV-2 virus-specific antibodies. An in-house urine-based ELISA was developed using recombinant SARS-CoV-2 nucleocapsid protein.

The presence of SARS-CoV-2 antibodies in urine was established, with 94% sensitivity and 100% specificity for the detection of anti-SARS-CoV-2 antibodies with the urine-based ELISA and 88% sensitivity and 100% specificity with a paired serum-based ELISA. The urine-based ELISA that detects anti-SARS-CoV-2 antibodies is a noninvasive method with potential application as a facile COVID-19 immunodiagnostic platform, which can be used to report the extent of exposure at the population level and/or to assess the risk of infection at the individual level.

Source: Ludolf F, Ramos FF, Bagno FF, Oliveira-da-Silva JA, Reis TAR, Christodoulides M, Vassallo PF, Ravetti CG, Nobre V, da Fonseca FG, Coelho EAF. Detecting anti-SARS-CoV-2 antibodies in urine samples: A noninvasive and sensitive way to assay COVID-19 immune conversion. Sci Adv. 2022 May 13;8(19):eabn7424. doi: 10.1126/sciadv.abn7424. Epub 2022 May 13. PMID: 35559681; PMCID: PMC9106288. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9106288/ (Full text)

Clearance of Persistent SARS-CoV-2 RNA Detection in a NFκB-Deficient Patient in Association with the Ingestion of Human Breast Milk: A Case Report

Abstract:

Currently, there are no evidence-based treatment options for long COVID-19, and it is known that SARS-CoV-2 can persist in part of the infected patients, especially those with immunosuppression. Since there is a robust secretion of SARS-CoV-2-specific highly-neutralizing IgA antibodies in breast milk, and because this immunoglobulin plays an essential role against respiratory virus infection in mucosa cells, being, in addition, more potent in neutralizing SARS-CoV-2 than IgG, here we report the clinical course of an NFκB-deficient patient chronically infected with the SARS-CoV-2 Gamma variant, who, after a non-full effective treatment with plasma infusion, received breast milk from a vaccinated mother by oral route as treatment for COVID-19. After such treatment, the symptoms improved, and the patient was systematically tested negative for SARS-CoV-2. Thus, we hypothesize that IgA and IgG secreted antibodies present in breast milk could be useful to treat persistent SARS-CoV-2 infection in immunodeficient patients.

Source: Sabino JS, Amorim MR, de Souza WM, Marega LF, Mofatto LS, Toledo-Teixeira DA, Forato J, Stabeli RG, Costa ML, Spilki FR, Sabino EC, Faria NR, Benites BD, Addas-Carvalho M, Stucchi RSB, Vasconcelos DM, Weaver SC, Granja F, Proenca-Modena JL, Vilela MMDS. Clearance of Persistent SARS-CoV-2 RNA Detection in a NFκB-Deficient Patient in Association with the Ingestion of Human Breast Milk: A Case Report. Viruses. 2022 May 13;14(5):1042. doi: 10.3390/v14051042. PMID: 35632784; PMCID: PMC9143223. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9143223/ (Full text)

Case Report: Therapeutic and immunomodulatory effects of plasmapheresis in long-haul COVID

Abstract:

Many patients with COVID-19 experience a range of debilitating symptoms months after being infected, a syndrome termed long-haul COVID. A 68-year-old male presented with lung opacity, fatigue, physical and cognitive weaknesses, loss of smell and lymphocytopenia. After rounds of therapeutic plasma exchange (TPE), the patient returned to normal activities and work. Mechanistically in the patient’s peripheral blood mononuclear cells (PBMCs), markers of inflammatory macrophages diminished and markers of lymphocytes, including natural killer (NK) cells and cytotoxic CD8 T-cells, increased. Circulating inflammatory proteins diminished, while positive regulators of tissue repair increased. This case study suggests that TPE has the capacity to treat long-haul COVID.

Source: Kiprov DD, Herskowitz A, Kim D, Lieb M, Liu C, Watanabe E, Hoffman JC, Rohe R, Conboy MJ, Conboy IM. Case Report: Therapeutic and immunomodulatory effects of plasmapheresis in long-haul COVID. F1000Res. 2021 Nov 24;10:1189. doi: 10.12688/f1000research.74534.2. PMID: 35464182; PMCID: PMC9021669. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021669/ (Full text)

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.

Read the rest of this article HERE.

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)

Persistent Brain Fog After Mild COVID Infection Tied to CSF Markers

Abstract:

As cases of coronavirus disease 2019 (COVID-19) mount worldwide, attention is needed on potential long-term neurologic impacts for the majority of patients who experience mild to moderate illness managed as outpatients. To date, there has not been discussion of persistent neurocognitive deficits in patients with milder COVID-19. We present two cases of non-hospitalized patients recovering from COVID-19 with persistent neurocognitive symptoms. Commonly used cognitive screens were normal, while more detailed testing revealed working memory and executive functioning deficits.

An observational cohort study of individuals recovering from COVID-19 (14 or more days following symptom onset) identified that among the first 100 individuals enrolled, 14 were non-hospitalized patients reporting persistent cognitive issues. These 14 participants had a median age of 39 years (interquartile range: 35-56), and cognitive symptoms were present for at least a median of 98 days (interquartile range: 71-120 following acute COVID-19 symptoms); no participants with follow-up evaluation reported symptom resolution. We discuss potential mechanisms to be explored in future studies, including direct viral effects, indirect consequences of immune activation, and immune dysregulation causing auto-antibody production.

Source: Hellmuth J, Barnett TA, Asken BM, Kelly JD, Torres L, Stephens ML, Greenhouse B, Martin JN, Chow FC, Deeks SG, Greene M, Miller BL, Annan W, Henrich TJ, Peluso MJ. Persistent COVID-19-associated neurocognitive symptoms in non-hospitalized patients. J Neurovirol. 2021 Feb;27(1):191-195. doi: 10.1007/s13365-021-00954-4. Epub 2021 Feb 2. PMID: 33528824; PMCID: PMC7852463. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852463/ (Full text)