Tag: long covid immunology

Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity

Most patients with Post COVID Syndrome (PCS) present with a plethora of symptoms without clear evidence of organ dysfunction. A subset of them fulfills diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptom severity of ME/CFS correlates with natural regulatory autoantibody (AAB) levels targeting several G-protein coupled receptors (GPCR).

In this exploratory study, we analyzed serum AAB levels against vaso- and immunoregulatory receptors, mostly GPCRs, in 80 PCS patients following mild-to-moderate COVID-19, with 40 of them fulfilling diagnostic criteria of ME/CFS. Healthy seronegative (n=38) and asymptomatic post COVID-19 controls (n=40) were also included in the study as control groups.

We found lower levels for various AABs in PCS compared to at least one control group, accompanied by alterations in the correlations among AABs. Classification using random forest indicated AABs targeting ADRB2, STAB1, and ADRA2A as the strongest classifiers (AABs stratifying patients according to disease outcomes) of post COVID-19 outcomes. Several AABs correlated with symptom severity in PCS groups. Remarkably, severity of fatigue and vasomotor symptoms were associated with ADRB2 AAB levels in PCS/ME/CFS patients.

Our study identified dysregulation of AAB against various receptors involved in the autonomous nervous system (ANS), vaso-, and immunoregulation and their correlation with symptom severity, pointing to their role in the pathogenesis of PCS.

Source: Franziska Sotzny, Igor Salerno Filgueiras, Claudia Kedor, Helma Freitag, Kirsten Wittke, Sandra Bauer, Nuno Sepúlveda, Dennyson Leandro Mathias da Fonseca, Gabriela Crispim Baiocchi, Alexandre H. C. Marques, Myungjin Kim, Tanja Lange, Desirée Rodrigues Plaça, Finn Luebber, Frieder M. Paulus, Roberta De Vito, Igor Jurisica, Kai Schulze-Forster, Friedemann Paul, Judith Bellmann-Strobl, Rebekka Rust, Uta Hoppmann, Yehuda Shoenfeld, Gabriela Riemekasten, Harald Heidecke, Otavio Cabral-Marques, Carmen Scheibenbogen. Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity. Front. Immunol., 27 September 2022
Sec. Autoimmune and Autoinflammatory Disorders https://doi.org/10.3389/fimmu.2022.981532 (Full text)

Impact of cross-coronavirus immunity in post-acute sequelae of COVID-19

Abstract:

Beyond the unpredictable acute illness caused by SARS-CoV-2, one-fifth of infections unpredictably result in long-term persistence of symptoms despite the apparent clearance of infection. Insights into the mechanisms that underlie post-acute sequelae of COVID-19 (PASC) will be critical for the prevention and clinical management of long-term complications of COVID-19. Several hypotheses have been proposed that may account for the development of PASC, including persistence of virus or the dysregulation of immunity. Among the immunological changes noted in PASC, alterations in humoral immunity have been observed in some patient subsets.

To begin to determine whether SARS-CoV-2 or other pathogen specific humoral immune responses evolve uniquely in PASC, we performed comprehensive antibody profiling against SARS-CoV-2 and a panel of endemic pathogens or routine vaccine antigens using Systems Serology in a cohort of patients with pre-existing rheumatic disease who either developed or did not develop PASC.

A distinct humoral immune response was observed in individuals with PASC. Specifically, individuals with PASC harbored less inflamed and weaker Fcγ receptor binding anti-SARS-CoV-2 antibodies and a significantly expanded and more inflamed antibody response against endemic Coronavirus OC43. Individuals with PASC, further, generated more avid IgM responses and developed an expanded inflammatory OC43 S2-specific Fc-receptor binding response, linked to cross reactivity across SARS-CoV-2 and common coronaviruses. These findings implicate previous common Coronavirus imprinting as a marker for the development of PASC.

Source: Jonathan D. Herman, Caroline Atyeo, Yonatan Zur, Claire E. Cook, Naomi J. Patel, Kathleen M. Vanni, Emily N. Kowalski, Grace Qian, Nancy A. Shadick, Douglas Laffenburger, Zachary S. Wallace, Jeffrey A. Sparks, Galit Alter. Impact of cross-coronavirus immunity in post-acute sequelae of COVID-19. medRxiv 2022.09.25.22280335; doi: https://doi.org/10.1101/2022.09.25.22280335 https://www.medrxiv.org/content/10.1101/2022.09.25.22280335v1.full-text (Full text)

Inflammation and autoreactivity define a discrete subset of patients with post-acute sequelae of COVID-19, or long-COVID

Abstract:

While significant attention has been paid to the immunologic determinants of disease states associated with COVID-19, their contributions to post-acute sequelae of COVID-19 (PASC) remain less clear. Due to the wide array of PASC presentations, it is critical to understand if specific features of the disease are associated with discrete immune processes, and whether those processes may be therapeutically targeted. To this end, we performed wide immunologic and serological characterization of patients in the early recovery phase of COVID-19 across a breadth of symptomatic presentations.

Using high-parameter proteomics screening and applied machine learning (ML), we identify clear signatures of immunologic activity between PASC patients and uncomplicated recovery, dominated by inflammatory cytokine signaling, neutrophil activity, and markers of cell death. Consistent with disease complexity, heterogeneity in plasma profiling reveals distinct PASC subsets with striking divergence in these ongoing inflammatory processes, here termed plasma quiescent (plaq) and inflammatory (infl) PASC.

In addition to elevated inflammatory blood proteomics, inflPASC patients display positive clinical tests of acute inflammation including C-reactive protein and fibrinogen, increased B cell activity with extrafollicular involvement coupled with elevated targeting of viral nucleocapsid protein and clinical autoreactivity. Further, the unique plasma signatures of PASC patients allowed for the creation of refined models with high sensitivity and specificity for the positive identification of inflPASC with a streamlined assessment of 12 blood markers. Additionally, refined ML modeling highlights the unexpected significance of several markers of potential diagnostic or therapeutic use for PASC in general, including the peptide hormone, epiregulin.

In all, this work identifies clear biological signatures of PASC with potential diagnostic and therapeutic potential and establishes clear disease subtypes that are both easily identifiable and highly relevant to ongoing efforts in both therapeutic targeting and epidemiological investigation of this highly complex disease.

Source: Matthew Woodruff, Kevin S Bonham, Fabliha A Anam, Tiffany Walker, Yusho Ishii, Candice Y Kaminski, Martin Runnstrom, Alexander Truong, Adviteeya Dixit, Jenny Han, Richard Ramonell, Natalie S. Haddad, Mark Rudoloph, Arezou Khosroshahi, Scott A Jenks, F. Eun-Hyung Lee, Ignacio Sanz. Inflammation and autoreactivity define a discrete subset of patients with post-acute sequelae of COVID-19, or long-COVID. medRxiv 2021.09.21.21263845; doi: https://doi.org/10.1101/2021.09.21.21263845.  (Full text available as PDF file)

COVID-19 immunopathology: From acute diseases to chronic sequelae

Abstract:

The clinical manifestation of coronavirus disease 2019 (COVID-19) mainly targets the lung as a primary affected organ, which is also a critical site of immune cell activation by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, recent reports also suggest the involvement of extrapulmonary tissues in COVID-19 pathology.

The interplay of both innate and adaptive immune responses is key to COVID-19 management. As a result, a robust innate immune response provides the first line of defense, concomitantly, adaptive immunity neutralizes the infection and builds memory for long-term protection. However, dysregulated immunity, both innate and adaptive, can skew towards immunopathology both in acute and chronic cases.

Here we have summarized some of the recent findings that provide critical insight into the immunopathology caused by SARS-CoV-2, in acute and post-acute cases. Finally, we further discuss some of the immunomodulatory drugs in preclinical and clinical trials for dampening the immunopathology caused by COVID-19.

Source: Arish M, Qian W, Narasimhan H, Sun J. COVID-19 immunopathology: From acute diseases to chronic sequelae. J Med Virol. 2022 Sep 3. doi: 10.1002/jmv.28122. Epub ahead of print. PMID: 36056655. https://onlinelibrary.wiley.com/doi/10.1002/jmv.28122 (Full text)

Low Prevalence of Interferon-α Autoantibodies in People Experiencing Long COVID Symptoms

Abstract:

Interferon (IFN)-specific autoantibodies have been implicated in severe COVID-19 and have been proposed as a potential driver of the persistent symptoms characterizing Long COVID, a type of post-acute sequelae of SARS-CoV-2 infection (PASC). We report than only two of 215 SARS-CoV-2 convalescent participants tested over 394 timepoints, including 121 people experiencing Long COVID symptoms, had detectable IFN-α2 antibodies. Both had been hospitalized during the acute phase of the infection. These data suggest that persistent anti-IFN antibodies, although a potential driver of severe COVID-19, are unlikely to contribute to Long COVID symptoms in the post-acute phase of the infection.

Source: Peluso MJ, Mitchell A, Wang CY, Takahashi S, Hoh R, Tai V, Durstenfeld MS, Hsue PY, Kelly JD, Martin JN, Wilson MR, Greenhouse B, Deeks SG, DeRisi JL, Henrich TJ. Low Prevalence of Interferon-α Autoantibodies in People Experiencing Long COVID Symptoms. J Infect Dis. 2022 Sep 12:jiac372. doi: 10.1093/infdis/jiac372. Epub ahead of print. PMID: 36089700.  https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac372/6696027 (Full text available as PDF file)

The majority of severe COVID-19 patients develop anti-cardiac autoantibodies

Abstract:

Severe cases of COVID-19 are characterized by an inflammatory burst, which is accompanied by multiorgan failure. The elderly population has higher risk for severe or fatal outcome for COVID-19. Inflammatory mediators facilitate the immune system to combat viral infection by producing antibodies against viral antigens. Several studies reported that the pro-inflammatory state and tissue damage in COVID-19 also promotes autoimmunity by autoantibody generation. We hypothesized that a subset of these autoantibodies targets cardiac antigens.

Here we aimed to detect anti-cardiac autoantibodies in severe COVID-19 patients during hospitalization. For this purpose, 104 COVID-19 patients were recruited, while 40 heart failure patients with dilated cardiomyopathy and 20 patients with severe aortic stenosis served as controls. Patients were tested for anti-cardiac autoantibodies, using human heart homogenate as a bait. Follow-up samples were available in 29 COVID-19 patients. Anti-cardiac autoantibodies were detected in 68% (71 out of 104) of severe COVID-19 patients.

Overall, 39% of COVID-19 patients had anti-cardiac IgG autoantibodies, while 51% had anti-cardiac autoantibodies of IgM isotype. Both IgG and IgM anti-cardiac autoantibodies were observed in 22% of cases, and multiple cardiac antigens were targeted in 38% of COVID-19 patients. These anti-cardiac autoantibodies targeted a diverse set of myocardial proteins, without apparent selectivity. As controls, heart failure patients (with dilated cardiomyopathy) had similar occurrence of IgG (45%, p = 0.57) autoantibodies, while significantly lower occurrence of IgM autoantibodies (30%, p = 0.03). Patients with advanced aortic stenosis had significantly lower number of both IgG (11%, p = 0.03) and IgM (10%, p < 0.01) type anti-cardiac autoantibodies than that in COVID-19 patients. Furthermore, we detected changes in the anti-cardiac autoantibody profile in 7 COVID-19 patients during hospital treatment.

Surprisingly, the presence of these anti-cardiac autoantibodies did not affect the clinical outcome and the prevalence of the autoantibodies did not differ between the elderly (over 65 years) and the patients younger than 65 years of age. Our results demonstrate that the majority of hospitalized COVID-19 patients produce novel anti-cardiac IgM autoantibodies. COVID-19 also reactivates resident IgG autoantibodies. These autoantibodies may promote autoimmune reactions, which can complicate post-COVID recuperation, contributing to post-acute sequelae of COVID-19 (long COVID).

Source: Fagyas M, Nagy B Jr, Ráduly AP, Mányiné IS, Mártha L, Erdősi G, Sipka S Jr, Enyedi E, Szabó AÁ, Pólik Z, Kappelmayer J, Papp Z, Borbély A, Szabó T, Balla J, Balla G, Bai P, Bácsi A, Tóth A. The majority of severe COVID-19 patients develop anti-cardiac autoantibodies. Geroscience. 2022 Sep 16:1–14. doi: 10.1007/s11357-022-00649-6. Epub ahead of print. PMID: 36112333; PMCID: PMC9483490. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9483490/ (Full text)

Severe fatigue as symptom of long COVID is characterized by increased expression of inflammatory genes in monocytes, increased serum pro-inflammatory cytokines, and increased CD8+ T-lymphocytes. A putative dysregulation of the immune-brain axis, the coagulation process, and auto-inflammation to explain the diversity of long COVID symptoms

Abstract:

Background. A significant proportion of patients with SARS-CoV-2 infection develops long COVID with fatigue as one of the most disabling symptoms. We performed clinical and immunologic profiling of fatigued and non-fatigued long COVID patients and age and gender matched healthy controls (HCs).

Methods. We included 37 long COVID patients with and 36 without severe fatigue and assessed inflammation-related monocyte gene expression, serum levels of inflammatory cytokines, and leukocyte and lymphocyte subsets 3-6 months after hospital discharge, and followed clinical symptoms up to one year.

Results. Long COVID with fatigue represented a severe variant with many symptoms (median 9 [IQR 5.0-10.0] symptoms) and signs of cognitive failure (41%) and depression (>24%). Symptoms persisted up to one year follow-up. Fatigued patients showed increased expression of inflammatory genes in monocytes, increased serum IL-6, TNF-α, galectin-9, and CXCL10, and increased CD8+ T-lymphocytes compared to HCs. Non-fatigued long COVID patients were arbitrarily divided in those with moderately severe disease (4 [2.5-5.0] symptoms, primarily impaired fitness, n=25) and those with mild disease (1 [1.0-2.0] symptom, n=11). Symptoms in non-fatigued long COVID patients persisted up to one year follow-up. Moderately severe patients showed reduced CD45RO- naive CD4+ T-lymphocytes and CD25+FOXP3+ regulatory CD4+ T-lymphocytes and limited monocyte and serum (galectin-9) inflammation. Mild patients showed monocyte and serum (IL-6, galectin-9) inflammation and decreased CD4+ T-lymphocyte subsets (T-helper 1 cells).

Conclusion. Long COVID with fatigue is associated with many concurrent and persistent symptoms up to one year after hospitalization and with clear signs of low grade inflammation and increased CD8+ T-lymphocytes. We showed that long COVID is a clinical and immunologic heterogeneous disorder. Diagnostic tools and personalized therapies combatting the diverse immune abnormalities might be required to alleviate the persisting disabling complaints of the patients.

Source: Julia C Berentschot, Hemmo A Drexhage, Daniel A Aynekulu Mersha, Annemarie JM Wijkhuijs, Corine H GeurtsvanKessel, Marion PG Koopmans, Jolanda Voermans, Majanka H Heijenbrok-Kal, L. Martine Bek, Gerard M Ribbers, Rita JG van den Berg-Emons, Joachim GJV Aerts, Willem A Dik, Merel E Hellemons. Severe fatigue as symptom of long COVID is characterized by increased expression of inflammatory genes in monocytes, increased serum pro-inflammatory cytokines, and increased CD8+ T-lymphocytes. A putative dysregulation of the immune-brain axis, the coagulation process, and auto-inflammation to explain the diversity of long COVID symptoms.  medRxiv 2022.09.15.22279970; doi: https://doi.org/10.1101/2022.09.15.22279970 (Full text available as PDF file)

The long COVID syndrome: A conundrum for the allergist/immunologist

Abstract:

Background: The long coronavirus disease 2019 (COVID-19) syndrome includes a group of patients who, after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit lingering mild-to-moderate symptoms and develop medical complications that can have lasting health problems.

Objective: The purpose of this report was to examine the current body of evidence that deals with the relationship of COVID-19 infection with the long COVID syndrome to define the possible immunologic mechanisms involved in the pathogenesis of long COVID and to describe potential strategies for the diagnosis and clinical management of the condition.

Methods: Extensive research was conducted in medical literature data bases by applying terms such as long COVID, post-COVID-19 condition, pathogenesis of long COVID, management of the long COVID syndrome.

Results: The post-COVID conditions, a more recent and less anxiety-inducing term for the patient than long COVID or “long haul,” is an umbrella term for a wide range of physical and mental health symptoms similar to those seen in patients with the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), experienced by some patients and are present ≥ 4 weeks after SARS-CoV-2 infection. Although the precise reason why long COVID develops is unknown, one of the major causes is thought to be related to chronic inflammation with overproduction of inflammatory cytokines responsible for the symptoms of the disorder.

Conclusion: Long COVID is a growing burden for millions of patients, health-care providers, and global health-care systems, and is a particular challenge for the allergist/immunologist. Many survivors of COVID-19 struggle with multiple symptoms, increased disability, reduced function, and poor quality of life. The allergist/immunologist can assist the total health-care team’s efforts in providing a comprehensive and coordinated approach to the management of these patients by promoting comprehensive vaccination and rehabilitation and social services that focus on improving physical, mental, and social well-being, and by establishing partnerships with specialists and other health-care professionals who can provide behavioral, lifestyle, and integrative approaches that may have much to offer in helping patients cope with their symptoms.

Source: Bellanti JA. The long COVID syndrome: A conundrum for the allergist/immunologist. Allergy Asthma Proc. 2022 Sep 1;43(5):368-374. doi: 10.2500/aap.2022.43.220059. PMID: 36065103. https://www.ingentaconnect.com/content/ocean/aap/2022/00000043/00000005/art00007;jsessionid=2d46805mm1b04.x-ic-live-02 (Full text available as PDF file)

Symptom burden and immune dynamics 6 to 18 months following mild SARS-CoV-2 infection -a case-control study

Abstract:

Background: The burden and duration of persistent symptoms after non-severe COVID-19 remains uncertain. This study aimed to assess post-infection symptom trajectories in home-isolated COVID-19 cases compared to age- and time-period matched seronegative controls, and investigate immunological correlates of long COVID.

Methods: A prospective case-control study conducted between February 28th and April 4th 2020 included home-isolated COVID-19 cases followed for 12 (n = 233) to 18 (n = 149) months, and 189 age-matched SARS-CoV-2 naive controls. We collected clinical data at baseline, 6, 12 and 18 months post-infection, and blood samples at 2, 4, 6 and 12 months for analysis of SARS-CoV-2 specific humoral and cellular responses.

Results: Overall, 46% (108/233) had persisting symptoms 12 months after COVID-19. Compared to controls, adult cases had a high risk of fatigue (27% excess risk, gender and comorbidity adjusted odds ratio [aOR] 5.86, 95% confidence interval [CI]3.27-10.5), memory problems (21% excess risk, aOR 7.42, CI 3.51-15.67), concentration problems (20% excess risk, aOR 8.88, CI 3.88-20.35), and dyspnea (10% excess risk, aOR 2.66, CI 1.22-5.79). The prevalence of memory problems increased overall from 6 to 18 months (excess risk 11.5%, CI 1.5, 21.5, p = 0.024) and among women (excess risk 18.7%, CI 4.4, 32.9, p = 0.010). Longitudinal spike IgG was significantly associated with dyspnea at 12 months. The spike-specific clonal CD4 + TCRβ depth was significantly associated with both dyspnea and number of symptoms at 12 months.

Conclusions: This study documents a high burden of persisting symptoms after mild COVID-19, and suggest that infection induced SARS-CoV-2 specific immune responses may influence long-term symptoms.

Source: Fjelltveit EB, Blomberg B, Kuwelker K, Zhou F, Onyango TB, Brokstad KA, Elyanow R, Kaplan IM, Tøndel C, Mohn KGI, Özgümüş T, Cox RJ, Langeland N; Bergen COVID-19 Research Group. Symptom burden and immune dynamics 6 to 18 months following mild SARS-CoV-2 infection -a case-control study. Clin Infect Dis. 2022 Aug 12:ciac655. doi: 10.1093/cid/ciac655. Epub ahead of print. PMID: 35959897; PMCID: PMC9384725. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9384725/ (Full text)

Mast cell activation syndrome and the link with long COVID

Abstract:

Mast cells are innate immune cells found in connective tissues throughout the body, most prevalent at tissue-environment interfaces. They possess multiple cell-surface receptors which react to various stimuli and, after activation, release many mediators including histamine, heparin, cytokines, prostaglandins, leukotrienes and proteases.

In mast cell activation syndrome, excessive amounts of inflammatory mediators are released in response to triggers such as foods, fragrances, stress, exercise, medications or temperature changes. Diagnostic markers may be difficult to assess because of their rapid degradation; these include urinary N-methyl histamine, urinary prostaglandins D2, DM and F2α and serum tryptase (which is stable) in the UK. Self-management techniques, medications and avoiding triggers may improve quality of life. Treatments include mast cell mediator blockers, mast cell stabilisers and anti-inflammatory agents. ‘Long COVID’ describes post-COVID-19 syndrome when symptoms persist for more than 12 weeks after initial infection with no alternative diagnosis.

Both mast cell activation syndrome and long COVID cause multiple symptoms. It is theorised that COVID-19 infection could lead to exaggeration of existing undiagnosed mast cell activation syndrome, or could activate normal mast cells owing to the persistence of viral particles. Other similarities include the relapse-remission cycle and improvements with similar treatments. Importantly, however, aside from mast cell disorders, long COVID could potentially be attributed to several other conditions.

Source: Arun S, Storan A, Myers B. Mast cell activation syndrome and the link with long COVID. Br J Hosp Med (Lond). 2022 Jul 2;83(7):1-10. doi: 10.12968/hmed.2022.0123. Epub 2022 Jul 26. PMID: 35938771. https://pubmed.ncbi.nlm.nih.gov/35938771/