Immunologic phenotype of patients with long-COVID syndrome of 1-year duration

Abstract

BackgroundThe pathophysiology of long-COVID remains unknown, and information is particularly limited for symptoms of very long duration. We aimed to assess the serological, T-cell immune responses and ANA titers of patients with long-COVID-19 syndrome of 1-year duration.MethodsProspective, longitudinal study of hospitalized COVID-19 patients followed-up for 12 months. Sequential blood samples and COVID-19 symptom questionnaires (CSQ) were obtained, and humoral and cellular immune responses, antinuclear antibodies (ANA) and inflammation biomarkers were analyzed.ResultsOf 154 patients discharged from hospital, 72 non-vaccinated with available CSQ in all visits were included. Of them, 14 (19.4%) reported persistent symptoms both at 6-months and 12-months, mainly asthenia (15.3%), myalgia (13.9%), and difficulty concentrating/memory loss (13.9%). Symptomatic patients were more frequently women, smokers, showed higher WHO severity score, and a trend to higher ICU admission. In the adjusted analysis, long-COVID syndrome was associated with lower frequency of detectable neutralizing antibodies (adjusted hazard ratio [aHR] 0.98; 95% confidence interval [CI], 0.97-0.99) and lower SARS-CoV-2-S1/S2 titers (aHR [95%CI] 0.14 [0.03–0.65]). T-cell immune response measured with a SARS-CoV-2-interferon-γ release assay was not different between groups. There was a higher frequency of positive ANA titers (≥160) in symptomatic patients (57.1% vs 29.3%, p=0.04), that was attenuated after adjustment aHR [95% CI] 3.37 [0.84-13.57], p=0.087. Levels of C-reactive protein and D-dimer were higher during follow-up in symptomatic patients, but with no differences at 12 months.ConclusionPatients with 1-year duration long-COVID-19 syndrome exhibit a distinct immunologic phenotype that includes a poorer SARS-CoV-2 antibody response, low-degree chronic inflammation that tends to mitigate, and autoimmunity.

COVID-19 therapy and vaccination: a clinical narrative review

“… 67 Poorer SARS-CoV-2 antibody response was noticed in those with 1-year duration long COVID syndrome. 68 …”

Cellular and molecular biomarkers of long COVID: a scoping review

“… 83 In addition, LC patients exhibit higher levels of specific immunoglobulins and lymphocytes against SARS-CoV-2 proteins, emphasizing a possible viral persistence, which has been previously reported in LC patients. 84 The sustained activation of the immune response as a result of prolonged exposure to viral antigens leads to the development of autoimmune diseases, 79 consistent with the auto-antibodies identified by the studies 34 , 55 included in this scoping review. Furthermore, Tregs, which inhibit the overactivation of T cells and maintain the immune system balance in autoimmune and inflammatory diseases, 80 are increased in LC patients for up to 11 months compared to recovered individuals, 34 , 64 but decreased when compared to healthy individuals at the acute phase 60 (consistent with another study 80 ).…”

“…The studies varied in their definition of LC as occurring between 1 33 , 34 , 44 , 45 , 49 , 50 , 51 and 12 52 months after the acute infection ( Supplementary Table S1 ). The instruments used to diagnose LC consisted primarily of patient-reported outcomes (PRO) questionnaires, study-specific questionnaires, 33 , 34 , 40 , 50 , 51 , 53 , 54 , 55 , 56 a CDC questionnaire, 31 , 43 , 44 the NICE guidelines, 57 or other criteria. 29 , 46 , 52 The symptoms of LC most reported across the studies (presented as median percentage across the studies/number of studies reporting the variable) were fatigue (43.8%; 15/23), dyspnea (30.0%; 13/23), anosmia/ageusia (20.40%; 12/23), cough (17.8%; 11/23), and chest pain (17.9%; 10/23), myalgia (30.8%; 8/23), sleep disorder (29.1%; 8/23), among others ( Table 1 ).…”

“… 50 At 12 months titers of SARS-CoV-2 S1/S2 IgG decreased in LC patients; however, increased autoimmunity related immunoglobulins, such as antinuclear antibodies (ANA) were associated with LC (HR 3.37 [95% CI 0.84–13.57]). 55 In addition, a proteomic analysis of microclots from blood samples of LC patients identified 23 significantly increased immunoglobulins ( Supplementary Table S1 ). 42 …”

The Challenge of Long COVID-19 Management: From Disease Molecular Hallmarks to the Proposal of Exercise as Therapy

“…Autoimmunity has also been related to molecular mimicry between peptides belonging to SARS-CoV-2 S glycoprotein and some human antigens particularly expressed by endocrine glands or cells such as the pituitary, adrenal glands [ 71 ], thyroid, and pancreatic beta-cells [ 72 ]. Recently, a characteristic immunologic profile characterized by low levels of neutralizing and anti-S antibodies with high anti-nuclear autoantibodies (ANA) and inflammatory markers was detected in patients reporting long COVID-19 symptoms for 1-year, demonstrating the presence of long-term immune system perturbations and autoimmunity [ 73 ].…”