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

Background: The 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. Methods: Prospective, 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. Results: Of 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. Conclusion: Patients 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.

Robust long-term immunity to SARS-CoV-2 in patients recovered from severe COVID-19 after interleukin-6 blockade.

BACKGROUND: Whether interleukin-6 (IL-6) blockade in patients with COVID-19 will affect the protective immunity against SARS-CoV-2 has become an important concern for anti-IL-6 therapy. We aimed to investigate the effects of IL-6 blockade on long-term immunity to SARS-CoV-2. METHODS: Prospective, longitudinal cohort study conducted in patients hospitalized for severe or critical COVID-19 with laboratory confirmed SARS-CoV-2 infection. We assessed humoral (anti-S1 domain of the spike [S], anti-nucleocapsid [N], anti-trimeric spike [TrimericS] IgG, and neutralizing antibodies [Nab]) and T-cell (interferon-γ release assay [IGRA]) responses and evaluated the incidence of reinfections over one year after infection in patients undergoing IL-6 blockade with tocilizumab and compared them with untreated subjects. FINDINGS: From 150 adults admitted with confirmed SARS-CoV-2 infection, 78 were 1:1 propensity score-matched. Patients receiving anti-IL6 therapy showed a shorter time to S-IgG seropositivity and stronger S-IgG and N-IgG antibody responses. Among unvaccinated subjects one year after infection, median (Q1-Q3) levels of TrimericS-IgG (295 vs 121 BAU/mL; p = 0.011) and Nab (74.7 vs 41.0 %IH; p = 0.012) were higher in those undergoing anti-IL6 therapy, and a greater proportion of them had Nab (80.6% vs 57.7%; p = 0.028). T-cell immunity was also better in those treated with anti-IL6, with higher median (Q1-Q3) interferon-γ responses (1760 [702-3992] vs 542 [35-1716] mIU/mL; p = 0.013) and more patients showing positive T-cell responses in the IGRA one year after infection. Patients treated with anti-IL6 had fewer reinfections during follow-up and responded to vaccination with robust increase in both antibody and T-cell immunity. INTERPRETATION: IL-6 blockade in patients with severe COVID-19 does not have deleterious effects on long-term immunity to SARS-CoV-2. The magnitude of both antibody and T-cell responses was stronger than the observed in non-anti-cytokine-treated patients with no increase in the risk of reinfections. FUNDING: Instituto de Salud Carlos-III (Spain).

Preemptive interleukin-6 blockade in patients with COVID-19.

Excessive interleukin-6 signaling is a key factor contributing to the cytokine release syndrome implicated in clinical manifestations of COVID-19. Preliminary results suggest that tocilizumab, a humanized monoclonal anti-interleukin-6 receptor antibody, may be beneficial in severely ill patients, but no data are available on earlier stages of disease. An anticipated blockade of interleukin-6 might hypothetically prevent the catastrophic consequences of the overt cytokine storm. We evaluated early-given tocilizumab in patients hospitalized with COVID-19, and identified outcome predictors. Consecutive patients with initial Sequential-Organ-Failure-Assessment (SOFA) score < 3 fulfilling pre-defined criteria were treated with tocilizumab. Serial plasma biomarkers and nasopharyngeal swabs were collected. Of 193 patients admitted with COVID-19, 64 met the inclusion criteria. After tocilizumab, 49 (76.6%) had an early favorable response. Adjusted predictors of response were gender, SOFA score, neutrophil/lymphocyte ratio, Charlson comorbidity index and systolic blood pressure. At week-4, 56.1% of responders and 30% of non-responders had cleared the SARS-CoV-2 from nasopharynx. Temporal profiles of interleukin-6, C-reactive protein, neutrophil/lymphocyte ratio, NT-ProBNP, D-dimer, and cardiac-troponin-I differed according to tocilizumab response and discriminated final in-hospital outcome. No deaths or disease recurrences were observed. Preemptive therapy with tocilizumab was safe and associated with favorable outcomes in most patients. Biological and clinical markers predicted outcomes.

Impact of interleukin-6 blockade with tocilizumab on SARS-CoV-2 viral kinetics and antibody responses in patients with COVID-19: A prospective cohort study.

BACKGROUND: The virological and immunological effects of the immunomodulatory drugs used for COVID-19 remain unknown. We evaluated the impact of interleukin (IL)-6 blockade with tocilizumab on SARS-CoV-2 viral kinetics and the antibody response in patients with COVID-19. METHODS: Prospective cohort study in patients admitted with COVID-19. Serial nasopharyngeal and plasma samples were measured for SARS-CoV-2 RNA and S-IgG/N-IgG titers, respectively. FINDINGS: 138 patients with confirmed infection were included; 76 (55%) underwent IL-6 blockade. Median initial SOFA (p = 0•016) and SARS-CoV-2 viral load (p<0•001, Mann-Whitney-Wilcoxon test) were significantly higher among anti-IL-6 users. Patients under IL-6 blockade showed delayed viral clearance in the Kaplan-Meier curves (HR 0•35 [95%CI] [0•15-0•81], log-rank p = 0•014), but an adjusted propensity score matching model did not demonstrate a significant relationship of IL-6 blockade with viral clearance (HR 1•63 [0•35-7•7]). Cox regression showed an inverse association between SARS-CoV-2 RNA clearance and the initial viral load (HR 0•35 [0•11-0•89]). Patients under the IL-6 blocker showed shorter median time to seropositivity, higher peak antibody titers, and higher cumulative proportion of seropositivity in the Kaplan Meier curves (HR 3•1 [1•9-5] for S-IgG; and HR 3•0 [1•9-4•9] for N-IgG; log-rank p<0•001 for both). However, no significant differences between groups were found in either S-IgG (HR 1•56 [0•41-6•0]) nor N-IgG (HR 0•96 [0•26-3•5]) responses in an adjusted propensity score analysis. INTERPRETATION: Our results suggest that in patients infected with SARS-CoV-2, IL-6 blockade does not impair the viral specific antibody responses. Although a delayed viral clearance was observed, it was driven by a higher initial viral load. The study supports the safety of this therapy in patients with COVID-19. FUNDING: Instituto de salud Carlos III (Spain).

Infection With Chlamydia trachomatis Increases the Risk of High-grade Anal Intraepithelial Neoplasia in People Living With Human Immunodeficiency Virus.

BACKGROUND: We aimed to assess the relationship between sexually transmitted infections (STIs)-including a large panel of human papillomavirus (HPV) genotypes-and high-grade anal intraepithelial neoplasia (HGAIN) in men who have sex with men (MSM) who were living with human immunodeficiency virus (HIV). METHODS: In a prospective study in an HIV cohort, participants underwent high-resolution anoscopy (HRA) for anorectal swabs collection to investigate STIs and for anal biopsy. Multiplex real-time polymerase chain reactions were performed, detecting several STIs and 28 HPV genotypes. Univariate and multivariate generalized linear models were used to analyze the relationships of variables of interest with HGAIN. RESULTS: There were 145 participants included; in 49, 2 HRAs were performed. Ureaplasma urealyticum (UU) was detected in 25 (17.2%) participants, Chlamydia trachomatis (CT) in 13 (9.0%), Mycoplasma genitalium (MG) in 4 (2.8%), HPV16 in 38 (26.2%), HPV52 in 29 (20%), and HPV53 and HPV42 in 28 (19.3%) participants each. There were 35 (24.1%) subjects diagnosed with HGAIN. In the univariate analysis, HGAIN was associated with CT, UU, MG, HPV16, HPV53, HPV68, and HPV70, and significant interactions were found between CT and HPV16 (odds ratio [OR] 31.0 95% confidence interval [CI] 4.3-221.7) and between UU and HPV16 (OR 8.8, 95% CI 2.1-37.5). In the adjusted model, CT, HPV16, HPV53, HPV70, the CD4+/CD8+ ratio, and the interaction between CT and HPV16 remained independent predictors of HGAIN. HPV16, HPV53, and HPV70 persisted in the second HRA in all the participants with recurrent HGAIN. CONCLUSIONS: Coinfection with CT may potentiate the oncogenic capability of HPV16 and increase the risk of HGAIN in people with HIV. HPV53 and HPV70 should be considered among the genotypes associated with HGAIN.