Corrigendum: Brief Research Report: Virus-Specific Humoral Immunity at Admission Predicts the Development of Respiratory Failure in Unvaccinated SARS-CoV-2 Patients.

[This corrects the article DOI: 10.3389/fimmu.2022.878812.].

Brief Research Report: Virus-Specific Humoral Immunity at Admission Predicts the Development of Respiratory Failure in Unvaccinated SARS-CoV-2 Patients.

Introduction: There is robust evidence indicating that the SARS-CoV-2-specific humoral response is associated with protection against severe disease. However, relatively little data exist regarding how the humoral immune response at the time of hospital admission correlates with disease severity in unimmunized patients. Our goal was toidentify variables of the humoral response that could potentially serve as prognostic markers for COVID-19 progressionin unvaccinated SARS-CoV-2 patients. Methods: A prospective cross-sectional study was carried out in a cohort of 160 unimmunized, adult COVID-19 patients from the Hospital Universitario 12Octubre. Participants were classified into four clinical groups based on disease severity: non-survivors with respiratory failure (RF), RF survivors, patients requiring oxygen therapy and those not receiving oxygen therapy. Serum samples were taken on admission and IgM, IgG, IgG subclass antibody titers were determined by ELISA, and neutralizing antibody titersusing a surrogate neutralization assay. The differences in the antibody titers between groups and the association between the clinical and analytical characteristics of the patients and the antibody titers were analyzed. Results: Patients that developed RF and survived had IgM titers that were 2-fold higher than non-survivors (p = 0.001), higher levels of total IgG than those who developed RF and succumbed to infection (p< 0.001), and than patients who required oxygen therapy (p< 0.05), and had 5-fold higher IgG1 titers than RF non-survivors (p< 0.001) and those who needed oxygen therapy (p< 0.001), and 2-fold higher than patients that did not require oxygen therapy during admission (p< 0.05). In contrast, RF non-survivorshad the lowest neutralizing antibodylevels, which were significantly lower compared those with RF that survived (p = 0.03). A positive correlation was found between IgM, total IgG, IgG1 and IgG3 titers and neutralizing antibody titers in the total cohort (p ≤ 0.0036). Conclusions: We demonstrate that patients with RF that survived infection had significantly higher IgM, IgG, IgG1 and neutralizing titers compared to patients with RF that succumb to infection, suggesting that using humoral response variables could be used as a prognostic marker for guiding the clinical management of unimmunized patients admitted to the hospital for SARS-CoV-2 infection.

Tocilizumab therapy in SARS-CoV-2 pneumonia: A matched retrospective cohort analysis Tocilizumab en el tratamiento de la neumonía por SARS-CoV-2: análisis de una cohorte retrospectiva pareada

Background The effect of immunomodulatory therapy with tocilizumab for coronavirus disease 2019 (COVID-19) in real-life clinical practice remains controversial. Methods Single-center retrospective matched cohort analysis including 47 consecutive patients treated with intravenous tocilizumab for severe COVID-19 pneumonia (“TCZ group”), matched by age, comorbidities, time from symptoms onset and baseline SpO2/FiO2 ratio with 47 patients receiving standard of care alone (“SoC group”). Results There were no significant differences between the TCZ and SoC groups in the rate of clinical improvement (hospital discharge and/or a decrease of ≥2 points on a six-point ordinal scale) by day 7 (51.1% [24/47] versus 48.9% [23/47];P-value = 1.000). No differences were observed at day 14 in terms of clinical improvement (72.3% versus 76.6%;P-value = 0.791), all-cause mortality (10.6% versus 12.8%;P-value = 1.000), and the composite of invasive mechanical ventilation and/or death (25.5% versus 23.4%;P-value = 1.000) either. Patients in the TCZ group had a more rapid normalization of C-reactive protein levels. Conclusions No apparent benefit was observed in patients with severe COVID-19 treated with tocilizumab as compared to a matched retrospective cohort.

Analysis of the factors predicting clinical response to tocilizumab therapy in patients with severe COVID-19.

BACKGROUND: Controversy remains about the efficacy of tocilizumab (TCZ) for the treatment of severe COVID-19. We aimed to analyze the profile of TCZ-respondent patients. METHODS: We retrospectively analyzed a cohort of patients with severe COVID-19 who received off-label TCZ after recommendation by a local committee and were admitted to the University Hospital "12 de Octubre" until May 2020. The primary end point was a significant clinical improvement (SCI) on day 14 after administration of TCZ. Factors independently related to SCI were analyzed by multivariate logistic regression models. RESULTS: Of 428 (63.3%) patients treated with TCZ, 271 (63.3%) experienced SCI. After adjustment for factors related to unfavorable outcomes, TCZ administration within the first 48 hours from admission (odds ratio [OR]: 1.98, 95% confidence Interval [95% CI]: 1.1-3.55; P = 0.02) and ALT levels >100 UI/L at day 0 (OR: 3.28; 95% CI: 1.3-8.1; P = 0.01) were independently related to SCI. The rate of SCI significantly decreased according to the time of TCZ administration: 70.2% in the first 48 hours from admission, 58.5% on days 3-7, and 45.1% after day 7 (P = 0.03 and P = 0.001, respectively). CONCLUSION: TCZ improves the prognosis of patients with COVID-19 the most if treatment starts within the first 48 hours after admission.

Discordance Between SARS-CoV-2-specific Cell-mediated and Antibody Responses Elicited by mRNA-1273 Vaccine in Kidney and Liver Transplant Recipients.

Severe acute respiratory syndrome coronavirus 2-specific cell-mediated immunity (SARS-CoV-2-CMI) elicited by mRNA-based vaccines in solid organ transplant (SOT) recipients and its correlation with antibody responses remain poorly characterized. METHODS: We included 44 (28 kidney, 14 liver, and 2 double organ) recipients who received the full series of the mRNA-1273 vaccine. SARS-CoV-2-CMI was evaluated at baseline, before the second dose, and at 2 wk after completion of vaccination by an ELISpot-based interferon-γ FluoroSpot assay using overlapping peptides covering the S1 domain. SARS-CoV-2 immunoglobulin G seroconversion and serum neutralizing activity against the spike protein were assessed at the same points by commercial ELISA and an angiotensin-converting enzyme-2/spike antibody inhibition method, respectively. Postvaccination SARS-CoV-2-CMI was compared with 28 healthcare workers who received the BNT162b2 vaccine. RESULTS: Positive SARS-CoV-2-CMI increased from 6.8% at baseline to 23.3% after the first mRNA-1273 dose and 59.5% after the completion of vaccination (P < 0.0001). Lower rates were observed for immunoglobulin G seroconversion (2.3%, 18.6%, and 57.1%, respectively) and neutralizing activity (2.3%, 11.6%, and 31.0%). There was a modest correlation between neutralizing titers and the magnitude of SARS-CoV-2-CMI (Spearman's rho: 0.375; P = 0.015). Fifteen recipients (35.7%) mounted SARS-CoV-2-CMI without detectable neutralizing activity, whereas 3 (7.1%) did the opposite, yielding poor categorical agreement (Kappa statistic: 0.201). Rates of positive SARS-CoV-2-CMI among SOT recipients were significantly decreased compared with nontransplant controls (82.1% and 100.0% after the first dose and completion of vaccination, respectively; P < 0.0001). Kidney transplantation, the use of tacrolimus and prednisone, and the number of immunosuppressive agents were associated with lower cell-mediated responses. Results remained unchanged when 3 recipients with prevaccination SARS-CoV-2-CMI were excluded. CONCLUSIONS: Two-thirds of SOT recipients mounted SARS-CoV-2-CMI following vaccination with mRNA-1273. Notable discordance was observed between vaccine-induced cell-mediated and neutralizing humoral immunities. Future studies should determine whether these patients with incomplete responses are effectively protected.

Immunogenicity of Anti-SARS-CoV-2 Vaccines in Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and/or a defective antibody response to T-dependent and T-independent antigens. CVID response to immunization depends on the antigen type, the vaccine mechanism, and the specific patient immune defect. In CVID patients, humoral and cellular responses to the currently used COVID-19 vaccines remain unexplored. Eighteen CVID subjects receiving 2-dose anti-SARS-CoV-2 vaccines were prospectively studied. S1-antibodies and S1-specific IFN-γ T cell response were determined by ELISA and FluoroSpot, respectively. The immune response was measured before the administration and after each dose of the vaccine, and it was compared to the response of 50 healthy controls (HC). The development of humoral and cellular responses was slower in CVID patients compared with HC. After completing vaccination, 83% of CVID patients had S1-specific antibodies and 83% had S1-specific T cells compared with 100% and 98% of HC (p = 0.014 and p = 0.062, respectively), but neutralizing antibodies were detected only in 50% of the patients. The strength of both humoral and cellular responses was significantly lower in CVID compared with HC, after the first and second doses of the vaccine. Absent or discordant humoral and cellular responses were associated with previous history of autoimmunity and/or lymphoproliferation. Among the three patients lacking humoral response, two had received recent therapy with anti-B cell antibodies. Further studies are needed to understand if the response to COVID-19 vaccination in CVID patients is protective enough. The 2-dose vaccine schedule and possibly a third dose might be especially necessary to achieve full immune response in these patients.

Tocilizumab therapy in SARS-CoV-2 pneumonia: A matched retrospective cohort analysis.

BACKGROUND: The effect of immunomodulatory therapy with tocilizumab for coronavirus disease 2019 (COVID-19) in real-life clinical practice remains controversial. METHODS: Single-center retrospective matched cohort analysis including 47 consecutive patients treated with intravenous tocilizumab for severe COVID-19 pneumonia ("TCZ group"), matched by age, comorbidities, time from symptoms onset and baseline SpO2/FiO2 ratio with 47 patients receiving standard of care alone ("SoC group"). RESULTS: There were no significant differences between the TCZ and SoC groups in the rate of clinical improvement (hospital discharge and/or a decrease of ≥2 points on a six-point ordinal scale) by day 7 (51.1% [24/47] versus 48.9% [23/47]; P-value=1.000). No differences were observed at day 14 in terms of clinical improvement (72.3% versus 76.6%; P-value=0.791), all-cause mortality (10.6% versus 12.8%; P-value=1.000), and the composite of invasive mechanical ventilation and/or death (25.5% versus 23.4%; P-value=1.000) either. Patients in the TCZ group had a more rapid normalization of C-reactive protein levels. CONCLUSIONS: No apparent benefit was observed in patients with severe COVID-19 treated with tocilizumab as compared to a matched retrospective cohort.

IL-6-based mortality prediction model for COVID-19: Validation and update in multicenter and second wave cohorts.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a highly variable condition. Validated tools to assist in the early detection of patients at high risk of mortality can help guide medical decisions. OBJECTIVE: We sought to validate externally, as well as in patients from the second pandemic wave in Europe, our previously developed mortality prediction model for hospitalized COVID-19 patients. METHODS: Three validation cohorts were generated: 2 external with 185 and 730 patients from the first wave and 1 internal with 119 patients from the second wave. The probability of death was calculated for all subjects using our prediction model, which includes peripheral blood oxygen saturation/fraction of inspired oxygen ratio, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, IL-6, and age. Discrimination and calibration were evaluated in the validation cohorts. The prediction model was updated by reestimating individual risk factor effects in the overall cohort (N = 1477). RESULTS: The mortality prediction model showed good performance in the external validation cohorts 1 and 2, and in the second wave validation cohort 3 (area under the receiver-operating characteristic curve, 0.94, 0.86, and 0.86, respectively), with excellent calibration (calibration slope, 0.86, 0.94, and 0.79; intercept, 0.05, 0.03, and 0.10, respectively). The updated model accurately predicted mortality in the overall cohort (area under the receiver-operating characteristic curve, 0.91), which included patients from both the first and second COVID-19 waves. The updated model was also useful to predict fatal outcome in patients without respiratory distress at the time of evaluation. CONCLUSIONS: This is the first COVID-19 mortality prediction model validated in patients from the first and second pandemic waves. The COR+12 online calculator is freely available to facilitate its implementation (https://utrero-rico.shinyapps.io/COR12_Score/).

Combination therapy with tocilizumab and corticosteroids for aged patients with severe COVID-19 pneumonia: A single-center retrospective study.

BACKGROUND: The role of combination immunomodulatory therapy with systemic corticosteroids and tocilizumab (TCZ) for aged patients with COVID-19-associated cytokine release syndrome remains unclear. METHODS: A retrospective single-center study was conducted on consecutive patients aged ≥65 years who developed severe COVID-19 between 03 March and 01 May 2020 and were treated with corticosteroids at various doses (methylprednisolone 0.5mg/kg/12h to 250mg/24h), either alone (CS group) or associated with intravenous tocilizumab (400-600mg, one to three doses) (CS-TCZ group). The primary outcome was all-cause mortality by day +14, whereas secondary outcomes included mortality by day +28 and clinical improvement (discharge and/or a ≥2 point decrease on a 6-point ordinal scale) by day +14. Propensity score (PS)-based adjustment and inverse probability of treatment weights (IPTW) were applied. RESULTS: Totals of 181 and 80 patients were included in the CS and CS-TCZ groups, respectively. All-cause 14-day mortality was lower in the CS-TCZ group, both in the PS-adjusted (hazard ratio [HR]: 0.34; 95% confidence interval [CI]: 0.17-0.68; P=0.002) and IPTW-weighted models (odds ratio [OR]: 0.38; 95% CI: 0.21-0.68; P=0.001). This protective effect was also observed for 28-day mortality (PS-adjusted HR: 0.38; 95% CI: 0.21-0.72; P=0.003). Clinical improvement by day +14 was higher in the CS-TCZ group with IPTW analysis only (OR: 2.26; 95% CI: 1.49-3.41; P<0.001). The occurrence of secondary infection was similar between both groups. CONCLUSIONS: The combination of corticosteroids and TCZ was associated with better outcomes among patients aged ≥65 years with severe COVID-19.

Effectiveness of anakinra for tocilizumab-refractory severe COVID-19: A single-centre retrospective comparative study.

OBJECTIVES: A subgroup of patients with SARS-CoV-2 infection was thought to have developed cytokine release syndrome and were treated with tocilizumab; however, a significant percentage of patients evolved. This study aimed to determine the usefulness of anakinra as a rescue treatment for patients with tocilizumab-refractory COVID-19 disease. METHODS: A prospective cohort of patients with COVID-19 pneumonia who received anakinra as salvage therapy after failure of tocilizumab were compared (1:1) with selected controls in a historical cohort of patients treated with tocilizumab. Cases and controls were matched by age, comorbidities, pulse oximetry oxygen saturation to fraction of inspired oxygen (SpO2/FiO2) ratio at baseline, and time elapsed since the initiation of treatment with tocilizumab. The primary outcome was the improvement in clinical status measured by a 6-point ordinal scale, from baseline to day 21. RESULTS: The study included 20 cases and 20 controls (mean age 65.3 ± 12.8 years, 65% males). No differences were found in the clinical improvement rates at 7, 14 and 21 days of follow-up. The in-hospital mortality rate for patients receiving anakinra was 55% vs. 45% in the control group (P = 0.527). CONCLUSIONS: Treatment with anakinra was not useful in improving the prognosis of patients with tocilizumab-refractory severe COVID-19.

Impact of viral load at admission on the development of respiratory failure in hospitalized patients with SARS-CoV-2 infection.

The aim of our study was to elucidate if SARS-CoV-2 viral load on admission, measured by real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) cycle threshold (Ct) value on nasopharyngeal samples, was a marker of disease severity. All hospitalized adult patients with a diagnosis of SARS-CoV-2 infection by rRT-PCR performed on a nasopharingeal sample from March 1 to March 18 in our institution were included. The study population was divided according to the Ct value obtained upon admission in patients with high viral load (Ct < 25), intermediate viral load (Ct: 25-30) and low viral load (Ct > 30). Demographic, clinical and laboratory variables of the different groups were analyzed to assess the influence of viral load on the development of respiratory failure during admission. Overall, 455 sequential patients were included. The median Ct value was 28 (IQR: 24-32). One hundred and thirty patients (28.6%) had a high viral load, 175 (38.5%) an intermediate viral load and 150 (33%) a low viral load. Advanced age, male sex, presence of cardiovascular disease and laboratory markers such as lactate dehydrogenase, lymphocyte count and C-reactive protein, as well as a high viral load on admission, were predictive of respiratory failure. A Ct value < 25 was associated with a higher risk of respiratory failure during admission (OR: 2.99, 95%IC: 1.57-5.69). SARS-CoV-2 viral load, measured through the Ct value on admission, is a valuable tool to predict the development of respiratory failure in COVID-19 inpatients.