COVID-19 in intensive care medicine.

The coronavirus disease 2019 (COVID-19) pandemic can lead to a severe course of disease in immunosuppressed patients requiring intensive care unit treatment even though a number of new vaccines and new antiviral drugs exist. One of the main reasons for this is the generally poorer immune response under immunosuppression. Therefore, it is all the more important to know the stages of the disease and to select the currently available therapeutic options accordingly.Copyright © 2023, The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.

Antiviral T-cell frequencies in a healthy population: Reference values for evaluating antiviral immune cell profiles in immunocompromised patients and their application during the SARS-CoV-2 pandemic

Background: Viral infections and reactivations (e.g. cytomegalovirus (CMV)) are a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT) and in patients with immunodeficiencies. Here, antiviral drugs are the mainstay of treatment, but they have side effects and cannot achieve complete viral clearance without prior reconstitution of functional virus-specific T cells (VSTs). Method(s): We performed serological testing and measured VST frequencies against 23 viral protein-derived peptide pools of 11 clinically relevant human viruses by Interferon-gamma (IFN-gamma) ELISpot assay in a cohort of healthy donors (n=151). Moreover, we performed in-depth immune profiling in patients actively infected with SARS-CoV-2 (n=92) and in unvaccinated, recovered COVID-19 patients (n=204) by ELISA, ELISpot, multicolor flow cytometry and multiplex analysis. Result(s): Based on serological testing, IFN-gamma ELISpot results, age and sex, we established normal ranges for VST frequencies in healthy donors for better interpretation of VST frequencies observed in immunocompromised patients. While in SARS-CoV-2 recovered patients, the antiviral immune response was characterized by a broad specificity, significantly lower T-cell responses were observed during active infection. Comparison with the previously established reference values for VST frequencies revealed an overall reduced T-cell functionality based on the lack of CMV-pp65-reactive T cells in CMV-seropositive COVID-19 patients, which was associated with an inflammatory milieu, expression of inhibitory molecules, and effector caspase activity in T cells. Conclusion(s): The established reference values are an invaluable tool for immune response assessment, therapeutic agent intensity and decision making in immunocompromised patients. Further, we provide evidence that the low T-cell response observed during SARS-CoV-2 infection is not exclusively due to lymphopenia, but rather due to checkpoint- and cell death-associated mechanisms, suggesting that these patients may benefit from SARS-CoV-2-specific T-cell therapy.

External Validation of the 4C Mortality Score and the qSOFA for Different Variants of Concerns of SARS-CoV-2 Using Data of the NAPKON Cross-Sectoral Cohort Platform (SUEP)

Background. Numerous predictive clinical scores with varying discriminatory performance have been developed in the context of the current coronavirus disease 2019 (COVID-19) pandemic. To support clinical application, we test the transferability of the frequently applied 4C mortality score (4C score) to the German prospective Cross-Sectoral Platform (SUEP) of the National Pandemic Cohort Network (NAPKON) compared to the non COVID-19 specific quick sequential organ failure assessment score (qSOFA). Our project aims to externally validate these two scores, stratified for the most prevalent variants of concerns (VOCs) of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) in Germany. Methods. A total of 685 adults with polymerase chain reaction (PCR)-detected SARS-CoV-2 infection were included from NAPKON-SUEP. Patients were recruited from 11/2020 to 03/2022 at 34 university and non-university hospitals across Germany. Missing values were complemented using multiple imputation. Predictive performance for in-hospital mortality at day of baseline visit was determined by area under the curve (AUC) with 95%-confidence interval (CI) stratified by VOCs of SARS-CoV-2 (alpha, delta, omicron) (Figure 1). Figure 1: Study flow chart with inclusion criteria and methodological workflow. Results. Preliminary results suggest a high predictive performance of the 4C score for in-hospital mortality (Table 1). This applies for the overall cohort (AUC 0.813 (95%CI 0.738-0.888)) as well as the VOC-strata (alpha: AUC 0.859 (95%CI 0.748-0.970);delta: AUC 0.769 (95%CI 0.657-0.882);omicron: AUC 0.866 (95%CI 0.724-1.000)). The overall mortality rates across the defined 4C score risk groups are 0.3% (low), 3.2% (intermediate), 11.6% (high), and 49.5% (very high). The 4C score performs significantly better than the qSOFA (Chi2-test: p=0.001) and the qSOFA does not seem to be a suitable tool in this context. Table 1: Discriminatory performance of the 4C Mortality Score and the qSOFA score within the validation cohort NAPKON-SUEP stratified by the Variant of Concerns of SARS-CoV- 2. Conclusion. Despite its development in the early phase of the pandemic and improved treatment, external validation of the 4C score in NAPKON-SUEP indicates a high predictive performance for in-hospital mortality across all VOCs. However, since the qSOFA was not specifically designed for this predictive issue, it shows low discriminatory performance, as in other validation studies. Any interpretations regarding the omicron stratum are limited due to the sample size.

Plasma with high titers of anti-SARS-Cov2 antibodies improves outcome of COVID-19 in patients with hematological malignancy and cancer in a randomized controlled trial

Background. Patients with hematological malignancy or other cancers as well as immunosuppression bear a high risk for severe COVID-19. Monoclonal antibodies (mAb) are efficient at early stages of the disease but may lose potency with new variants. Trials on plasma from convalescent donors in unselected patients have not shown clinical benefit. No randomized trials focussing on patients with underlying disease have been published. Methods. We conducted an open-label, multicenter, randomized controlled trial to evaluate efficacy of plasma (CVP - convalescent or after vaccination) in patients with COVID-19 at high risk for adverse outcome in Germany. We assessed the effect of high-titer CVP (2 units from different donors, 238-337 ml each, on subsequent days). Patients with hematological or other malignancy (group 1), immunosuppression (group 2), age >50 and <=75 years and lymphopenia and/or high D-dimers (group 3) or age >75 years (group 4) who were hospitalized with confirmed SARS-CoV-2 infection and with an oxygen saturation <=94% were included. Primary outcome measure was time to clinical improvement on a seven-point ordinal scale, secondary outcome was mortality (Janssen et al. Trials 2020 Oct 6;21(1):828). Results. Overall, 133 patients were randomized, 68 received CVP with an additional 10 patients as a crossover on day 10. Median age (range) was 68 years (39-95) in the CVP group and 70 (38-90) in controls. For the entire cohort, no significant difference was seen in time to improvement (median days: CVP 12.5 vs. control 18;HR 1.24 (95% confidence interval (CI) 0.83-1.85), p=0.29). Subgroup analysis (group 1+2) revealed shortened time to improvement (median days CVP 13 vs. control 32;HR 2.03 (95%CI 1.17-3.6), p=0.01) and mortality was reduced (mortality CVP n=6 (18%) vs. control n=10 (29%). No significant differences in time to improvement were observed in group 3 or 4 (HR 0.72 (95%CI 0.41-1.28), p=0.26). No relevant adverse events were observed. Conclusion. CVP improves time to clinical improvement and mortality for COVID-19 patients with underlying hematological disease/cancer or other reasons of impaired immune response. Even with new variants, high-titer CVP may offer a widely available and inexpensive therapy option in high-risk groups. Funding. BMBF FKZ 01KI20152;EudraCT 2020-001632-10.

COVID-19 in der Intensivmedizin

The coronavirus disease 2019 (COVID-19) pandemic can lead to a severe course of disease in immunosuppressed patients requiring intensive care unit treatment even though a number of new vaccines and new antiviral drugs exist. One of the main reasons for this is the generally poorer immune response under immunosuppression. Therefore, it is all the more important to know the stages of the disease and to select the currently available therapeutic options accordingly.

Humoral and Cellular Immunity against Different Sars-Cov-2 Variants Is Detectable but Reduced in Vaccinated Kidney Transplant Recipients

Solid organ transplant recipients have an increased morbidity and mortality after SARS-CoV-2 infection. Immune responses after the third/fourth vaccination against SARS-CoV-2 are insufficiently studied in patients after kidney transplantation (KTX). We analyzed immune responses at a median of 4 months after the third/fourth vaccination in KTX patients and compared them to healthy controls. Cellular immunity was assessed using interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) ELISpot assays. Neutralizing antibody titers were assessed against SARS-CoV-2 D614G (wild type) and the variants alpha, delta and omicron by a cell culture-based neutralization assay. Humoral immunity was also determined by a competitive fluorescence assay, using 11 different variants of SARS-CoV-2. Antibody ratios were measured by ELISA. KTX patients showed significantly lower SARSCoV- 2-specific IFN-gamma responses after booster vaccination than healthy controls. However, the SARS-CoV-2 specific IL-2 responses were comparable to the T cell responses of healthy controls. Cell culture-based neutralizing antibody titers were 1.3-fold higher in healthy controls for D614G, alpha and delta and 7.8-fold higher for omicron (p < 0.01). Healthy controls had approximately 2-fold higher concentrations of potential neutralizing antibodies against all 11 variants than KTX patients. However, more than 60% of the KTX patients exhibited antibodies to variants of SARS-CoV-2. In conclusion, KTX patients should be partly protected against SARSCoV- 2, either by cross-reactive T cells, especially those producing IL-2, or by neutralizing antibodies to SARSCoV- 2 variants.

A RANDOMIZED CONTROLLED CLINICAL TRIAL DEMONSTRATES THAT PLASMA FROM CONVALESCENT AND VACCINATED DONORS IMPROVES OUTCOME OF COVID-19 IN PATIENTS WITH HEMATOLOGICAL DISEASE, CANCER OR IMMUNOSUPPRESSION

Background: Therapy options are limited for COVID-19 patients with hematological disease, cancer, immunosuppression or adanced age. Een though no benefit was obsered for conalescent plasma in unselected patients with COVID-19, retrospectie data suggest that it could be effectie in patients unable to mount a sufficient immune response upon SARS-CoV-2 infection. Plasma from accinated donors has not been systematically assessed for COVID-19 treatment. Aims: We conducted a randomized clinical trial to address plasma efficacy in patients at high risk for an aderse outcome. Methods: COVID-19 patients with confirmed SARS-CoV-2 infections and oxygen saturation <=94% were randomized (NCT05200754). Patients receied conalescent or accinated SARS-CoV-2 plasma in two bags (238 - 337 ml plasma each) from different donors on day 1 and 2 (PLASMA) or standard of care (CONTROL). Randomization was stratified according to four clinical patient groups, hematological/solid cancer (group-1), treatment or disease associated immunosuppression (group 2), high risk disease by standard parameters (group-3) or age >=75 years (group-4). Mechanically entilated patients were not eligible. Plasma was obtained from donors with high leel neutralizing actiity (titer >=1:80) either after SARS-CoV-2 infection (conalescent) or after accination with at least two doses of mRNA accines (accinated). Crossoer for the control group was allowed at day 10. The primary endpoint was time to improement as two points on a seen-point ordinal scale or lie discharge from the Hospital (IMPROVEMENT) with prespecified analyses of subgroups (Janssen M, et al. Trials 2020 Oct 6;21(1):828). Results: A total of 133 patients were randomized with 68 receiing PLASMA with a median age of 68 years (range 36-95) or CONTROL (n=65, of which n=10 (15.4%) crossed oer at day 10) with a median age of 70 years (range 38-90). The distribution of the four predefined groups was group-1, n=53;group-2, n=18;group-3, n=35;and group-4, n=27. The intention to treat analysis reealed a non-significant shorter time to IMPROVEMENT for patients in PLASMA (median 12.5 days, 95%-CI [10;16]) compared to patients in CONTROL (median 18 days, 95%-CI [11;28] ), hazard ratio 1.24, 95% confidence interal [0.83;1.85], p=0.29). Oerall, 27 patients died (PLASMA, n=12;CONTROL, n=15;p=0.80). Predefined subgroup analysis reealed a clinically significant benefit in patients with hematological malignancies, other cancers or immunosuppression (group-1, group-2, n=71). With a median time to improement of 13 days (95%-CI [9;19]) for PLASMA and 32 days (95%-CI [17;57]) for CONTROL(HR 2.03, 95%-CI [1.17;3.6], p=0.01). A sensitiity analysis reealed that IMPROVEMENT appeared to be seen een earlier with accinated (median 10 days, 95%-CI [8;14]) compared to conalescent SARS-CoV-2 plasma (median 13 days, 95%-CI [6;38]) and CONTROL. Within group-1 and group-2, six patients in PLASMA (18.2%) and 10 in CONTROL (28.6%) died. No significant differences in improement were obsered in group-3 and group-4 with a HR of 0.72 (95%-CI [0.41;1.28], p=0.26). Within group-3 and group-4, six patients in PLASMA (18.8%) and fie in CONTROL (16.7%) died. No preiously unknown side effects of plasma therapy emerged within the trial. Summary/Conclusion: Plasma from conalescent and particularly accinated donors improed outcome of COVID-19 patients with an underlying hematological disease /cancer or other reasons of impaired immune response. Plasma did not improe outcome in immune-competent patients with other risk factors and/or older age. (Figure Presented).

[Acute renal failure in COVID-19]. / Akutes Nierenversagen bei COVID-19.

Acute kidney injury (AKI) is a frequent complication in coronavirus disease 2019 (COVID-19). It is often linked to progressive respiratory failure and is associated with increased morbidity and mortality. The AKI is presumably of multifactorial origin, whereby direct viral infestation of the kidneys also seems to be involved. Specific treatment procedures for AKI associated with COVID-19 are currently missing. In addition, the role of extracorporeal procedures in the treatment of COVID-19 could so far not be clarified. Latest data indicate persistent loss of renal function following COVID-19-associated AKI. Therefore, a re-evaluation of renal function following recovery from COVID-19 should be recommended.

Humoral Response to SARS-CoV-2-Vaccination with BNT162b2 (Pfizer-BioNTech) in Patients on Hemodialysis

mRNA-based SARS-CoV-2 vaccines offer a preventive strategy against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections that is of interest in the care of patients on hemodialysis (HDP). We measured humoral immune responses in 72 HDP after standard vaccination with two doses of the mRNA-based SARS-CoV-2 vaccine BNT162b2 (Pfizer-BioNTech). Antibody responses were evaluated with an anti-SARS-CoV-2 IgG ChemiLuminescent ImmunoAssay (CLIA) two weeks after the second dose. In addition, SARS-CoV-2 IgG was determined in a control of 16 healthy healthcare workers (HCW). The control group of HCW has shown a strong antibody response with a median (MD (Q1;Q3)) antibody titer of 800.0 AU/mL (520.5;800.0). In comparison to HCW, HDP under 60 years of age responded equally (597.0 AU/mL (410.5;800.0), p = 0.051). However, the antibody responses of the HDP negatively correlated with age (r² = 0.2954 p < 0.0001), leading to significantly lower antibody titers in HDP over 60 years (280.0 AU/mL (45.7;477.0), p < 0.0001). To thoroughly understand the immunogenicity of the new mRNA-based vaccines in HDP, longitudinal data on the effectiveness and durability of antibody responses are needed. Modifications of immunization schedules should be considered in HDP with low or without antibody responsiveness after standard vaccination to boost immune reactivity and prolong protective effects in these vulnerable patients.

SARS-CoV-2 Diagnostic - What is Really Sensible?

The PCR-test for SARS-CoV-2 represents the state of the art in diagnosing COVID-19 disease as at November 2020. However, above all this is time-consuming. In future, so-called antigen tests could be carried out quickly and as a point-of-care method to facilitate the diagnosis of COVID-19. Changes in serological biomarkers (such as D-dimers, troponin T, CRP) can help to identify patients at risk for a severe COVID-19 course. A routine screening CT thorax to identify COVID-19 pneumonia is currently not recommended by most radiological societies. However, the number of CT examinations is increasing steadily and radiological diagnosis in COVID-19 patients with pulmonary symptoms is becomingmore and more important.

Transplant patients are able to mount sars-cov-2-reactive t-cell response with the magnitude and functionality comparable to non-immunosuppressed patients

Introduction: The optimal management of COVID-19 in transplant patients is not defined so far. The major concern is the ability of transplant patients to generate a sufficient antiviral response under immunosuppressive treatment. Methods: Here, we analysed T-cell immunity directed against Spike, Membrane and Nucleocapsid proteins of SARS-CoV-2 in a small cohort of 6 transplant patients (TP) with COVID-19 in comparison to 28 non-immunosuppressed patients (NIP). Results: The median patient age of transplant cohort (3 renal transplant, 1 lung, and 1 combined liver-kidney and 1 pancreas-kidney) as well as gender did not differ from NIP. We also did not find statistical differences for the time between the diagnosis of COVID-19 and analysis of T-cell immunity between the two cohorts. Notably, despite immunosuppressive therapy, we were able to detect a strong antiviral response in transplant patients. TP generated SARSCoV-2 reactive T-cells against all three proteins with predominance of CD4 + T cells with pro-inflammatory Th1 phenotype. Moreover, SARS-CoV-2 reactive CD4 + and CD8 + T cells were able to produce multiple pro-inflammatory cytokines demonstrating their potential protective capacity. Of interest, the frequencies and cytokine production patterns of SARS-CoV-2 reactive T-cells did not show any differences between TP and NIP. Conclusion: A strong polyfunctional T-cell response directed against all three SARS-CoV-2 proteins can be generated in transplant despite immunosuppressive treatment. In comparison to non-immunosuppressed patients, the antiviral immunity is non-inferior. Since the dosage of immunosuppression in analysed patients was reduced, further studies are required to assess the antiviral immunity under standard immunosuppression.

Pre-existing sars-cov-2 reactive t cells in renal transplant patients

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused unprecedented public health and economical challenges worldwide. Cellular immunity is known to be crucial for the virus clearance. Recent data demonstrate pre-existing SARS-CoV-2-reactive T cells in samples of healthy blood donors collected before SARS-CoV-2 pandemics. The presence of these potentially protective T cells in SARS-CoV-2 naive population can be explained by cross-reactivity to the endemic common cold coronavirus. Whether such cells are also detectable in immunosuppressed patients is not known so far. Methods: We analysed the presence of SARS-CoV-2-cross-reactive T cell immunity in samples of 10 renal transplant patients (RTX) collected in 2019 before the onset of SARS-CoV-2 pandemics. Samples of 10 non-immunosuppressed/ immune competent SARS-CoV-2 naive patients matched to transplant patients were analysed as controls. T-cell reactivity against Spike-, Nucleocapsid-, and Membrane-SARS-CoV-2 proteins were analysed by multiparameter flow cytometry. Results: 50% of analysed RTX showed CD4 + T-cells reactive against at least one SARS-CoV-2 protein. CD8 + T cells reactive against at least one SARSCoV2 protein were demonstrated in 30% of RTX. Notably, the detected cells were of differentiated memory phenotype producing several Th1 cytokines including IFNg, TNFa, IL-2, as well as Granzyme B. The frequencies and cytokine expression pattern of SARS-CoV-2 reactive T-cells did not differ between transplant and non-transplant cohorts. Conclusion: Despite immunosuppressive treatment and underlined renal disease, transplant patients were able to generate cellular immunity crossreactive to SARS-CoV-2. The magnitude and functionality of the pre-existing immunity was non-inferior compared to the immune competent cohort. Although several pro-inflammatory cytokines were produced by the detected T cells, further studies are required to prove their antiviral protection.