COVID-19 und Krebs

V562 Vakzin-induzierte thrombotische Thrombozytopenie (VITT)

Christiane Dobbelstein, Hannover, D

Introduction: An unexpected accumulation of thrombotic events with thrombocytopenia emerged in association with the AZD1222 vaccine against COVID-19. We report our initial experience with emphasis on presenting characteristics, treatment, and short-term outcome.

Methods: This is a retrospective, consecutive cohort of all patients admitted to Hannover Medical School between 8th March and 4th April 2021 with known or suspected thromboembolic events and thrombocytopenia within 2 weeks after vaccination with AZD1222.

Results: Five patients were admitted during the observation period. These were women between 41 and 67 years of age, who had received AZD1222 5 to 11 days before. Clinical manifestations ranged from cerebral sinus vein thrombosis, splanchnic vein thrombosis, arterial ischemic stroke, and
thrombotic microangiopathy (TMA) to mild symptoms without abnormal imaging results. Thrombocytopenia ranged between 12 and 105 /nl. All patients had markedly elevated D-Dimer. Heparin- induced thrombocytopenia (HIT) workup revealed anti-platelet factor 4 autoantibodies in sera from all patients. Platelet aggregation by these antibodies was observed in the presence of buffer or AZD1222 but suppressed by heparin. Treatment consisted of anticoagulation (heparin or argatroban), dexamethasone and, in severe cases, intravenous immunoglobulin (IVIG) or eculizumab. Two patients treated with anticoagulation, dexamethasone and IVIG had subsequent major thromboembolic events. One patient presenting with a picture of TMA responded to anticoagulation and eculizumab. Another patient responded to thrombolysis and eculizumab after failure of anticoagulation and IVIG. Long-term sequelae are expected in two patients with severe cerebrovascular events while remaining three patients have fully recovered. Anti-PF4 antibodies declined in recovering patients over a period of 8 weeks.

Conclusions: The triad of thromboembolic events, thrombocytopenia and anti-PF4 autoantibodies is characteristic of VITT. The spectrum of clinical manifestations ranged from mild to unusually severe. Anticoagulation alone is not always sufficient to prevent recurrent or progressive thromboembolic events. IVIG and eculizumab are potential treatment options but their effects are currently uncertain.

 

V344 Kreuzreaktive und Covid-19-induzierte Immunantworten gegen SARS-CoV-2 11:57 bei Krebspatienten

Malte Roerden, Tübingen, D

Cancer patients are at increased risk for critical illness upon COVID-19. We assessed antibody and T cell responses in unexposed and SARS-CoV-2 convalescent cancer patients to characterize SARS-CoV-2 immunity and to identify immunological parameters contributing to increased morbidity and mortality in COVID-19 cancer patients. Immune responses were assessed in unexposed (n = 199) and SARS- CoV-2-infected cancer patients (n = 17), comprising different hematological malignancies (HM) and solid tumor entities. T cell responses were assessed by IFN-g ELISPOT using previously defined cross-reactive and SARS-CoV-2-specific T cell epitopes (Nelde et al., Nat Immunol 2021). SARS-CoV-2 convalescents without cancer (n = 193) and unexposed healthy volunteers (HV, n = 94) served as reference groups.

Whereas pre-existing SARS-CoV-2 cross-reactive CD4+ T cell responses were detectable in a high proportion of HV (78%) and solid tumor patients (77%), frequency was substantially lower in unexposed HM patients (34%). Concordantly, HM patients showed significantly higher proportions of CD4+ T cells expressing PD-1, LAG-3 and TIM-3, indicating T cell exhaustion as a potential underlying cause for the reduced T cell reactivity.

In SARS-CoV-2 convalescents, no difference in antibody positivity was noted between cancer patients and HV. T cell response analyses showed comparable recognition frequencies of SARS-CoV-2-specific HLA class I and HLA-DR epitopes in both groups, whereas the frequency of HLA-DR cross-reactive T cell responses was significantly reduced in cancer patients. Again, this was attributable to a markedly reduced frequency of cross-reactive CD4+ T cell responses in HM patients. Analysis of T cell responses to single HLA-DR peptides (n = 20) after 12-day in vitro expansion further revealed reduced T cell expandability for 73% of SARS-CoV-2-derived peptides in COVID-19 cancer patients. Moreover, diversity of SARS-CoV-2 T cell responses (i.e. recognition of multiple different T cell epitopes) was significantly reduced in COVID-19 HM patients (20% recognized peptides) compared to solid tumor patients (35%) and HV (50%), and reduced T cell diversity was associated with a more severe course of COVID-19.

In summary, our results identify impaired SARS-CoV-2 T cell immunity as a determinant for poor outcome of COVID-19 in cancer patients, particularly in HM. These findings guide the development of therapeutic measures and vaccines for this vulnerable patient population.

 

V489 Späte versus frühe Gabe von Rekonvaleszentenplasma bei hopitalizierten 12:09 Patienten mit COVID-19: Ergebnisse der randomisierten unverblindeten Studie CAPSID
Sixten Körper, Ulm, D

Background: Several observational studies suggested efficacy of COVID-19 convalescent plasma (CCP) but the results of several randomized clinical trials of CCP are not consistent. The trials differ in treatment schedules in terms of timing, volume and antibody content of CCP as well as enrolled patient populations and endpoints. The CAPSID was designed at the beginning of the pandemic and assessed the efficacy of neutralizing antibody containing high-dose COVID-19 convalescent plasma (CCP) in hospitalized patients with severe COVID-19.

Methods: Patients (n=105) in 13 hospitals in Germany were randomized to either receive standard treatment and three units of CCP on days 1, 3 and 5 (total dose 846 ml) (n=53) or standard treatment alone (n=52). Patients in the control group with progress on day 14 could receive CCP (crossover group; n=7) on days 15, 17 and 19. The primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria of severe COVID-19 on day 21. For Cross over patients a propensity matching with patients of the plasma group was performed.

Results: Neutralizing antibodies were present at baseline in 18.2% of CCP and 19.2% of control group patients. In the ITT analysis the primary outcome occurred in 43.4% of patients in the CCP and 32.7% in the control group (p=0.32). The CCP group showed a trend for shorter times to clinical improvement (40 days, p=0.27) and discharge from hospital (20 days, p=0.24). Among those in the CCP group who received a higher or lower cumulative amount of neutralizing antibodies the primary outcome occurred in 56.0% and 32.1% of patients The high titer group showed significantly shorter intervals to clinical improvement or hospital discharge and a better overall survival (p=0.02).

None of the patients in the crossover group (CG) achieved clinical improvement and survived. Comparing the CG to 14 CCP patients matched by baseline characteristics resulted in worse OS in the CG group (p=0.02) while comparison with 6 day 14 matched patients showed equal OS.

Interpretation: CCP added to standard treatment did not result in a significant difference in the primary and secondary outcomes. A pre-defined subgroup analysis showed a signal of benefit for CCP among those who received a larger amount of neutralizing antibodies. A progress on day 14 is an indicator for poor outcome in COVID-19. Late administration of CCP is not supported by our results.


V428 Der Schweregrad einer COVID-19 Erkrankung wird beeinflusst von der 12:21 Hyperaktivierung und der migratorischen Kapazität von T-Zellen
Simon Völkl, Erlangen, D

Introduction: COVID-19 is a life-threatening disease leading to bilateral pneumonia and respiratory failure. The underlying reasons why a smaller percentage of patients present with severe pulmonary symptoms whereas the majority is only mildly affected, are to date not well understood.

Methods: We analyzed immune cell dynamics in patients with mild (NIH Score 4+5) and severe (NIH Score 1-3) cases of SARS-CoV2 infection. Patients with mild courses presented with COVID-19 specific, mostly respiratory symptoms, however no one required treatment in the ICU, mechanical ventilation nor died due to COVID-19. Patients with a severe course of disease were treated in the ICU department of our hospital, all of them needed supplementary oxygen. Mortality rate of the cohort with severely ill patients was 33%.

Results: Given that T cells play a critical role in the elimination of viral infections, we studied this lymphoid compartment in COVID-19 patients. Compared to healthy controls, patients with SARS-CoV2 infection presented increased T cell activation and proliferation and a decline of naive CD8 T-cells. Interestingly, activation markers on T cells were further enhanced in patients with severe courses of COVID-19 disease. Furthermore, the CD8 T-cell compartment in patients with mild COVID-19 exhibited a shift towards terminal differentiation. In contrast, severe cases showed an expansion of effector cells, which correlated with increased cell activation. To determine whether T-cells might be primed for homing to specific tissues during SARS-CoV-2 infection, we checked for particular chemokine receptors in our cohorts. We found the lung homing receptor CCR4 and the proinflammatory receptor CCR5 strongly upregulated on CD8 T-cells in patients with severe COVID-19 infection, mainly characterized by pulmonary failure and requirement of mechanical ventilation, however not in mild COVID-19 disease. Moreover, CD8 T-cells from patients with severe disease exhibited reduced CCR7 expression, pointing towards enhanced attracting to sites of inflammation and limited homing to secondary lymphoid organs. Further analysis revealed a linear relationship between CCR4 expression and CD8 T-cell activation and effector differentiation in patients with severe disease.

Conclusion: Taken together, our data support the critical involvement of T cells in the pathogenesis of SARS-CoV2 infection and link clinical severity to T-cell hyperactivation and altered migratory capacity.

 

V590 Hohe - und anhand des prognostischen 4C Scores unterschätzte - Mortalität 12:33 bei Patienten mit aktiver maligner Erkrankung und schwerer COVID-19 Infektion. Ergebnisse aus einem multizentrischen österreichischen Register
Simon Udovica, Wien, A

Introduction: Various registries of patients with cancer and COVID-19 have recently emerged and patients with cancer are reported to be at increased risk for severe outcomes of COVID-19. Yet, many studies lack a direct control group and include “cancer patients” with different baseline parameters, such as combining inpatients and outpatients, and including patients with both active malignancy and a past history of cancer.

Methods: Here, we analyze the outcomes of a cohort of consecutive patients admitted to our COVID-19 ward for severe COVID-19, comparing patients with active malignancy with a control group without ongoing malignant disease. We also evaluate the usefulness of the prognostic 4C Mortality Score that estimates in-hospital mortality for COVID-19 patients. The primary endpoint was COVID-19-associated mortality. Fisher's Exact Test was used for univariable tests and binary log-regression for multivariable analysis.

Results: Overall, more than 600 patients with COVID-19 were treated at our units. 245 Patients hospitalized with severe COVID-19 between 3/2020 and 3/2021 were included in the analysis. Among those, 89 patients (36.3%) had active malignancy. COVID-19 associated mortality was significantly higher in cancer patients than in the control group (48.81% vs. 27.56%; OR: 2.50, p=0.002). Age (median: 74 vs. 76 years), number of comorbidities other than cancer (mean: 1.63 vs. 1.84) and fraction of patients treated at an ICU (17.98% vs. 14.74%) were comparable between both groups (p=n.s.). In multivariable analysis, active malignancy (OR: 2.47) and poor ECOG status ≥3 (OR: 2.04) were the strongest predictors of COVID-19 related death. In non-cancer patients, the mortality rate of 27.56% was almost exactly that predicted by the prognostic 4C score (27.26%). However, in cancer patients the observed mortality rate of 48,81% was significantly higher than that predicted by the 4C score (32.15%; p=0.03).

Conclusion: Cancer patients with severe COVID-19 have a high mortality and their mortality rate is underestimated by the 4C Mortality Score. Hence, we advocate strict preventive measures and prioritization in vaccination campaigns for this vulnerable group of patients.