Applied Hedgehog Conservation Research.

Hedgehogs (Order Eulipotyphla, Family Erinaceidae, Subfamily Erinaceinae) are familiar and popular spiny mammals, but they face many challenges in modern human-dominated environments [...].

Durvalumab Plus Gemcitabine and Cisplatin in Patients with Advanced Biliary Tract Cancer: An Exploratory Analysis of Real-World Data.

BACKGROUND: The combination of gemcitabine and cisplatin (gem/cis) with the anti-PD-L1-antibody durvalumab was recently approved as first line therapy for biliary tract cancer (BTC) based on the results of the TOPAZ-1 trial. OBJECTIVE: We aim to analyse the feasibility and efficacy of the triple combination therapy in patients with BTC in a real-world setting and in correspondence with the genetic alterations of the cancer. METHODS: In this single-centre retrospective analysis, all patients with BTC and treated with durvalumab plus gem/cis from April 2022 to September 2023 were included. Survival and treatment response were investigated, within the context of the inclusion and exclusion criteria of TOPAZ-1 and in correspondence with genetic alterations of the cancer. RESULTS: In total, 35 patients, of which 51% met the inclusion criteria of the TOPAZ-1 trial, were analysed. Patients treated within TOPAZ-1 criteria did not have a significantly different median overall survival and progression free survival than the rest of the patients (10.3 versus 9.7 months and 5.3 versus 5 months, respectively). The disease control rate of patients within the TOPAZ-1 criteria was 61.1%, in comparison to 58.8% in the rest of patients. A total of 51 grade 3 and 4 adverse events were observed without significant differences in the subgroups. No specific correlating patterns of genetic alterations with survival and response were observed. CONCLUSIONS: The treatment of advanced patients with BTC with durvalumab and gem/cis, even beyond the inclusion criteria of the TOPAZ-1 trial, shows promising safety.

Anti-HLA-B7/HLA-B44 strong cross immunoreactivity observed in flow cytometry HLA-B27 immunotyping.

Cross reactivities are known for human leukocyte antigen inside HLA-B7 related Cross-Reactive Group (B7CREG). Some CE-IVD flow-cytometry kits use double monoclonal antibodies (mAb) to distinguish HLA-B27 and HLA-B7 but practice reveals more complexes results. This study explores the performances of this test. Analysis of 466 consecutive cases using HLA-B27 IOTest™ kit on a Navios™ cytometer from Beckman-Coulter, partially compared to their genotypes. Expected haplotypes HLA-B27-/HLA-B7- (undoubtedly HLA-B27 negative) and HLA-B27+/HLA-B7- (undoubtedly HLA-B27+) were clearly identified according to the manufacturer's instructions. On the opposite, patients strongly labeled with anti-HLA-B7 showed three different phenotypes regarding anti-HLA-B27 labeling: (1) most of the cases were poorly labeled in accordance with cross reactivity inside B7CREG (HLA-B27-/HLA-B7+ haplotype); (2) rare cases had strong B7 and B27 labeling corresponding to HLA-B27+/HLA-B7+ haplotype; (3) even less cases had strong labeling by anti-HLA-B7 but non for anti-HLA-B27, all expressing HLA-B44 and no B7CREG molecules. Surprisingly, more cases were not labeled with anti-HLA-B7 antibody but partially labeled with anti-HLA-B27 suggesting another cross reactivity out of B7CREG. mAb HLA typing suggests new, cross reactivities of anti-HLA-B27 antibody to more molecules out of B7CREG and of anti-HLA-B7 antibody but not anti-HLA-B27 to HLA-B44 molecule also out of B7CREG. HLA-B27 could surely be excluded in most samples labeled with HLA-B27, below a "grey zone" on intermediate intensity. More comparison is needed in future studies.

On the water transport mechanism through the microporous layers of operando polymer electrolyte fuel cells probed directly by X-ray tomographic microscopy.

Product water transport via the microporous layer (MPL) and gas diffusion layer (GDL) substrate during polymer electrolyte fuel cell (PEFC) operation was directly and quantitatively observed by X-ray tomographic microscopy (XTM). The liquid water distribution in two types of MPLs with different pore size distributions (PSDs) was characterized as a function of the inlet gas relative humidity (RH) and current density under humid operating conditions at 45 °C. During the first minute of PEFC operation, liquid water mainly accumulated at the catalyst layer (CL)/MPL interface and in the GDL substrate close to the flow fields. Furthermore, under all tested conditions, saturation in the MPL was low (<25%), whereas under the rib, the saturation in the GDL was up to ca. 70%. Based on these XTM results, it is confirmed that in the high porosity MPLs, vapor transport was non-negligible even at high humidity conditions. Therefore, on top of the widely discussed MPL pore size and its distribution, it is proposed that the lower thermal conductivity from the high porosity of MPLs can also be a main cause of promoted vapor transport, reducing water saturation near the CL.

Providing the basis for a patient-centred and effective screening for cancer-related fatigue (MERLIN study): design of a longitudinal observational study.

INTRODUCTION: Cancer-related fatigue (CRF) is a frequent and burdensome sequela of cancer and cancer therapies. It can persist from months to years and has a substantial impact on patients' quality of life and functioning. CRF is often still not adequately diagnosed and insufficiently treated. According to guideline recommendations, patients should be routinely screened for CRF from cancer diagnosis onwards. We will investigate how an effective screening should be designed regarding timing, frequency, screening type and cut-off points. METHODS AND ANALYSIS: MERLIN is a longitudinal observational study that will include 300 patients with cancer at the beginning of cancer therapy. The main study centre is the National Center for Tumour Diseases Heidelberg, Germany. Patients answer five items to shortly screen for CRF at high frequency during their therapy and at lower frequency during the post-treatment phase for 18 months. Further, CRF is assessed at wider intervals based on the Cella criteria, the Brief Fatigue Inventory impact scale, the quality of life fatigue questionnaire (QLQ-FA12) and the fatigue and cognitive items of the quality of life core questionnaire (QLQ-C30), both of the European Organisation for Research and Treatment of Cancer. Important psychological, socio-demographical or medical factors, which may exacerbate CRF are assessed. All assessments are performed online. Receiver operating curves, areas under the curve, sensitivity, specificity, positive and negative predictive values and likelihood ratios will be calculated to determine optimal short screening modalities. ETHICS AND DISSEMINATION: The study was approved by the ethics committee of the Medical Faculty of the Heidelberg University, Germany (approval number: S-336/2022). Written informed consent is obtained from all participants. The study is conducted in full conformance with the principles of the Declaration of Helsinki. Results will be published in peer-reviewed scientific journals, presented at conferences and communicated to clinical stakeholders to foster the implementation of an effective CRF management. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov; registration number: NCT05448573.

Multi-Institutional Evaluation of Pathologists' Assessment Compared to Immunoscore.

BACKGROUND: The Immunoscore (IS) is a quantitative digital pathology assay that evaluates the immune response in cancer patients. This study reports on the reproducibility of pathologists' visual assessment of CD3+- and CD8+-stained colon tumors, compared to IS quantification. METHODS: An international group of expert pathologists evaluated 540 images from 270 randomly selected colon cancer (CC) cases. Concordance between pathologists' T-score, corresponding hematoxylin-eosin (H&E) slides, and the digital IS was evaluated for two- and three-category IS. RESULTS: Non-concordant T-scores were reported in more than 92% of cases. Disagreement between semi-quantitative visual assessment of T-score and the reference IS was observed in 91% and 96% of cases before and after training, respectively. Statistical analyses showed that the concordance index between pathologists and the digital IS was weak in two- and three-category IS, respectively. After training, 42% of cases had a change in T-score, but no improvement was observed with a Kappa of 0.465 and 0.374. For the 20% of patients around the cut points, no concordance was observed between pathologists and digital pathology analysis in both two- and three-category IS, before or after training (all Kappa < 0.12). CONCLUSIONS: The standardized IS assay outperformed expert pathologists' T-score evaluation in the clinical setting. This study demonstrates that digital pathology, in particular digital IS, represents a novel generation of immune pathology tools for reproducible and quantitative assessment of tumor-infiltrated immune cell subtypes.

FRET causing misleading signal from fluorescein excited by the violet laser in flow cytometry.

Multiple immunolabeling introduces high risks of interferences between fluorescences. As an example, in analyzing T cell clonality, we recently reported a fluorescence resonance energy transfer (FRET) effect providing an unexpected signal on B770 (PE-Cy7) detector, on the Vß-PE positive CD3 APC-Alexa750+ T cell subsets. Here, we report another FRET effect produced by the violet laser in Vß-FITC positive CD3-Pacific Blue (PB) T cells providing signal on V550 (Krome Orange; KrO) detector. The study was performed on fresh whole blood, labeled with anti-CD3-PB, CD8-KrO, Vbeta FITC, Vbeta PE, CD4 AA750 then fixed, treated for erythrolysis, and washed before analysis on DxFlex cytometer from Beckman Coulter. Data were analyzed using Kaluza software. Using this panel, we repeatedly observed an added CD8dim-KrO (V550) cell population on all Vß FITC positive T cells. The unexpected green signal excited by the violet laser was still observed after removing anti-CD8-KrO (FMO) but disappeared where either anti-CD3-PB or anti-Vß-FITC was removed. The effect was also observed with an anti-TCR gamma delta-FITC labeling, but not with another FITC labeled antibody targeting a protein out of the CD3-TCR complex. The analysis of fluorochrome spectra confirms that PB emission and FITC excitation spectra partly overlap. This observation clearly reminds users that FRET can give misleading results in case of labeling of very close markers with complementary fluorochromes. This risk has to be considered in panel design. These observations clearly highlight the potential for FRET to give misleading results in cases where very close markers are labeled with complementary fluorochromes. This risk must be considered when designing panels. To our knowledge, this is the first description of a FRET between PB and FITC as acceptor thus excited by the violet laser.

Development of Antibodies to Ustekinumab Is Associated with Loss of Response in Patients with Inflammatory Bowel Disease.

Monitoring of anti-drug antibodies in patients on ustekinumab is not routinely recommended in patients with inflammatory bowel disease (IBD) due to low rates of immunogenicity. AIM OF STUDY: The purpose of this study was to investigate the relationship between anti-drug antibodies detected by a drug-tolerant assay and loss of response (LOR) to therapy in a cohort of patients with IBD being treated with ustekinumab. PATIENTS AND METHODS: This retrospective study consecutively enrolled all adult patients with moderate to severe active IBD who had at least 2 years of follow-up after ustekinumab was initiated. LOR was defined as CDAI > 220 or HBI > 4 for Crohn's disease (CD) and partial Mayo subscore > 3 for ulcerative colitis (UC) and with a modification in disease management. RESULTS: Ninety patients were included (78 CD and 12 UC; mean age 37 years). Median levels of anti-ustekinumab antibodies (ATU) were significantly higher in patients with LOR compared to those with ongoing clinical response (15.2 µg/mL-eq CI (7.9-21.5) and 4.7 µg/mL-eq CI (2.1-10.5), respectively; p = 0.04). The area under the ROC curve (AUROC) for ATU in predicting LOR was 0.76. The optimal cut-off point for identifying patients with LOR was 9.5 µg/mL-eq with a sensitivity of 80% and specificity of 85%. Uni- and multivariate analyses showed that serum ATU ≥ 9.5 µg/mL-eq (hazard ratio (HR) 2.54, 95%CI (1.80-5.93)), p = 0.022, prior vedolizumab (HR 2.78, 95%CI (1.09-3.34), p = 0.019) and prior azathioprine (HR 0.54, 95%CI (0.20-0.76), p = 0.014) exposures were the only factors independently associated with LOR to UST. CONCLUSION: In our real-life cohort, ATU was identified as an independent predictor of LOR to ustekinumab in patients with IBD.

Prior COVID-19 Immunization Does Not Cause IgA- or IgG-Dependent Enhancement of SARS-CoV-2 Infection.

Antibody-dependent enhancement (ADE) can increase the rates and severity of infection with various viruses, including coronaviruses, such as MERS. Some in vitro studies on COVID-19 have suggested that prior immunization enhances SARS-CoV-2 infection, but preclinical and clinical studies have demonstrated the contrary. We studied a cohort of COVID-19 patients and a cohort of vaccinated individuals with a heterologous (Moderna/Pfizer) or homologous (Pfizer/Pfizer) vaccination scheme. The dependence on IgG or IgA of ADE of infection was evaluated on the serum samples from these subjects (twenty-six vaccinated individuals and twenty-one PCR-positive SARS-CoV-2-infected patients) using an in vitro model with CD16- or CD89-expressing cells and the Delta (B.1.617.2 lineage) and Omicron (B.1.1.529 lineage) variants of SARS-CoV-2. Sera from COVID-19 patients did not show ADE of infection with any of the tested viral variants. Some serum samples from vaccinated individuals displayed a mild IgA-ADE effect with Omicron after the second dose of the vaccine, but this effect was abolished after the completion of the full vaccination scheme. In this study, FcγRIIIa- and FcαRI-dependent ADE of SARS-CoV-2 infection after prior immunization, which might increase the risk of severe disease in a second natural infection, was not observed.

Monitoring of Both Humoral and Cellular Immunities Could Early Predict COVID-19 Vaccine Efficacy Against the Different SARS-CoV2 Variants.

Reliable immunoassays are essential to early predict and monitor vaccine efficacy against SARS-CoV-2. The performance of an Interferon Gamma Release Assay (IGRA, QuantiFERON® SARS-CoV-2), and a current anti-spike serological test, compared to a plaque reduction neutralization test (PRNT) taken as gold standard were compared. Eighty vaccinated individuals, whose 16% had a previous history of COVID-19, were included in a longitudinal prospective study and sampled before and two to four weeks after each dose of vaccine. In non-infected patients, 2 doses were required for obtaining both positive IGRA and PRNT assays, while serology was positive after one dose. Each dose of vaccine significantly increased the humoral and cellular response. By contrast, convalescent subjects needed a single dose of vaccine to be positive on all 3 tests. Both IGRA and current serology assay were found predictive of a positive titer of neutralizing antibodies that is correlated with vaccine protection. Patients over 65 or 80 years old had a significantly reduced response. The response tended to be better with the heterologous scheme (vs. homologous) and with the mRNA-1273 vaccine (vs. BNT162b2) in the homologous group, in patients under 55 and under 65 years old, respectively. Finally, decrease intensity or absence of IGRA response and to a less extent of anti-spike serology were also correlated to reinfection which has occurred during the follow up. In conclusion, both IGRA and current anti-spike serology assays could be used at defined thresholds to monitor the vaccine response against SARS-CoV-2 and to simply identify non-responding individuals after a complete vaccination scheme. Two available specific tests (IGRA and anti-spike antibodies) could early assess the vaccine-induced immunity against SARS-CoV-2 at the individual scale, to potentially adapt the vaccination scheme in non-responder patients.

Facing Danger: Exploring Personality and Reactions of European Hedgehogs (Erinaceus europaeus) towards Robotic Lawn Mowers.

The populations of European hedgehog (Erinaceus europaeus) are in decline, and it is essential that research identifies and mitigates the factors causing this. Hedgehogs are increasingly sharing habitats with humans, being exposed to a range of dangers in our backyards. Previous research has documented that some models of robotic lawn mowers can cause harm to hedgehogs. This study explored the personality and behaviour of 50 live hedgehogs when facing an approaching, disarmed robotic lawn mower. By combining a novel arena and novel object test, we found that 27 hedgehogs could be categorised as "shy" and 23 as "bold", independently of sex and age. The encounter tests with a robotic lawn mower showed that the hedgehogs positioned themselves in seven different ways. Personality did not affect their reactions. Adult hedgehogs tended to react in a shyer manner, and the hedgehogs, generally, acted less boldly during their second encounter with the robotic lawn mower. Additionally, our results show that bold individuals reacted in a more unpredictable way, being more behaviourally unstable compared to the shy individuals. This knowledge will be applied in the design of a standardised hedgehog safety test, eventually serving to produce and approve hedgehog-friendly robotic lawn mowers.

Occurrence and Characteristics of Cut Injuries in Hedgehogs in Germany: A Collection of Individual Cases.

The number of European hedgehogs (Erinaceus europaeus) is in long-term decline across Europe. Recently, an additional threat to hedgehogs' lives has been cutting injuries caused by garden care equipment, but to date, there have been no reliable data on their spatial and temporal occurrence as well as characteristics such as mortality rate. Usually, found injured hedgehogs are admitted to care centres. In this study, data on hedgehogs with cutting injuries were collected from care centres throughout Germany. Over a period of 16 months, data on a total of 370 hedgehogs with cut injuries were reported by 71 care centres. At least 60% of these hedgehogs were found more than 12 h after the accident and at least 47% did not survive as a result of the injury. The comparatively high mortality rate coupled with a possible high number of unreported cases of hedgehogs with laceration injuries show that these accidents pose an additional, serious danger to hedgehogs, both impacting the welfare of individual animals and having a broader effect on the conservation potential of this species. Moreover, the data collected objectify the current discussion on the need for possible technical or political solutions to prevent such injuries.

Testing the Impact of Robotic Lawn Mowers on European Hedgehogs (Erinaceus europaeus) and Designing a Safety Test.

Previous research has established that some models of robotic lawn mowers are potentially harmful to hedgehogs. As the market for robotic lawn mowers is expanding rapidly and the populations of European hedgehogs (Erinaceus europaeus) are in decline, it is important to investigate this risk further to understand the potential threat which some robotic lawn mowers may pose to hedgehogs. We tested 19 models of robotic lawn mowers in collision with hedgehog cadavers to measure their effect on hedgehogs. Our results showed that some models of robotic lawn mowers may injure hedgehogs, whereas others are not harmful to them. Apart from one single incidence, all robotic lawn mowers had to physically touch the hedgehog carcasses to detect them. Larger hedgehog cadavers were less likely to be "injured", with height being the most influential measure of size. The firmness of the tested hedgehog cadavers (frozen or thawed) did not influence the outcome of the collision tests. Neither the position of the hedgehog cadavers nor the selected technical features of the lawn mowers affected the probability of injury. Based on the results, we designed a standardised safety test to measure the effect of a specific model of robotic lawn mower on hedgehogs.

Human leukocyte antigen-B27 typing by flow cytometry: Comparison of three CE-IVD methods.

BACKGROUND: The human leukocyte antigen B27 (HLA-B27), associated with chronic inflammatory diseases is thus widely performed for diagnostic purposes. Genotyping by molecular biology is the current gold standard for HLA-B27 typing, but cheaper and faster flow cytometry methods have been developed. METHODS: In this report, we compare analytical performances of three CE-IVD flow cytometry kits: IOTest™ and DuraClone B27™ from Beckman Coulter and BD HLA-B27™ from BD Biosciences on a Navios™ cytometer as compared to molecular biology. RESULTS: Routine analyses could conclude for HLA-B27 in197 patients (23.2%) and was not conclusive for 66 patients (7%, 8%). The experience revealed the needs to complete IOTest™ with a lineage marker (like CD3-APC) and a standardization procedure in detection of fluorescence. Comparative analysis considering 23/44 non-conclusive samples as negative, pointed out a 100% sensitivity and specificity of IOTest™ in determining genetically proved HLA-B27. Specificity of the BD HLA-B27TM kit was 94% (two false positives) sticking to the manufacturer instructions but raised to 100% and 94% sensitivity with a cutoff at 8.5 (225 on FACSdiva's scale). DISCUSSION: The DuraClone B27™ specificity was poor using the manufacturer cutoff but raised to 100% with a 8.0 cutoff instead of 15. CONCLUSION: The three flow cytometry kits displayed satisfying performances but need adjustments. The DuraClone B27™ kit seems to be the best while the IOTest™ kit is not conclusive in 8% of cases. In most cases the use of molecular biology can be spared, but genotyping remains essential for patients whose HLA-B27 status cannot be determined with confidence by flow cytometry.

Increased Immunity against the Oral Germs Porphyromonas gingivalis and Prevotella intermedia in Different Categories of Juvenile Idiopathic Arthritis.

(1) Background: The link between periodontal disease and rheumatoid arthritis (RA) is now widely reported. Several studies suggest the role of Porphyromonas gingivalis (P. gingivalis) in the pathophysiology of RA and some observations highlight the improvement of the disease activity induced by therapies against P. gingivalis. We have very little data on the prevalence of P. gingivalis carriage in patients with juvenile idiopathic arthritis (JIA) and its possible involvement in the pathophysiology of inflammatory joint diseases in children. (2) Methods: The specific IgG responses against P. gingivalis and Prevotella intermedia (P. intermedia) were determined in a cohort of 101 patients with JIA and 19 patients with other autoimmune diseases (inflammatory bowel disease and type 1 diabetes). (3) Results: Specific anti-P. gingivalis and anti-P. intermedia IgG titers were higher in JIA group than in control groups. These differences were mainly observed in the oligoarthritis group. The same pattern was observed in enthesitis-related arthritis (ERA). (4) Conclusions: Children with oligoarticular and ERA subsets had higher IgG titers to P. gingivalis and P. intermedia. These results suggest involvement of an oral dysbiosis in the occurrence of JIA in these subgroups.

Validation Study of a New Random-Access Chemiluminescence Immunoassay Analyzer i-TRACK10® to Monitor Infliximab and Adalimumab Serum trough Levels and Anti-Drug Antibodies.

Background. Monitoring of biological TNF inhibitors is a very important tool to guide clinical decisions using specialized algorithms, especially in gastroenterology. A new chemiluminescent instrument (i-TRACK10® from Theradiag) could replace ELISA techniques to calculate the dosage of drugs and anti-drug antibodies. In this bi-centric study, we explored the analytical performances of i-TRACK10® using manual or automated (DS2®) ELISA Lisa-Tracker® assays, and compared the results. Patients and methods. Intra- and inter-run performances were evaluated with i-TRACK10® in two different laboratories and for two different ranges of values for infliximab, adalimumab, and their respective antibodies. Patients' samples were used in the labs to compare the results obtained between the new instrument and either the manual Lisa-Tracker® or the automated DS2. Results. Intra- and inter-run performances were satisfactory, with values between 1.8% and 16.1% (for inter-run imprecision at low/medium values of infliximab). Results were generally comparable between assays. with the lowest value of correlation at 0.59 (anti-adalimumab dosage between i-TRACK10® and manual ELISA). Most often, values of drugs and anti-drug antibodies were higher with i-TRACK10® than with manual ELISA assay, and correlation values were better with automated ELISA. Agreements were globally acceptable, and the lowest coefficients of 0.7 was obtained for adalimumab values between i-TRACK10® and the two ELISA methods, and for anti-adalimumab values between i-TRACK10® and manual ELISA. The type of assay can potentially induce a change in the class of patients and lead to divergent therapeutic decisions. Conclusions. The new random-access instrument i-TRACK10® presents many advantages in a routine laboratory: rapidity, the possibility of standardization, usability, and expansion of the measurement range. Despite the relatively good agreement of results, it is preferable to use the same assay in longitudinal follow-up of a patient, because quantitative results were not completely equivalent especially for anti-drug antibodies.

On the role of pore constrictions in gas diffusion electrodes.

Water management by gas diffusion electrodes is a fundamental aspect of the performance of electrochemical cells. Herein, we introduce the characteristic constrictions size as a descriptor for microporous layers (MPL). This parameter is calculated by volumetric analysis of focused ion beam nanotomography and compared to mercury intrusion porosimetry measurements.

Dynamics of circulating calprotectin accurately predict the outcome of moderate COVID-19 patients.

BACKGROUND: Severe COVID-19 is associated with a high circulating level of calprotectin, the S100A8/S100A9 alarmin heterodimer. Baseline calprotectin amount measured in peripheral blood at diagnosis correlates with disease severity. The optimal use of this biomarker along COVID-19 course remains to be delineated. METHODS: We focused on patients with a WHO-defined moderate COVID-19 requiring hospitalization in a medical ward. We collected plasma and serum from three independent cohorts (N = 626 patients) and measured calprotectin amount at admission. We performed longitudinal measures of calprotectin in 457 of these patients (1461 samples) and used a joint latent class mixture model in which classes were defined by age, body mass index and comorbidities to identify calprotectin trajectories predicting the risk of transfer into an intensive care unit or death. FINDINGS: After adjustment for age, sex, body mass index and comorbidities, the predictive value of baseline calprotectin in patients with moderate COVID19 could be refined by serial monitoring of the biomarker. We discriminated three calprotectin trajectories associated with low, moderate, and high risk of poor outcome, and we designed an algorithm available as online software (https://calpla.gustaveroussy.fr:8443/) to monitor the probability of a poor outcome in individual patients with moderate COVID-19. INTERPRETATION: These results emphasize the clinical interest of serial monitoring of calprotectin amount in the peripheral blood to anticipate the risk of poor outcomes in patients with moderate COVID-19 hospitalized in a standard care unit. FUNDING: The study received support (research grants) from ThermoFisher immunodiagnostics (France) and Gustave Roussy Foundation.

Cytokine release syndrome-like serum responses after COVID-19 vaccination are frequent and clinically inapparent under cancer immunotherapy.

Patients with cancer frequently receive immune-checkpoint inhibitors (ICIs), which may modulate immune responses to COVID-19 vaccines. Recently, cytokine release syndrome (CRS) was observed in a patient with cancer who received BTN162b2 vaccination under ICI treatment. Here, we analyzed adverse events and serum cytokines in patients with 23 different tumors undergoing (n = 64) or not undergoing (n = 26) COVID-19 vaccination under ICI therapy in a prospectively planned German single-center cohort study (n = 220). We did not observe clinically relevant CRS (≥grade 2) after vaccination (95% CI 0-5.6%; Common Terminology of Adverse Events v.5.0) in this small cohort. Within 4 weeks after vaccination, serious adverse events occurred in eight patients (12.5% 95% CI 5.6-23%): six patients were hospitalized due to events common under cancer therapy including immune related adverse events and two patients died due to conditions present before vaccination. Despite absence of CRS symptoms, a set of pairwise-correlated CRS-associated cytokines, including CXCL8 and interleukin-6 was >1.5-fold upregulated in 40% (95% CI 23.9-57.9%) of patients after vaccination. Hence, elevated cytokine levels are common and not sufficient to establish CRS diagnosis.