Persistent immune abnormalities discriminate post-COVID syndrome from convalescence.

BACKGROUND: Innate lymphoid cells (ILCs) are key organizers of tissue immune responses and regulate tissue development, repair, and pathology. Persistent clinical sequelae beyond 12 weeks following acute COVID-19 disease, named post-COVID syndrome (PCS), are increasingly recognized in convalescent individuals. ILCs have been associated with the severity of COVID-19 symptoms but their role in the development of PCS remains poorly defined. METHODS AND RESULTS: Here, we used multiparametric immune phenotyping, finding expanded circulating ILC precursors (ILCPs) and concurrent decreased group 2 innate lymphoid cells (ILC2s) in PCS patients compared to well-matched convalescent control groups at > 3 months after infection or healthy controls. Patients with PCS showed elevated expression of chemokines and cytokines associated with trafficking of immune cells (CCL19/MIP-3b, FLT3-ligand), endothelial inflammation and repair (CXCL1, EGF, RANTES, IL-1RA, PDGF-AA). CONCLUSION: These results define immunological parameters associated with PCS and might help find biomarkers and disease-relevant therapeutic strategies.

Multidisciplinary rehabilitation with a focus on physiotherapy in patients with Post Covid19 condition: an observational pilot study.

There is a lack of interventions that treat the Post-Covid-19 Condition (PCC) itself. Accordingly, treatment guidelines recommend physiotherapy interventions to alleviate symptoms and enhance functioning. In cases where unimodal treatments prove ineffective, non-organ-specific multidisciplinary bio-psycho-social rehabilitation (MBR) programs are a suitable option. In a pilot observational study with assessments at the entry and end of treatment we aimed to evaluate the feasibility of a 3-week day clinic MBR program and explore its effects on physical functioning in PCC patients with fatigue and reduced physical capacity. Patient selection was based on an interdisciplinary assessment involving a physician, a psychologist and a physiotherapist. Feasibility was determined based on full participation (≥ 8 of 9 days) and maintenance of stable endurance in the 6-Minute Walk Test (6MWT). From 37 patients included in the study, 33 completed the MBR (mean age: 43 ± 12 years, 73% female). Four patients discontinued the MBR, with two of them having reported deterioration of PCC symptoms. The 6MWT showed a numerical improvement from 501 ± 97 m to 512 ± 87 m, although it did not reach statistical significance. These results support the feasibility of outpatient MBR with a focus on active physiotherapy interventions in PCC patients with fatigue. This study aligns with previous research supporting the effectiveness of physiotherapy and rehabilitation in PCC patients. However, further research is needed to address possible different treatment responses and varying treatment approaches in subgroups of PCC patients.

Headache severity in patients with post COVID-19 condition: a case-control study.

Post COVID-19 conditions (PCC) present with a wide range of symptoms. Headache is one of the most frequently reported neurological symptoms by patients with PCC. We aimed to assess the prevalence of headache in patients with PCC who attended the Post-COVIDLMU outpatient department at LMU University Hospital in Munich. We hypothesized that headaches occur more frequently in patients with PCC than in the control group. Patients answered a questionnaire containing sociodemographic characteristics, their current symptoms, and prior psychiatric and somatic diagnoses, the WHO Quality of Life assessment (WHOQOL-BREF), 9-item Patient Health Questionnaire (PHQ-9), and the Fatigue Severity Scale (FSS). 188 PCC patients were included in this study and compared to a control group of patients with a history of COVID-19 or a different infectious disease - but no consecutive post-infectious condition (nc=27). 115 (61%) of our PCC patients were female. The median age was 41 years. 60 (32%, p = 0.001) had a pre-existing psychiatric diagnosis. PCC was associated with worse outcomes in all four domains of the WHOQOL-BREF (p < 0.001), high levels of fatigue (FSS; p < 0.001), and a higher likeliness for symptoms of depression (PHQ-9; p < 0.001). We were able to confirm that psychiatric disorders are more frequently associated with headaches in PCC patients. Headache should be assessed and treated in the context of PCC not only by neurologists but by multi-professional teams and regarding all PCC symptoms.

Characterization of cognitive symptoms in post COVID-19 patients.

Cognitive symptoms (CS) belong to the most common manifestations of the Post COVID-19 (PC) condition. We sought to objectify CS in PC patients using routine diagnostic assessments: neurocognitive testing (NCT) and brain imaging (BI). Further, we investigated possible associations of CS with patient reported outcomes (PROs), and risk factors for developing CS. Clinical data and PROs of 315 PC patients were assessed at a mean of 6 months after SARS-CoV-2 infection. 231 (73.3%) patients reported any sort of CS. Among them, 78 underwent NCT and 55 received BI. In NCT, the cognitive domains most affected were the working memory, attention, and concentration. Nonetheless, pathological thresholds were exceeded only in few cases. Neurocognitive performance did not differ significantly between patients complaining of severe (n = 26) versus non-severe (n = 52) CS. BI findings were abnormal in 8 (14.5%) cases with CS but were most likely not related to PC. Patients reporting high severity of CS scored worse in the PHQ-9, FSS, WHOQOL-BREF, were more likely to report impaired sleep, and had a higher prevalence of psychiatric diagnoses. Overall, NCT could confirm mild impairment in some but not all PC patients with CS, while BI studies were abnormal in only few cases. CS severity did not affect NCT results, but severe CS were associated with symptoms of depression (PHQ-9), fatigue (FSS), reduced quality of life (WHOQOL-BREF) and higher prevalence of psychiatric illnesses. These findings support the importance of NCT, BI, and neuro-psychological assessment in the work-up of PC patients reporting CS. TRIAL REGISTRATION: Trial registration number and date of registration: DRKS00030974, 22 Dec 2022, retrospectively registered.

Effects of cognitive training and group psychotherapy on cognitive performance of post COVID-19 patients: an exploratory and non-randomized clinical trial.

Cognitive complaints are common signs of the Post COVID-19 (PC) condition, but the extent and type of cognitive impairment may be heterogeneous. Little is known about neuropsychological treatment options. Preliminary evidence suggests cognitive symptoms may improve with cognitive training and naturally over time. In this clinical trial, we examined whether participation in a weekly group consisting of cognitive training and group psychotherapy is feasible and would exert beneficial effects on cognitive performance in PC and whether improvements were associated with intervention group participation or represented a temporal improvement effect during syndrome progression. 15 PC patients underwent an 8-week intervention. Cognitive performance was assessed before and after each intervention group participation. A control group of 15 PC patients with subjective neurocognitive or psychiatric complaints underwent two cognitive assessments with comparable time intervals without group participation. To attribute changes to the intervention group participation, interaction effects of group participation and time were checked for significance. This is an exploratory, non-randomized, non-blinded controlled clinical trial. Within the intervention group, significant improvements were found for most cognitive measures. However, significant time x group interactions were only detected in some dimensions of verbal memory and visuo-spatial construction skills. Significant time effects were observed for attention, concentration, memory, executive functions, and processing speed. The intervention setting was feasible and rated as helpful and relevant by the patients. Our results suggest that cognitive symptoms of PC patients may improve over time. Patients affected by both neurocognitive impairments and mental disorders benefit from group psychotherapy and neurocognitive training. The present study provides evidence for a better understanding of the dynamic symptomatology of PC and might help to develop further studies addressing possible therapy designs. The main limitations of this exploratory feasibility trial are the small sample size as well as the non-randomized design due to the clinical setting.

Prognostic value of the International Metabolic Prognostic Index for lymphoma patients receiving chimeric antigen receptor T-cell therapy.

PURPOSE: Chimeric antigen receptor T-cell therapy (CART) prolongs survival for patients with relapsed/refractory B-cell non-Hodgkin's lymphoma. The recently introduced International Metabolic Prognostic Index (IMPI) was shown to improve prognostication in the first-line treatment of large B-cell lymphoma. Here, we investigate the prognostic value of the IMPI for progression-free (PFS) and overall survival (OS) in the setting of CD19 CART. METHODS: Consecutively treated patients with baseline 18F-FDG PET/CT imaging and follow-up imaging at 30 days after CART were included. IMPI is composed of age, stage, and metabolic tumor volume (MTV) at baseline and was compared with the International Prognostic Index (IPI). Both indices were grouped into quartiles, as previously described for IPI. In addition, the continuous IMPI was subdivided into tertiaries for better separation of risk groups. Overall response rate (ORR), depth of response (DoR), and PFS were determined based on Lugano criteria. Proportional Cox regression analysis studied association of IMPI and IPI with PFS and OS. RESULTS: Thirty-nine patients were included. The IPI was 1 in 23%, 2 in 21%, 3 in 26%, 4 in 21%, and 5 in 10% of the patients. IMPIlow risk, IMPIintermediate risk, and IMPIhigh risk patients had 30-day ORR of 69%, 62%, and 62% and 30-day DoR of - 67%, - 66%, and - 54% with a PFS of 187 days, 97 days, and 87 days, respectively. ORR and DoR showed no correlation with lower IMPI (r = 0.065, p = 0.697). Dividing patients into three risk groups showed a significant trend for PFS stratification (p = 0.030), while IPI did not (p = 0.133). Neither IPI nor IMPI yielded a significant association with OS after CART (both p > 0.05). CONCLUSION: In the context of CART, the IMPI yielded prognostic value regarding PFS estimation. In contrast with IMPI in the first-line DLBCL setting, we did not observe a significant association of IMPI at baseline with OS after CART.

Treatment, outcome and re-vaccination of patients with SARS-CoV-2 vaccine-associated immune thrombocytopenia.

PURPOSE: Following the emergency use authorization of BNT162b2 by the Food and Drug administration (FDA) in early December 2020, mRNA- and vector-based vaccines became an important means of reducing the spread and mortality of the COVID-19 pandemic. The European Medicines Agency labelled immune thrombocytopenia (ITP) as a rare adverse reaction of unknown frequency after vector-, but not mRNA-vaccination. Here, we report on the long-term outcome of 6 patients who were diagnosed with de-novo, vaccine-associated ITP (VA-ITP), and on the outcome of subsequent SARS-CoV-2 re-vaccinations. METHODS: Patients were included after presenting to our emergency department. Therapy was applied according to ITP guidelines. Follow-up data were obtained from outpatient departments. Both mRNA- or vector-based vaccines were each used in 3 cases, respectively. RESULTS: In all patients, the onset of symptoms occurred after the 1st dose of vaccine was applied. 5 patients required treatment, 3 of them 2nd line therapy. All patients showed a complete response eventually. After up to 359 days of follow-up, 2 patients were still under 2nd line therapy with thrombopoietin receptor agonists. 5 patients have been re-vaccinated with up to 3 consecutive doses of SARS-CoV-2 vaccines, 4 of them showing stable platelet counts hereafter. CONCLUSION: Thrombocytopenia after COVID-19 vaccination should trigger a diagnostic workup to exclude vaccine-induced immune thrombotic thrombocytopenia (VITT) and, if confirmed, VA-ITP should be treated according to current ITP guidelines. Re-vaccination of patients seems feasible under close monitoring of blood counts and using a vaccine that differs from the one triggering the initial episode of VA-ITP.

Substantial differences in perception of disease severity between post COVID-19 patients, internists, and psychiatrists or psychologists: the Health Perception Gap and its clinical implications.

Patient-reported outcome measures (PROMs) such as the Numeric Pain Rating Scale (NPRS) or Likert scales addressing various domains of health are important tools to assess disease severity in Post COVID-19 (PC) patients. By design, they are subjective in nature and prone to bias. Our findings reveal substantial differences in the perception of disease severity between patients (PAT), their attending internists (INT) and psychiatrists/psychologists (PSY). Patients rated almost all aspects of their health worse than INT or PSY. Most of the differences were statistically highly significant. The presence of fatigue and mood disorders correlated negatively with health perception. The physical health section of the WHO Quality of Life Assessment (WHOQoL-BREF) and Karnofsky index correlated positively with overall and mental health ratings by PAT and INT. Health ratings by neither PAT, PSY nor INT were associated with the number of abnormal findings in diagnostic procedures. This study highlights how strongly perceptions of disease severity diverge between PC patients and attending medical staff. Imprecise communication, different experiences regarding health and disease, and confounding psychological factors may explain these observations. Discrepancies in disease perception threaten patient-physician relationships and pose strong confounders in clinical studies. Established scores (e.g., WHOQoL-BREF, Karnofsky index) may represent an approach to overcome these discrepancies. Physicians and psychologists noting harsh differences between a patient's and their own perception of the patient's health should apply screening tools for mood disorders (i.e., PHQ-9, WHOQoL-BREF), psychosomatic symptom burden (SSD-12, FCV-19) and consider further psychological evaluation. An interdisciplinary approach to PC patients remains imperative. Trial Registration Number & Date of Registration: DRKS00030974, 22 Dec 2022, retrospectively registered.

Lymphoma tumor burden before chimeric antigen receptor T-Cell treatment: RECIL vs. Lugano vs. metabolic tumor assessment.

Purpose: High tumor burden has emerged as a negative predictor of efficacy in chimeric antigen receptor T-cell therapy (CART) in patients with refractory or relapsed large B-cell lymphoma. This study analyzed the deviation among imaging-based tumor burden (TB) metrics and their association with progression-free (PFS) and overall survival (OS). Materials and methods: In this single-center observational study, we included all consecutively treated patients receiving CD19 CART with available baseline PET-CT imaging. Imaging-based TB was determined based on response evaluation criteria in lymphoma (RECIL), the Lugano criteria, and metabolic tumor volume. Total, nodal and extranodal TB were represented, according to the respective criteria, by sum of longest diameters (TBRECIL), sum of product of perpendicular diameters (TBLugano), and metabolic tumor volume (TBMTV). Correlation statistics were used for comparison. Proportional Cox regression analysis studied the association of TB metrics with PFS and OS. Results: 34 consecutive patients were included (median age: 67 years, 41% female) with total median baseline TBRECIL of 12.5 cm, TBLugano of 4,030 mm2 and TBMTV of 330 mL. The correlation of TBRECIL and TBLugano with TBMTV was strong (ρ=0.744, p<0.001 and ρ=0.741, p<0.001), with lowest correlation for extranodal TBRECIL with TBMTV (ρ=0.660, p<0.001). Stratification of PFS was strongest by total TBMTV>50% (HR=2.915, p=0.042), whereas total TBRECIL>50% and total TBLugano>50% were not significant (both p>0.05). None of the total TB metrics were associated with OS (all p>0.05). Conclusion: Pre-CART TB metrics vary significantly based on the assessment method, impacting their association with survival outcomes. The correlation between TBRECIL, TBLugano and TBMTV was influenced by disease phenotype and prior bridging therapy. TB method of assessment must be considered when interpreting the impact of TB on outcomes in clinical trials. Considering the heterogeneity, our results argue for standardization and harmonization across centers.

PET/CT imaging for tumour response assessment to immunotherapy: current status and future directions.

Recent immunotherapeutic approaches have evolved as powerful treatment options with high anti-tumour responses involving the patient's own immune system. Passive immunotherapy applies agents that enhance existing anti-tumour responses, such as antibodies against immune checkpoints. Active immunotherapy uses agents that direct the immune system to attack tumour cells by targeting tumour antigens. Active cellular-based therapies are on the rise, most notably chimeric antigen receptor T cell therapy, which redirects patient-derived T cells against tumour antigens. Approved treatments are available for a variety of solid malignancies including melanoma, lung cancer and haematologic diseases. These novel immune-related therapeutic approaches can be accompanied by new patterns of response and progression and immune-related side-effects that challenge established imaging-based response assessment criteria, such as Response Evaluation Criteria in Solid tumours (RECIST) 1.1. Hence, new criteria have been developed. Beyond morphological information of computed tomography (CT) and magnetic resonance imaging, positron emission tomography (PET) emerges as a comprehensive imaging modality by assessing (patho-)physiological processes such as glucose metabolism, which enables more comprehensive response assessment in oncological patients. We review the current concepts of response assessment to immunotherapy with particular emphasis on hybrid imaging with 18F-FDG-PET/CT and aims at describing future trends of immunotherapy and additional aspects of molecular imaging within the field of immunotherapy.

Urinary Frequency as a Possibly Overlooked Symptom in COVID-19 Patients: Does SARS-CoV-2 Cause Viral Cystitis?

The current coronavirus disease 2019 (COVID-19) pandemic is a challenge for physicians in triaging patients in emergency rooms. We found a potentially dangerous overlap of classical urinary symptoms and the as yet not fully described symptoms of COVID-19. After a patient was primarily triaged as a urosepsis case and then subsequently diagnosed with COVID-19, we focused on an increase in urinary frequency as a symptom of COVID-19 and identified this in seven males out of 57 patients currently being treated in our COVID-19 wards. In the absence of any other causes, urinary frequency may be secondary to viral cystitis due to underlying COVID-19 disease. We propose consideration of urinary frequency as an anamnestic tool in patients with infective symptoms to increase awareness among urologists during the current COVID-19 pandemic to prevent fatal implications of misinterpreting urological symptoms.

RIG-I-based immunotherapy enhances survival in preclinical AML models and sensitizes AML cells to checkpoint blockade.

Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic immune receptor sensing viral RNA. It triggers the release of type I interferons (IFN) and proinflammatory cytokines inducing an adaptive cellular immune response. We investigated the therapeutic potential of systemic RIG-I activation by short 5'-triphosphate-modified RNA (ppp-RNA) for the treatment of acute myeloid leukemia (AML) in the syngeneic murine C1498 AML tumor model. ppp-RNA treatment significantly reduced tumor burden, delayed disease onset and led to complete remission including immunological memory formation in a substantial proportion of animals. Therapy-induced tumor rejection was dependent on CD4+ and CD8+ T cells, but not on NK or B cells, and relied on intact IFN and mitochondrial antiviral signaling protein (MAVS) signaling in the host. Interestingly, ppp-RNA treatment induced programmed death ligand 1 (PD-L1) expression on AML cells and established therapeutic sensitivity to anti-PD-1 checkpoint blockade in vivo. In immune-reconstituted humanized mice, ppp-RNA treatment reduced the number of patient-derived xenografted (PDX) AML cells in blood and bone marrow while concomitantly enhancing CD3+ T cell counts in the respective tissues. Due to its ability to establish a state of full remission and immunological memory, our findings show that ppp-RNA treatment is a promising strategy for the immunotherapy of AML.