Molecular epidemiology and disease severity of influenza virus infection in patients with haematological disorders

nfluenza virus infection is a common cause of self‐limiting respiratory tract infection(RTI), however immunocompromised patients are at an increased risk for a severecourse of disease or fatal outcome. We therefore aimed to gain a betterunderstanding of the molecular epidemiology of influenza viruses from patientswith haematological disorders and their impact on the clinical course of disease.Molecular analysis using polymerase chain reaction (PCR) of nasopharyngeal swabswas performed for influenza virus in haematological patients at the HeidelbergUniversity Hospital. Clinical data was evaluated to identify associated risk factors.For phylogenetic analysis, the hemagglutinin (HA) gene was sequenced. Out of 159influenza positive patients, 117 patients developed upper RTI (influenza A:n= 73;influenza B:n= 44). Lower RTI was observed inn= 42 patients (26%),n= 22/42patients developed severe disease andn= 16/159 (10.1%) patients died. Risk factorsfor lower RTI were nosocomial infection (p= 0.02), viral shedding for≥14 days(p= 0.018), IgG levels <6 g/dL (p= 0.046), bacterial/fungal co‐infections (p< 0.001).Risk factors for fatal outcome were age≥65 years (p= 0.032), bacterial/fungal(p≤0.001) co‐infections and high viral load (p= 0.026). Sequencing of the HA gene(n= 115) revealed subtype A(H3N2) (n= 46), A(H1N1)pdm09 (n= 24), B/Victoria(n= 34), B/Yamagata (n= 11). There was no correlation between influenza (sub)typeand lower RTI. Influenza infection in haematological patients is associated withsignificant morbidity and mortality, the risk for aggravating co‐infections, prolongedviral shedding and nosocomial transmission emphasizing the need for infectioncontrol.Peer Reviewe

Comprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities

The outcomes of patients with multiple myeloma (MM) refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) remain poor. In this study, we performed whole genome and transcriptome sequencing of 39 heavily pretreated relapsed/refractory MM (RRMM) patients to identify mechanisms of resistance and potential therapeutic targets. We observed a high mutational load and indications of increased genomic instability. Recurrently mutated genes in RRMM, which had not been previously reported or only observed at a lower frequency in newly diagnosed MM, included NRAS, BRAF, TP53, SLC4A7, MLLT4, EWSR1, HCFC2, and COPS3. We found multiple genomic regions with bi-allelic events affecting tumor suppressor genes and demonstrated a significant adverse impact of bi-allelic TP53 alterations on survival. With regard to potentially resistance conferring mutations, recurrently mutated gene networks included genes with relevance for PI and IMiD activity; the latter particularly affecting members of the Cereblon and the COP9 signalosome complex. We observed a major impact of signatures associated with exposure to melphalan or impaired DNA double-strand break homologous recombination repair in RRMM. The latter coincided with mutations in genes associated with PARP inhibitor sensitivity in 49% of RRMM patients; a finding with potential therapeutic implications. In conclusion, this comprehensive genomic characterization revealed a complex mutational and structural landscape in RRMM and highlights potential implications for therapeutic strategies

IKZF1/3 and CRL4-CRBN E3 ubiquitin ligase mutations and IMiD resistance in multiple myeloma

The work was supported by the Deutsche Forschungsgemeinschaft (KFO216), the IZKF, the BTHA and the CDW Stiftung (KMK). UM was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences, University of Würzburg.S

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Cellular Immune Response after Vaccination in Patients with Cancer&mdash;Review on Past and Present Experiences

Patients with cancer are at particular risk for infection but also have diminished vaccine responses, usually quantified by the level of specific antibodies. Nonetheless, vaccines are specifically recommended in this vulnerable patient group. Here, we discuss the cellular part of the vaccine response in patients with cancer. We summarize the experience with vaccines prior to and during the SARS-CoV-2 pandemic in different subgroups, and we discuss why, especially in patients with cancer, T cells may be the more reliable correlate of protection. Finally, we provide a brief outlook on options to improve the cellular response to vaccines

Carfilzomib, Lenalidomide, and Dexamethasone Followed by Salvage Autologous Stem Cell Transplant with or without Maintenance for Relapsed or Refractory Multiple Myeloma

Salvage high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is a treatment option for relapsed and/or refractory multiple myeloma (RRMM). No data are available on salvage HDCT/ASCT following re-induction treatment with state-of-the-art triplet regimens. We retrospectively report on 44 patients receiving salvage HDCT/ASCT following re-induction with carfilzomib/lenalidomide/dexamethasone (KRd). All patients received frontline HDCT/ASCT with median time to progression (TTP1) of 2.9 (1.2–13.5) years, enabling paired comparison of frontline and salvage HDCT/ASCT. After re-induction and before salvage transplant, 25/44 patients (57%) attained ≥ very good partial response (VGPR), which increased to 34/44 (77%) at best response after salvage HDCT/ASCT. Median progression-free survival (PFS) was 23.3 months from salvage HDCT/ASCT. Patients with ≥ VGPR at the time of salvage HDCT/ASCT and those receiving maintenance treatment post salvage HDCT/ASCT had significantly superior PFS (hazard ratio (HR) 0.19, p = 0.001 and HR 0.20, p = 0.009). In patients achieving at least an equal depth of response before salvage HDCT/ASCT as before frontline HDCT/ASCT, PFS after salvage HDCT/ASCT was comparable to the frontline situation (p = 0.3). This is the first report of state-of-the-art triplet re-induction and salvage HDCT/ASCT for RRMM after frontline transplantation. Deep remissions achieved with KRd translate into prolonged PFS following salvage HDCT/ASCT and are enhanced by maintenance treatment

Sexual size dimorphism is associated with reproductive life history trait differentiation in coexisting sepsid flies

Organismal life histories evolve as syndromes, resulting in correlated evolutionary differentiation of key traits that ultimately aid in discerning species. Reproductive success depends both on the absolute body size of an individual and its size relative to the opposite sex: sexual size dimorphism. In an attempt to further elucidate their coexistence and ecological diversification, we compared standard life history (first reproduction, clutch size, egg size) and associated reproductive trait differentiation of 15 widespread European sepsid fly species (Diptera: Sepsidae) under laboratory common garden conditions. Despite relatively uniform body sizes, sexual dimorphism ranged from female‐ to male‐biased, and development time varied twofold across species. We expected, and found, the abundant and relatively large species (Sepsis cynipsea, punctum, thoracica) with often male‐biased SSD to lay larger but fewer eggs and show fast‐developing, fast‐reproducing life histories with aggressive (coercive) mating behavior characterized by short mating latencies and male conflict. In contrast, the smaller and more dispersed species with female‐biased SSD (S. flavimana, orthocnemis, violacea) laid smaller but more eggs, showing a generally slower life history with long and delayed copulation and oviposition, high mating reluctance fostering extensive inter‐sexual conflict, and more elaborate male (pre‐)copulatory courtship. Two Saltella species were exceptional, being large, developing slowly, nevertheless copulating soon after adult emergence, profusely and briefly. The documented life history differentiation seems partly driven by sexual selection leading to male‐biased dimorphism, rather than undetermined ecological selection, but regardless appears insufficient to explain the coexistence and diversification of these sepsid species in European pastoral landscapes

Retrospective, Observational Analysis on the Impact of SARS-CoV-2 Variant Omicron in Hospitalized Immunocompromised Patients in a German Hospital Network—The VISAGE Study

Aims: Endemic SARS-CoV-2 infections still burden the healthcare system and represent a considerable threat to vulnerable patient cohorts, in particular immunocompromised (IC) patients. This study aimed to analyze the in-hospital outcome of IC patients with severe SARS-CoV-2 infection in Germany. Methods: This retrospective, observational study, analyzed administrative data from inpatient cases (n = 146,324) in 84 German Helios hospitals between 1 January 2022 and 31 December 2022 with regard to in-hospital outcome and health care burden in IC patients during the first 12 months of Omicron dominance. As the primary objective, in-hospital outcomes of patients with COVID-19-related severe acute respiratory infection (SARI) were analyzed by comparing patients with (n = 2037) and without IC diagnoses (n = 14,772). Secondary analyses were conducted on IC patients with (n = 2037) and without COVID-19-related SARI (n = 129,515). A severe in-hospital outcome as a composite endpoint was defined per the WHO definition if one of the following criteria were met: intensive care unit (ICU) treatment, mechanical ventilation (MV), or in-hospital death. Results: In total, 12% of COVID-related SARI cases were IC patients, accounting for 15% of ICU admissions, 15% of MV use, and 16% of deaths, resulting in a higher prevalence of severe in-hospital courses in IC patients developing COVID-19-related SARI compared to non-IC patients (Odds Ratio, OR = 1.4, p p p p p < 0.001). Conclusions: Our findings highlight the vulnerability of IC patients to severe COVID-19. The persistently high prevalence of severe outcomes in these patients in the Omicron era emphasizes the necessity for continuous in-hospital risk assessment and monitoring of IC patients

Antibiotic Prophylaxis or Granulocyte-Colony Stimulating Factor Support in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation

We compare, in this manuscript, antibiotic prophylaxis versus granulocyte-colony stimulating factor (G-CSF) support as anti-infective strategies, in patients with multiple myeloma (MM), undergoing high-dose therapy followed by autologous stem cell transplantation (HDT/ASCT). At our institution, antibiotic prophylaxis after HDT/ASCT in MM was stopped in January 2017 and replaced by G-CSF support in March 2017. Consecutive MM patients who received HDT/ASCT between March 2016 and July 2018 were included in this single-center retrospective analysis. In total, 298 patients and 353 individual cases of HDT/ASCT were evaluated. In multivariate analyses, G-CSF support was associated with a significantly shortened duration of severe leukopenia &lt; 1/nL (p &lt; 0.001, hazard ratio (HR) = 16.22), and hospitalization (estimate = −0.19, p &lt; 0.001) compared to antibiotic prophylaxis. Rates of febrile neutropenia, need of antimicrobial therapy, transfer to intensive care unit, and death, were similar between the two groups. Furthermore, antibiotic prophylaxis was associated with a significantly increased risk for the development of multidrug resistant bacteria especially vancomycin-resistant Enterococcus faecium compared to G-CSF support (odds ratio (OR) = 17.38, p = 0.01). Stop of antibiotic prophylaxis as an anti-infective strategy was associated with a reduction in overall resistance rates of bacterial isolates. These results indicate that G-CSF support should be the preferred option in MM patients undergoing HDT/ASCT