Adenovirus-induced hemorrhagic cystitis after CD19-targeted chimeric antigen receptor T-cell therapy in a patient with large B-cell lymphoma.

Chimeric antigen receptor (CAR) T cells targeting CD19 have changed the treatment landscape of patients with relapsed/refractory diffuse large B-cell lymphoma. Infections are one of the most frequent complications after CAR T-cell therapy. Most of these infections are bacterial, although viral infections can also occur in this setting. Adenovirus-induced hemorrhagic cystitis is a rare infectious complication and is usually observed after bone marrow or solid organ transplantation. Herein we report a case of adenovirus-induced hemorrhagic cystitis in a patient experiencing urinary symptoms within the first month after CAR T-cell infusion. Based on our experience and a literature review, we discuss the diagnostic approach and potential treatment options for this infrequent infection after CAR T-cell therapy.

Lymphoma is an aggressive blood cell cancer. A treatment called chimeric antigen receptor (CAR) T-cell therapy has recently been developed for patients with lymphoma and other blood cancers. CAR T-cell therapy is based on the genetic change of the patient's T cells. T cells are a type of white blood cell, which help to attack cancer. CAR T-cell treatment is very effective, but it also carries a risk of adverse events, including infections. These infections can be caused by bacteria or viruses and can affect several organs, including the bladder. Patients with blood cancers who develop bladder infections can have severe pain and bleeding. These bleeding bladder infections are mostly caused by adenovirus or BK virus and are usually seen in patients who have received a bone marrow transplant. However, these infections are rarely observed in patients receiving CAR T cells. We report here a case of bleeding bladder infection caused by adenovirus in a patient receiving CAR T-cell therapy. We discuss the diagnostic approach and possible treatment options for this rare infection in CAR T-cell patients.

CMV hyperimmune globulin as salvage therapy for recurrent or refractory CMV infection in children undergoing hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) is a major cause of allogeneic hematopoietic stem cell transplant (HSCT)-related morbidity and mortality. Treatment failure continues to be a major issue in patients with CMV infection due to both drug resistance and intolerance. This single-center brief retrospective analysis of a case series aims to investigate the safety and efficacy of CMV-hyperimmune globulin as salvage therapy for CMV infection in children undergoing HSCT. Fifteen pediatric patients received human CMV-specific immunoglobulin (CMVIG) between July 2018 and December 2021 as a salvage therapy for refractory or recurrent CMV infection. At the time of CMVIG prescription, eight children presented with recurrent CMV infection and seven with refractory CMV infection. The overall response rate was 67% at 50 days from the CMVIG administration [95% confidence interval (CI): 44-88]. Overall survival (OS) from CMVIG administration at 100 days was 87% (95% CI: 56-96), and OS from HSCT at 1 year was 80% (95% CI: 50-93). Four patients died, three unrelated to CMV infection and one due to CMV pneumonia. CMVIG as salvage therapy was well tolerated, and no infusion-related adverse events were observed.

Kinetics of cellular and humoral immunogenicity and effectiveness of SARS-CoV-2 booster vaccination in hematologic neoplasms.

Data on the effect of booster SARS-CoV-2 vaccination are mainly focused on humoral immunogenicity, while the kinetics of vaccine-induced cellular response and its correlation with effectiveness in hematologic patients are less explored. Our aim was to evaluate the longitudinal cellular and humoral immunogenicity induced by two and three doses of the mRNA-1273 SARS-CoV-2 vaccine in 270 patients with hematologic malignancies, and its relationship with the severity of breakthrough SARS-CoV-2 infection. Results indicate that at 23 weeks after the second dose, the seroconversion rate declined from 68.5% to 59.3%, with a reduction in median anti-S titers from 1577 to 456 BAU/mL, mainly in patients over 65 years of age or chronic lymphocytic leukemia (CLL) patients undergoing active therapy. Cellular immunogenicity, however, remained positive in 84.4% of cases. A third vaccine dose seroconverted 42.7% (41/96) and triggered cellular response in 36.7% (11/30) of previously negative patients. Notably, only 7.2% (15/209) of patients failed to develop both humoral and cellular response. Active therapy, anti-CD20 antibodies, lymphopenia, hypogammaglobulinemia, and low CD19+ cell count were associated with poor humoral response, while active disease, GvHD immunosuppressive therapy, lymphopenia, and low CD3+ , CD4+ , CD56+ cell count determined an impaired cellular response. After 13.8 months of follow-up, the incidence of SARS-CoV-2 infection was 24.8% (67/270), including 6 (9%) severe/critical cases associated with a weaker cellular (median interferon gamma (IFN-γ) 0.19 vs. 0.35 IU/mL) and humoral response (median anti-S titer <4.81 vs. 788 BAU/mL) than asymptomatic/mild cases. In conclusion, SARS-CoV-2 booster vaccination improves humoral response and COVID-19 severity is associated with impaired vaccine-induced immunogenicity.

Emergence of Delta and Omicron variants carrying resistance-associated mutations in immunocompromised patients undergoing sotrovimab treatment with long-term viral excretion.

OBJECTIVES: To monitor the early emergence of genetic mutations related to reduced susceptibility to monoclonal anti-body (mAb)-based treatment in immunocompromised patients with long-term viral excretion using whole-genome sequencing at a tertiary university hospital in Barcelona, Spain. METHODS: Serial severe acute respiratory syndrome coronavirus 2-positive samples (mid-December 2021-mid-March 2022) from eight immunosuppressed, fully vaccinated patients (for solid-organ transplantation or haematologic malignancies) with long-term viral excretion despite undergoing mAb therapy (sotrovimab) for coronavirus disease 2019 were selected. Whole-genome sequencing was performed following the ARTIC, version 4.1, protocol on the MiSeq platform. Mutations in the coding sequence of the spike protein with a frequency of ≥5% were studied. RESULTS: A total of 37 samples from the studied cases were analysed. All the cases, except one, were confirmed to have the Omicron variant BA.1; one had Delta (AY.100). Thirty-four different mutations were detected within the receptor-binding domain of the spike protein in 62.5% of patients, eight of which were not lineage related and located in the sotrovimab target epitope (P337L, E340D, E340R, E340K, E340V, E340Q, R346T and K356T). Except for P337L, all changes showed a significant increase in frequency or fixation after the administration of sotrovimab. Some of them have been associated with either reduced susceptibility to mAb therapy, such as those at position 340, or the acquisition of a new glycosylation site (346 and 356 positions). CONCLUSIONS: This study highlights the importance of monitoring for early in vivo selection of mutations associated with reduced susceptibility to mAb therapy, especially in immunocompromised patients receiving anti-viral drugs, whose immune response is not able to control viral replication, resulting in long-term viral shedding, and those receiving selective evolution pressure. Virologic surveillance of genetically resistant viruses to available anti-viral therapies is considered a priority for both patients and the community.

Impact of Cytomegalovirus Replication in Patients with Aggressive B Cell Lymphoma Treated with Chimeric Antigen Receptor T Cell Therapy.

Data are scarce on cytomegalovirus (CMV) replication in patients receiving CD19-directed chimeric antigen receptor (CAR) T cell treatment. Here we describe the incidence, severity, and management of CMV infection in patients with aggressive B cell lymphoma treated with CAR T cell therapy. In this retrospective observational study, we analyzed CMV viral load and its clinical impact in patients with aggressive B cell lymphoma receiving CAR T cell therapy between July 2018 and December 2021 at a single center. Patients with a negative baseline CMV IgG or a previous allogeneic stem cell transplantation were excluded. CMV replication was determined in whole blood. Overall, 105 patients met the study's inclusion criteria. Ten patients presented with CMV replication before CAR T cell infusion and were analyzed separately. Forty-two of the remaining 95 patients (44%) had at least 1 positive CMV determination, with a viral load ≥1000 IU/mL in 21 patients (22%). Four patients in the main cohort (N = 95) and 4 patients in the preinfusion replication group (N = 10) achieved a viral load >10,000 IU/mL. Only 7 patients received preemptive antiviral treatment. No CMV end-organ disease was reported. The sole independent risk factor associated with CMV viremia ≥1000 IU/mL was dexamethasone treatment (odds ratio, 8.4; 95% confidence interval, 2.4 to 36.6; P = .002). Based on our findings, we designed an algorithm for CMV management in this setting. CMV replication is relatively frequent in patients with aggressive B cell lymphoma receiving CAR T cell therapy. It is usually self-limited and not associated with end-organ disease. Patients receiving dexamethasone or harboring CMV replication before infusion might benefit from active surveillance and preemptive treatment strategies.

Epstein-Barr virus-associated risk factors for post-transplant lymphoproliferative disease in pediatric liver transplant recipients.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) are the most common de novo malignancies after liver transplantation (LT) in children. The aim of our study was to assess the role of pre-LT EBV status and post-LT EBV viral load as risk factors for developing PTLD in a cohort of pediatric LT recipients. METHODS: Data of all children who underwent LT between January 2002 and December 2019 were collected. Two cohorts were built EBV pre-LT primary infected cohort and EBV post-LT primary infected cohort. Moreover, using the maximal EBV viral load, a ROC curve was constructed to find a cutoff point for the diagnosis of PTLD. RESULTS: Among the 251 patients included in the study, fifteen PTLD episodes in 14 LT recipients were detected (2 plasmacytic hyperplasia, 10 polymorphic PTLD, 2 monomorphic PTLD, and 1 Classical-Hodgkin's lymphoma). Patients of the EBV post-LT primary infected cohort were 17.1 times more likely to develop a PTLD than patients of the EBV pre-LT primary infected cohort (2.2-133.5). The EBV viral load value to predict PTLD was set at 211 000 UI/mL (93.3% sensitivity and 77.1% specificity; AUC 93.8%; IC 0.89-0.98). In EBV post-LT primary infected cohort, patients with a viral load above 211 000 were 30 times more likely to develop PTLD than patients with a viral load below this value (OR 29.8; 3.7-241.1; p < 0.001). CONCLUSIONS: The combination of pretransplant EBV serological status with EBV post-transplant viral load could be a powerful tool to stratify the risk of PTLD in pediatric LT patients.

Commercialized kits to assess T-cell responses against SARS-CoV-2 S peptides. A pilot study in health care workers.

BACKGROUND: It is crucial to assess the levels of protection generated by natural infection or SARS-CoV-2 vaccines, mainly in individuals professionally exposed and in vulnerable groups. Measuring T-cell responses may complement antibody tests currently in use as correlates of protection. Our aim was to assess the feasibility of a validated assay of T-cell responses. METHODS: Twenty health-care-workers (HCW) were included. Antibody test to SARS-CoV-2 N and S-proteins in parallel with a commercially available whole-blood-interferon-gamma-release-assay (IGRA) to S-peptides and two detection methods, CLIA and ELISA were determined. RESULTS: IGRA test detected T-cell responses in naturally exposed and vaccinated HCW already after first vaccination dose. The correlation by the two detection methods was very high (R>0.8) and sensitivity and specificity ranged between 100 and 86% and 100-73% respectively. Even though there was a very high concordance between specific antibody levels and the IGRA assay in the ability to detect immune response to SARS-CoV-2, there was a relatively low quantitative correlation. In the small group primed by natural infection, one vaccine dose was sufficient to reach immune response plateau. IGRA was positive in one, with Ig(S) antibody negative vaccinated immunosuppressed HCW illustrating another advantage of the IGRA-test. CONCLUSION: Whole-blood-IGRA-tests amenable to automation and constitutes a promising additional tool for measuring the state of the immune response to SARS-CoV-2; they are applicable to large number of samples and may become a valuable correlate of protection to COVID-19, particularly for vulnerable groups at risk of being re-exposed to infection, as are health-care-workers.

Cellular and humoral immunogenicity of the mRNA-1273 SARS-CoV-2 vaccine in patients with hematologic malignancies.

Recent studies have shown a suboptimal humoral response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines in patients diagnosed with hematologic malignancies; however, data about cellular immunogenicity are scarce. The aim of this study was to evaluate both the humoral and cellular immunogenicity 1 month after the second dose of the mRNA-1273 vaccine. Antibody titers were measured by using the Elecsys and LIAISON anti-SARS-CoV-2 S assays, and T-cell response was assessed by using interferon-γ release immunoassay technology. Overall, 76.3% (184 of 241) of patients developed humoral immunity, and the cellular response rate was 79% (184 of 233). Hypogammaglobulinemia, lymphopenia, active hematologic treatment, and anti-CD20 therapy during the previous 6 months were associated with an inferior humoral response. Conversely, age >65 years, active disease, lymphopenia, and immunosuppressive treatment of graft-versus-host disease (GVHD) were associated with an impaired cellular response. A significant dissociation between the humoral and cellular responses was observed in patients treated with anti-CD20 therapy (the humoral response was 17.5%, whereas the cellular response was 71.1%). In these patients, B-cell aplasia was confirmed while T-cell counts were preserved. In contrast, humoral response was observed in 77.3% of patients undergoing immunosuppressive treatment of GVHD, whereas only 52.4% had a cellular response. The cellular and humoral responses to the SARS-CoV-2 mRNA-1273 vaccine in patients with hematologic malignancies are highly influenced by the presence of treatments such as anti-CD20 therapy and immunosuppressive agents. This observation has implications for the further management of these patients.

Host-dependent editing of SARS-CoV-2 in COVID-19 patients.

A common trait among RNA viruses is their high capability to acquire genetic variability due to viral and host mechanisms. Next-generation sequencing (NGS) analysis enables the deep study of the viral quasispecies in samples from infected individuals. In this study, the viral quasispecies complexity and single nucleotide polymorphisms of the SARS-CoV-2 spike gene of coronavirus disease 2019 (COVID-19) patients with mild or severe disease were investigated using next-generation sequencing (Illumina platform). SARS-CoV-2 spike variability was higher in patients with long-lasting infection. Most substitutions found were present at frequencies lower than 1%, and had an A → G or T → C pattern, consistent with variants caused by adenosine deaminase acting on RNA-1 (ADAR1). ADAR1 affected a small fraction of replicating genomes, but produced multiple, mainly non-synonymous mutations. ADAR1 editing during replication rather than the RNA-dependent RNA polymerase (nsp12) was the predominant mechanism generating SARS-CoV-2 genetic variability. However, the mutations produced are not fixed in the infected human population, suggesting that ADAR1 may have an antiviral role, whereas nsp12-induced mutations occurring in patients with high viremia and persistent infection are the main source of new SARS-CoV-2 variants.

Screening for asymptomatic STIs in HIV-infected men who have sex with men.

We aimed to study the prevalence, characteristics and risk factors of asymptomatic sexually transmitted infections (STIs) in HIV-infected men who have sex with men (MSM). We conducted a prospective cross-sectional study, including asymptomatic HIV-infected MSM attending regular visits between December 2014 and December 2017. Of the 301 patients included, 60 patients (19.9%) presented at least one STI. The most common STI was syphilis (33 of 69 STIs), followed by chlamydia (19 of 69), gonorrhoea (10 of 69), hepatitis C virus (4 of 69) and lymphogranuloma venereum (3 of 69). Illicit drug use during sex was the only variable significantly associated with the presence of an STI on multivariate analysis (OR 2.13; 95% CI 1.17-3.89). We were unable to identify a subgroup of patients where we could potentially avoid STI screening. Our findings support current guidelines that recommend routine screening for all HIV-infected MSM regardless of their self-reported sexual history.

Is antibody-mediated rejection in kidney transplant recipients a risk factor for developing cytomegalovirus or BK virus infection? Results from a case-control study.

BACKGROUND: Data are scarce on cytomegalovirus (CMV) and BK virus (BKV) infection after antibody-mediated rejection (ABMR). OBJECTIVES: We hypothesized that the immunological response in patients with ABMR or the immune modulation associated with its treatment could predispose to CMV and BKV infection. Our objective was to investigate this hypothesis. STUDY DESIGN: We conducted a single-center, matched case-control study (1:2 ratio) to analyze CMV and BKV replication during the first year after the ABMR diagnosis in kidney transplant recipients. Adult recipients with a histopathological diagnosis of ABMR between 2007-2015 were included as cases. Controls were kidney recipients who underwent transplantation immediately before and after the index case. RESULTS: Fifty-eight patients diagnosed with ABMR (33 chronic active ABMR and 25 acute ABMR), with their matched controls (116) were included. Forty-four cases received treatment for ABMR, including plasmapheresis (41), immunoglobulins (40), and rituximab (31). Within 1 year after ABMR, cases showed CMV replication more often than controls (9/58, 15.5% vs 7/116, 6%, OR = 4.21, CI 1.10-16.16, p = 0.04). Over the study period, CMV PCR determinations were requested more frequently in cases than controls (46/58, 79.3% vs 63/116, 54.3%, OR = 4.58, CI 1.92-10.9, p = 0.001). On multivariate analysis adjusted for CMV PCR determinations, retransplantation, antithymocyte globulin treatment and methylprednisolone treatment for acute rejection, CMV replication remained more common in cases than in controls (OR = 2.41, CI 0.49-11.73, p = 0.28). There were no differences in BKV replication in either urine or blood. CONCLUSIONS: ABMR may be a risk factor for CMV but not for BKV replication in kidney transplant recipients.

Molecular epidemiology and molecular characterization of respiratory syncytial viruses at a tertiary care university hospital in Catalonia (Spain) during the 2013-2014 season.

BACKGROUND: Human respiratory syncytial virus (HRSV) is the main cause of lower respiratory tract infections among infants and young children. OBJECTIVES: The molecular epidemiology and characterization of HRSV strains detected at a Spanish tertiary hospital during the 2013-2014 season is reported. STUDY DESIGN: Phylogenetic analysis and molecular characterization of HRSV laboratory-confirmed respiratory samples were performed, based on coding sequences of G and F proteins. RESULTS: HRSV infection was laboratory-confirmed in respiratory samples from 320 patients of which 223 (70%) were less than 2 years of age and none undergoing Palivizumab treatment. HRSV was detected at varying levels throughout the season with a maximum rate in the week 52/2013, right before the beginning of the influenza epidemic. Whilst both HRSV groups were found co-circulating, HRSV-B group clearly predominated. The phylogenetic analyses from 139 HVR-2 sequences revealed that most characterized strains belonged to ON1 and BA9 genotypes. Three different phylogenetic subgroups could be distinguished within these genotypes. In addition, three strains (out of the 52 randomly selected) were carrying amino acid substitutions in the epitope A of the F protein, one of them previously related to Palivizumab resistance. CONCLUSIONS: The results of the present study highlight the importance of a continuous HRSV surveillance to monitor not only the introduction of new genotypes on circulation but also the emergence of viral variants with new genetic characteristics that can affect the antigenicity features and the susceptibility to the only current prophylaxis treatment and also for the future development of HRSV vaccines.

First Enterovirus D68 (EV-D68) cases detected in hospitalised patients in a tertiary care university hospital in Spain, October 2014.

Several outbreaks of Enterovirus 68 (EV-D68) have recently been reported in the USA and Canada, causing substantial hospitalisation of children with severe respiratory disease. The acute flaccid paralysis detected in the USA and Canada among children with EV-D68 infection has raised concerns about the aetiological role of this EV serotype in severe neurological disease. The circulation of EV-D68 in the general European population seems to be low, but European Centre for Disease Prevention and Control (ECDC) recommends being vigilant to new cases, particularly in severely ill hospitalised patients. In October 2014, enteroviruses were detected in respiratory samples collected from five hospitalised patients, children and adults. Phylogenetic analysis of partial VP1 sequences confirmed that the detected enteroviruses belonged to the D68 serotype, which were also similar to strains reported in USA (2014). However, all five patients developed respiratory symptoms, but only one required ICU admission. None of the patients described had symptoms of neurological disease. Other considerations related to the detection methods used for the diagnosis of respiratory enteroviruses are also discussed. In conclusion, additional evidence has been provided that supports the role of EV-D68 in respiratory infections in hospitalised patients.