Young, Jo-Anne H

Abstract Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, viral, and fungal infections were recorded in 527 (15.7%), 374 (11.2%), and 108 patients (3.2%), respectively, with corresponding infection densities of 0.23, 0.15, and 0.04 per 100 patient days. After a 24-month median follow-up, 1482 patients (44%) had died, with infection as the primary cause in 173 cases (12%). The 100-day infection-related mortality (IRM) was 1.6% (95% confidence interval, 1.2-2.0). Patients with a Karnofsky performance score of ≤80, infection history before CAR T-cell therapy, axi-cel therapy, severe cytokine release syndrome (grade ≥3), and severe immune effector cell–associated neurotoxicity syndrome (grade ≥3) had increased infection risk. Infections within 100 days were an independent risk factor for inferior overall survival beyond day 100 after CD19 CAR T-cell therapy. In conclusion, study results show a significant incidence of infection and IRM in patients with R/R LBCL treated with CD19 CAR T-cell therapy. Furthermore, results identify patients at a heightened risk of infection, offering insights to guide potential interventions aimed at mitigating infection and improving patient outcomes after CAR T-cell therapy.

Abstract Background Despite advances in clinical microbiology, the diagnosis of invasive fungal infections remains challenging. Giant magnetoresistance (GMR) is a novel technology that enables the detection of trace amounts of cell-free DNA (cfDNA). We evaluated a high-multiplex molecular diagnostic assay coupled with GMR-enabled lab-on-a-chip technology that can detect 18 different fungal species. Methods Analytical performance was evaluated in spiked plasma samples. After amplification, cfDNA was digested. Residual single-stranded DNA was flowed over a GMR sensor that was surface-coated with probes specific to different fungal species. After hybridization, magnetic beads bound to the probe complexes produced a GMR signal that was detected by the sensors. Clinical performance was determined using residual serum samples collected before the initiation of antifungal treatment from 20 patients with infection. Results The limit of detection of the assay ranged from 5 to 50 copies per polymerase chain reaction (PCR) reaction. Nonspecific signals were not observed in the spiked samples. Fungal cfDNA was detected in 80% of patients with invasive candidiasis (3/4 with candidemia, 5/6 with invasive candidiasis without candidemia), all 3 cases of invasive pulmonary aspergillosis, and all 3 cases of disseminated histoplasmosis. cfDNA was not detected in 2 patients with cryptococcosis (both had negative blood cultures) and 2 patients with Pneumocystis pneumonia. Conclusions We developed a novel GMR-enabled multiplex PCR assay detecting fungal pathogens that have been prioritized for public health action. Clinical sensitivity was highest in cases of presumed angioinvasion and dissemination. This technology has the potential for use in the clinical microbiology laboratory setting.

AbstractBackgroundClostridioides difficile infection (CDI) is a significant cause of morbidity and mortality in recipients of solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT). In retrospective single center analyses, severe disease and relapse are common. We undertook an international, prospective cohort study to estimate the response to physician determined antibiotic treatment for CDI in patients with SOT and HSCT.MethodsAdults with a first episode of CDI within the first 2 years of SOT or HSCT were enrolled. Demographics, comorbidities, and medication history were collected, and over 90 days of follow‐up clinical cure, recurrences, and complications were assessed. Logistic regression was used to study associations of baseline predictors of clinical cure and recurrence. Odds ratios (ORs) and 95% confidence intervals (CIs) are cited.ResultsA total of 132 patients, 81 SOT and 51 HSCT (32 allogeneic), were enrolled with a median age of 56 years; 82 (62%) were males and 128 (97%) were hospitalized at enrollment. One hundred and six (80.3%) were diagnosed by DNA assay. CDI occurred at a median of 20 days post‐transplant (interquartile range, IQR: 6–133). One hundred and eight patients (81.8%) were on proton pump inhibitors; 126 patients (95.5%) received antibiotics within the 6 weeks before CDI. The most common initial CDI treatments prescribed, on or shortly before enrollment, were oral vancomycin alone (50%) and metronidazole alone (36%). Eighty‐three percent (95% CI: 76, 89) of patients had clinical cure; 18% (95% CI: 12, 27) of patients had recurrent CDI; global clinical cure occurred in 65.2%. Of the 11 patients who died, two (1.5% of total) were related to CDI. In multivariable logistic regression analyses, the type of initial treatment was associated with clinical cure (p = .009) and recurrence (p = .014). A history of cytomegalovirus (CMV) after transplant was associated with increased risk of recurrence (44% with versus 13% without CMV history; OR: 5.7, 95% CI: 1.5, 21.3; p = .01).ConclusionsAmong adults who develop CDI after SOT or HSCT, despite their immunosuppressed state, the percentage with clinical cure was high and the percentage with recurrence was low. Clinical cure and recurrence varied by type of initial treatment, and CMV viremia/disease was associated with an increased risk of recurrence.

AbstractBackgroundThe optimal treatment for respiratory syncytial virus (RSV) infection in adult immunocompromised patients is unknown. We assessed the management of RSV and other non‐influenza respiratory viruses in Midwestern transplant centers.MethodsA survey assessing strategies for RSV and other non‐influenza respiratory viral infections was sent to 13 centers.ResultsMultiplex polymerase chain reaction assay was used for diagnosis in 11/12 centers. Eight of 12 centers used inhaled ribavirin (RBV) in some patient populations. Barriers included cost, safety, lack of evidence, and inconvenience. Six of 12 used intravenous immunoglobulin (IVIG), mostly in combination with RBV. Inhaled RBV was used more than oral, and in the post‐stem cell transplant population, patients with lower respiratory tract infection (LRTI), graft‐versus‐host disease, and more recent transplantation were treated at higher rates. Ten centers had experience with lung transplant patients; all used either oral or inhaled RBV for LRTI, 6/10 treated upper respiratory tract infection (URTI). No center treated non‐lung solid organ transplant (SOT) recipients with URTI; 7/11 would use oral or inhaled RBV in the same group with LRTI. Patients with hematologic malignancy without hematopoietic stem cell transplantation were treated with RBV at a similar frequency to non‐lung SOT recipients. Three of 12 centers, in severe cases, treated parainfluenza and metapneumovirus, and 1/12 treated coronavirus.ConclusionsTreatment of RSV in immunocompromised patients varied greatly. While most centers treat LRTI, treatment of URTI was variable. No consensus was found regarding the use of oral versus inhaled RBV, or the use of IVIG. The presence of such heterogeneity demonstrates the need for further studies defining optimal treatment of RSV in immunocompromised hosts.

Key PointsHCT recipients have increased susceptibility to herpes zoster, but live-attenuated vaccines are not appropriate for highly immunocompromised people. An adjuvanted subunit vaccine against herpes zoster elicits strong immune responses with an acceptable safety profile in adult autologous HCT recipients.