Hematopoietic stem cell transplant recipients are at increased risk of infection and immune dysregulation due to reception of cytotoxic chemotherapy; development of graft versus host disease, which necessitates treatment with immunosuppressive medications; and placement of invasive catheters. The prevention and management of infections in these vulnerable hosts is of utmost importance and a key "safety net" in stem cell transplantation. In this review, we provide updates on the prevention and management of CMV infection; invasive fungal infections; bacterial infections; Clostridium difficile infection; and EBV, HHV-6, adenovirus and BK infections. We discuss novel drugs, such as letermovir, isavuconazole, meropenem-vaborbactam and bezlotoxumab; weigh the pros and cons of using fluoroquinolone prophylaxis during neutropenia after stem cell transplantation; and provide updates on important viral infections after hematopoietic stem cell transplant (HSCT). Optimizing the prevention and management of infectious diseases by using the best available evidence will contribute to better outcomes for stem cell transplant recipients, and provide the best possible "safety net" for these immunocompromised hosts.

Background Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 is increasingly utilized in the treatment of a variety of hematologic malignancies. While efficacious, this therapy is associated with prolonged cytopenias and immunosuppression. Open questions remain regarding the distribution of infections beyond the first year of therapy and infectious risk stratification. We identified a cohort of CAR T-cell recipients to address these gaps in the literature. Methods We retrospectively analyzed adult patients who received CAR T-cell therapy at our center including their infectious outcomes up to two years following cell infusion. Descriptive statistics and Mann-Whitney testing were used when appropriate. A time-to-event analysis was made assessing time from cell infusion to first infection. Univariate Kaplan-Meier (KM) analyses with log-rank testing and cox regression analysis identified significant predictors for inclusion into a multi-variate cox model of risk of first infection. Results Baseline characteristics of the 75 patients are listed in Table 1. Etiology of infection changed in distribution over time from predominantly nosocomial pathogens more so to respiratory viruses and pneumonia (Figure 1). In univariate KM failure analyses, receipt of tocilizumab or development of neurotoxicity was associated with more rapid onset of first infection (log-rank p-values = 0.0361, 0.0417, respectively) (Figure 2). Multivariate cox regression demonstrated that higher neutrophil count at apheresis was inversely associated with onset of infection (hazard ratio (HR) 0.81; 95% CI .67-.98; p-value .028), while development of neurotoxicity (HR 5.51; 95% CI 1.15–26.5; p-value .033) and receipt of tocilizumab (HR 3.93; 95% CI 1.15–13.42; p-value .029) were associated with onset of infection. Baseline patient population characteristics as described by frequency (n) and percent of total population or median and inter-quartile range (IQR). Abbreviations - CAR: Chimeric Antigen Receptor. ECOG: Eastern Cooperative Oncology Group Performance Score. DLBCL: Diffuse large B cell lymphoma. HGBL: High grade B-cell lymphoma. TFL: Transformed follicular lymphoma. MCL: Mantle-cell lymphoma. PMBCL: Primary mediastinal large B-cell lymphoma. ALL: acute lymphoblastic leukemia. MM: Multiple myeloma. IVIG: Intravenous immune globulin. ANC: Absolute neutrophil count. ALC: Absolute lymphocyte count. IgG: Immunoglobulin G levels. *Indicates missing data on 1 patient, percent relative to n of 74 for these variables. The letter "a" indicates there was one patient each with PMBCL, ALL or MM. Abbreviations - RVI: Respiratory Viral Infection, UTI: Urinary Tract Infection, CDI: Clostridium dificile infection, CAR: Chimeric Antigen Receptor. *Indicates graphical result truncation of RVI number between 30 days and 1-year post-CAR T-cell infusion (n=24), which is the most predominant infection. “Other” infections within 30 days of cell infusion included 2 episodes of cellulitis, and one episode each of sialadenitis, Aspergillus pneumonia and empyema. “Other” infections between 30 days and 1-year post-cell infusion included 1 each of oral HSV, intra-abdominal infection, empyema, conjunctivitis, cellulitis, bacterial sinusitis and tooth abscess. “Other” infections between 1- and 2-years post-cell infusion included shingles and bacterial sinusitis (1 each). Kaplan-Meier failure curves of proportion of patients who developed their first infection (failure) following CAR T-cell infusion by day since cell infusion. Right censoring at two years of follow up, death, or disease progression, whichever came first. A. Curves separated by receipt of tocilizumab (red dashed line) versus no receipt of tocilizumab (solid blue line) during period of follow up. Log-rank test p = 0.0361. B. Curves separated by development of CAR T-cell neurologic toxicity (red dashed line), also known as immune effector cell-associated neurotoxicity syndrome (ICANS) as documented by diagnostic criteria from American Society of Transplant and Cellular Therapy (ASTCT) versus no ICANS (solid blue line). Log-rank test p = 0.0417. Conclusion The pattern of infections following CAR T-cell infusion changes over time, transitioning from nosocomial infections to respiratory viral infections. The multi-variate cox model of time to first infection demonstrated neutropenia at apheresis, tocilizumab receipt and development of neurotoxicity predicted more rapid onset of infection. Strategies to mitigate inflammatory complications may reduce infection. Disclosures All Authors: No reported disclosures.

Background Infectious Disease (ID) physicians have historically had higher levels of burnout compared to other medical specialties. Fellows are not immune to the pressures that attendings experience in the course of clinical care. The Accreditation Council for Graduate Medical Education now requires programs to formally promote well-being amongst trainees. We created a structural intervention to improve fellow well-being and conducted a before-and-after study demonstrating effectiveness. Methods We restructured our institution’s inpatient ID clinical services, which increased attending presence on weekends and afternoons to help with clinical volume. A survey including the Maslach Burnout Inventory for Medical Personnel (MBI-HSS(MP)) and wellness metrics was completed by our 5 fellows before and after the intervention. Consult volume and efficiency were assessed before and after the intervention. Descriptive statistics, paired t-tests or Wilcoxon signed-rank tests were utilized as appropriate for data normality. Qualitative survey responses were coded into key domains until saturation was reached for analysis. Results Post-intervention MBI-HSS(MP) mean scores significantly improved for emotional exhaustion (EE) [3.3 to 2.3, p-value .0089]. Personal accomplishment and depersonalization metrics improved but were not significant. Survey items assessing time for education, learning to service balance, satisfaction and wellness all improved but were not significant (Table 1). Consult volume was the most frequent domain associated with dissatisfaction, and was described as the most improved domain since intervention (Table 2). Clinical work volumes were the same, if not higher, in the post intervention period (Table 3). All 5 fellows completed surveys before and after the intervention. The pre and post intervention means with standard errors (SE) or frequency of responses are listed in the table as well as p- values for Wilcoxon-signed rank or paired t-test (depending on normality of that variable). For “education versus service balance” fellows used a visual analogue scale (0-100) to assess their views of balance of education (lower values) to service (higher values) while on General Infectious Disease consults (GID). Fellows were asked to rate their “satisfaction” with GID on a visual analogue scale from 0-100 with lower values as dissatisfaction and higher values as satisfaction. EE, DP, and PA are metrics used in the Maslach Burnout Inventory for Medical Personnel (MBI-SS(MP)). The values of the MBI questions are mean responses across items in their respective inventories, with higher values for EE and DP meaning more frequent negative experiences, and higher values for PA meaning more frequent positive experiences. For MBI, scores indicate how frequently feelings occur: 1, a few times/year; 2, monthly; 3, a few times monthly; 4, weekly; 5, a few times/week. Fellows were also asked to give the frequency at which they were able to teach or complete responsibilities at home (such as childcare, cleaning, cooking, grocery shopping) while on GID. Responses truncated only to frequencies selected by respondents. Responses to the last two questions were numerically coded for statistical analysis. * Indicates statistical significance (p < .05). Free text survey responses were analyzed by authors, resulting in the generation of key conceptual response domains; this process continued until saturation was reached, leading to the coding of text responses as above. Examples from text responses included in parenthesis. Prompt 1 was given to the 5 fellows before and after the intervention leading to 10 responses. Prompt 2 was given to the 5 fellows only following intervention. Variables were assessed pre and post intervention. Max list size is the maximum number of patients on the general infectious disease (GID) consult service, bumped consults is the number of consults not seen until the following work day, curbside consults is the number of consults where recommendations were given without seeing the patient, last rec is the time of delivery of the last recommendation, pages is the raw number of pages received in a day by the GID fellow and COVID-19 census is the total number of patients admitted to our center with COVID-19. *Indicates statistical significance (p < .05) by paired t-test. IQR signifies inter-quartile range. Conclusion We found that an intervention addressing structural contributors to burnout was effective in reducing EE and perception of clinical volume. This finding was significant despite stable to increased clinical volumes and the added stress of the cotemporaneous Omicron outbreak of COVID-19. Disclosures Aniruddha Hazra, MD, Gilead Sciences: Grant/Research Support.

A 40-year-old woman with HIV (CD4 270, viral load undetectable) from Zambia presented with fevers, urinary tract infection symptoms, sterile pyuria and haematuria. She was found to have genitourinary tuberculosis (TB) via mycobacterial culture of urine and ascites, and treated with rifabutin, isoniazid, pyrazinamide and ethambutol. She later had multiple episodes of asymptomatic transaminitis, triggering changes to both TB and HIV regimens. The patient then presented with diffuse rash, fevers, transaminitis and eosinophilia concerning for drug reaction with eosinophilia and systemic symptoms (DRESS). After initial improvement on discontinuation of likely responsible medications and completion of corticosteroid therapy, the patient returned with acute liver failure. This new episode was felt to be severe organ dysfunction due to DRESS, and she was treated with a prolonged corticosteroid taper and changes to her TB regimen. She has since completed therapy for TB, has improving CD4 counts and is without evidence of liver dysfunction.