Plasma Microbial Cell-Free DNA Sequencing in Immunocompromised Patients With Pneumonia: A Prospective Observational Study.

BACKGROUND: Pneumonia is a common cause of morbidity and mortality, yet a causative pathogen is identified in a minority of cases. Plasma microbial cell-free DNA sequencing may improve diagnostic yield in immunocompromised patients with pneumonia. METHODS: In this prospective, multicenter, observational study of immunocompromised adults undergoing bronchoscopy to establish a pneumonia etiology, plasma microbial cell-free DNA sequencing was compared to standardized usual care testing. Pneumonia etiology was adjudicated by a blinded independent committee. The primary outcome, additive diagnostic value, was assessed in the Per Protocol population (patients with complete testing results and no major protocol deviations) and defined as the percent of patients with an etiology of pneumonia exclusively identified by plasma microbial cell-free DNA sequencing. Clinical additive diagnostic value was assessed in the Per Protocol subgroup with negative usual care testing. RESULTS: Of 257 patients, 173 met Per Protocol criteria. A pneumonia etiology was identified by usual care in 52/173 (30.1%), plasma microbial cell-free DNA sequencing in 49/173 (28.3%) and the combination of both in 73/173 (42.2%) patients. Plasma microbial cell-free DNA sequencing exclusively identified an etiology of pneumonia in 21/173 patients (additive diagnostic value 12.1%, 95% confidence interval [CI], 7.7% to 18.0%, P < .001). In the Per Protocol subgroup with negative usual care testing, plasma microbial cell-free DNA sequencing identified a pneumonia etiology in 21/121 patients (clinical additive diagnostic value 17.4%, 95% CI, 11.1% to 25.3%). CONCLUSIONS: Non-invasive plasma microbial cell-free DNA sequencing significantly increased diagnostic yield in immunocompromised patients with pneumonia undergoing bronchoscopy and extensive microbiologic and molecular testing. CLINICAL TRIALS REGISTRATION: NCT04047719.

Risk factors, management, and clinical outcomes of invasive Mycoplasma and Ureaplasma infections after lung transplantation.

Mollicute infections, caused by Mycoplasma and Ureaplasma species, are serious complications after lung transplantation; however, understanding of the epidemiology and outcomes of these infections remains limited. We conducted a single-center retrospective study of 1156 consecutive lung transplants performed from 2010-2019. We used log-binomial regression to identify risk factors for infection and analyzed clinical management and outcomes. In total, 27 (2.3%) recipients developed mollicute infection. Donor characteristics independently associated with recipient infection were age ≤40 years (prevalence rate ratio [PRR] 2.6, 95% CI 1.0-6.9), White race (PRR 3.1, 95% CI 1.1-8.8), and purulent secretions on donor bronchoscopy (PRR 2.3, 95% CI 1.1-5.0). Median time to diagnosis was 16 days posttransplant (IQR: 11-26 days). Mollicute-infected recipients were significantly more likely to require prolonged ventilatory support (66.7% vs 21.4%), undergo dialysis (44.4% vs 6.3%), and remain hospitalized ≥30 days (70.4% vs 27.4%) after transplant. One-year posttransplant mortality in mollicute-infected recipients was 12/27 (44%), compared to 148/1129 (13%) in those without infection (P <.0001). Hyperammonemia syndrome occurred in 5/27 (19%) mollicute-infected recipients, of whom 3 (60%) died within 10 weeks posttransplant. This study highlights the morbidity and mortality associated with mollicute infection after lung transplantation and the need for better screening and management protocols.

Epidemiology of Infections in Lung Transplant Recipients Treated With Belatacept.

BACKGROUND: Belatacept is a costimulatory blocker that can be used to prevent and treat rejection in lung transplant recipients (LuTRs). The epidemiology of infections in belatacept-treated LuTRs has not been systematically evaluated. METHODS: We performed a single-center retrospective study of all adult LuTRs who received belatacept as prevention or treatment of antibody-mediated rejection (desensitization) or as part of maintenance immunosuppression from January 1, 2011, to June 30, 2022. We assessed the epidemiology of infections that occurred within 12 months following the first belatacept dose. RESULTS: Fifty-two LuTRs received at least one dose of belatacept as either desensitization (n = 32) or maintenance immunosuppression (n = 20). Among 45 patients who were cytomegalovirus (CMV) donor and/or recipient seropositive, nine (20%) developed CMV infection. Seven (77%) CMV infections occurred despite valganciclovir prophylaxis and four (44%) were associated with antiviral resistance. Three (6%) LuTRs developed Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disorder (PTLD). Twenty-five (48%) LuTRs developed 43 bacterial infections and five (10%) developed proven or probable invasive fungal disease. Incidence rates of viral, bacterial, and fungal infections were similar between the desensitization and maintenance groups: incidence rate ratios (95% confidence interval) were 0.70 (0.32-1.57), 1.31 (0.70-2.46), and 2.82 (0.31-25.2), respectively. Infection/PTLD prompted belatacept discontinuation in eight (15%) patients. CONCLUSIONS: In the first year after belatacept initiation, LuTRs commonly developed CMV infections, EBV+ PTLD, and bacterial infections. Multicenter collaborations are needed to better understand infection risks in LuTRs treated with belatacept.

Epidemiology, management, and clinical outcomes of extrapulmonary Mycobacterium abscessus complex infections in heart transplant and ventricular assist device recipients.

Nontuberculous mycobacteria are emerging pathogens, yet data on the epidemiology and management of extrapulmonary nontuberculous mycobacteria infections in orthotopic heart transplantation (OHT) and ventricular assist device (VAD) recipients are scarce. We retrospectively reviewed records of OHT and VAD recipients who underwent cardiac surgery at our hospital and developed Mycobacterium abscessus complex (MABC) infection from 2013 to 2016 during a hospital outbreak of MABC linked to heater-cooler units. We analyzed patient characteristics, medical and surgical management, and long-term outcomes. Ten OHT patients and 7 patients with VAD developed extrapulmonary M. abscessus subspecies abscessus infection. The median time from presumed inoculation during cardiac surgery to the first positive culture was 106 days in OHT and 29 days in VAD recipients. The most common sites of positive cultures were blood (n = 12), sternum/mediastinum (n = 8), and the VAD driveline exit site (n = 7). The 14 patients diagnosed when alive received combination antimicrobial therapy for a median of 21 weeks, developed 28 antibiotic-related adverse events, and underwent 27 surgeries. Only 8 (47%) patients survived longer than 12 weeks after diagnosis, including 2 patients with VAD who experienced long-term survival after an explantation of infected VADs and OHT. Despite aggressive medical and surgical management, OHT and VAD patients with MABC infection experienced substantial morbidity and mortality.

Multicenter study of universal prophylaxis versus pre-emptive therapy for patients at intermediate risk (R+) for CMV following heart transplantation.

INTRODUCTION: Heart transplant (HT) recipients with prior exposure to cytomegalovirus (CMV R+) are considered intermediate risk for CMV-related complications. Consensus guidelines allow for either universal prophylaxis (UP) or preemptive therapy (PET) (serial CMV testing) approaches to CMV prevention in such patients. Whether an optimal approach to mitigate CMV related risks exists in this setting remains uncertain. We therefore assessed the utility of PET as compared to UP in CMV R+ HT recipients. METHODS: Retrospective analysis of all CMV R+ HT recipients from 6 U.S. centers between 2010 and 2018 was performed. The primary outcome was the development of CMV DNAemia or end-organ disease resulting in the initiation/escalation of anti-CMV therapy. The secondary outcome was CMV-related hospitalization. Additional outcomes included incidence of acute cellular rejection (ACR) ≥ grade 2R, death, cardiac allograft vasculopathy (CAV), and leukopenia. RESULTS: Of 563 CMV R+ HT recipients, 344 (61.1%) received UP. PET was associated with increased risk for the primary (adjusted HR 3.95, 95% CI: 2.65-5.88, p < .001) and secondary (adjusted HR 3.19, 95% CI: 1.47-6.94, p = .004) outcomes, and with increased ACR ≥ grade 2R (PET 59.4% vs. UP 34.4%, p < .001). Incidence of detectable CAV was similar at 1 year (PET 8.2% vs. UP 9.5%, p = .698). UP was associated with increased incidence of leukopenia within 6 months post-HT (PET 34.7% vs. UP 43.6%, p = .036). CONCLUSION: The use of a PET CMV prophylaxis strategy in intermediate risk HT recipients associated with increased risk of CMV infection and CMV-related hospitalization, and may associate with worse post-HT graft outcomes.

Invasive Mycobacterium abscessus Complex Infection After Cardiac Surgery: Epidemiology, Management, and Clinical Outcomes.

BACKGROUND: We recently mitigated a clonal outbreak of hospital-acquired Mycobacterium abscessus complex (MABC), which included a large cluster of adult patients who developed invasive infection after exposure to heater-cooler units during cardiac surgery. Recent studies have detailed Mycobacterium chimaera infections acquired during cardiac surgery; however, little is known about the epidemiology and clinical courses of cardiac surgery patients with invasive MABC infection. METHODS: We retrospectively collected clinical data on all patients who underwent cardiac surgery at our hospital and subsequently had positive cultures for MABC from 2013 through 2016. Patients with ventricular assist devices or heart transplants were excluded. We analyzed patient characteristics, antimicrobial therapy, surgical interventions, and clinical outcomes. RESULTS: Ten cardiac surgery patients developed invasive, extrapulmonary infection from M. abscessus subspecies abscessus in an outbreak setting. Median time from presumed inoculation in the operating room to first positive culture was 53 days (interquartile range [IQR], 38-139 days). Disseminated infection was common, and the most frequent culture-positive sites were mediastinum (n = 7) and blood (n = 7). Patients received a median of 24 weeks (IQR, 5-33 weeks) of combination antimicrobial therapy that included multiple intravenous agents. Six patients required antibiotic changes due to adverse events attributed to amikacin, linezolid, or tigecycline. Eight patients underwent surgical management, and 6 patients required multiple sternal debridements. Eight patients died within 2 years of diagnosis, including 4 deaths directly attributable to MABC infection. CONCLUSIONS: Despite aggressive medical and surgical management, invasive MABC infection after cardiac surgery caused substantial morbidity and mortality. New treatment strategies are needed, and compliance with infection prevention guidelines remains critical.

Invasive Fungal Infection After Lung Transplantation: Epidemiology in the Setting of Antifungal Prophylaxis.

BACKGROUND: Lung transplant recipients commonly develop invasive fungal infections (IFIs), but the most effective strategies to prevent IFIs following lung transplantation are not known. METHODS: We prospectively collected clinical data on all patients who underwent lung transplantation at a tertiary care academic hospital from January 2007-October 2014. Standard antifungal prophylaxis consisted of aerosolized amphotericin B lipid complex during the transplant hospitalization. For the first 180 days after transplant, we analyzed prevalence rates and timing of IFIs, risk factors for IFIs, and data from IFIs that broke through prophylaxis. RESULTS: In total, 156 of 815 lung transplant recipients developed IFIs (prevalence rate, 19.1 IFIs per 100 surgeries, 95% confidence interval [CI] 16.4-21.8%). The prevalence rate of invasive candidiasis (IC) was 11.4% (95% CI 9.2-13.6%), and the rate of non-Candida IFIs was 8.8% (95% CI 6.9-10.8%). First episodes of IC occurred a median of 31 days (interquartile range [IQR] 16-56 days) after transplant, while non-Candida IFIs occurred later, at a median of 86 days (IQR 40-121 days) after transplant. Of 169 IFI episodes, 121 (72%) occurred in the absence of recent antifungal prophylaxis; however, IC and non-Candida breakthrough IFIs were observed, most often representing failures of micafungin (n = 16) and aerosolized amphotericin B (n = 24) prophylaxis, respectively. CONCLUSIONS: Lung transplant recipients at our hospital had high rates of IFIs, despite receiving prophylaxis with aerosolized amphotericin B lipid complex during the transplant hospitalization. These data suggest benefit in providing systemic antifungal prophylaxis targeting Candida for up to 90 days after transplant and extending mold-active prophylaxis for up to 180 days after surgery.

Use of Letermovir as Salvage Therapy for Drug-Resistant Cytomegalovirus Retinitis.

Treatment options for drug-resistant cytomegalovirus (CMV) are limited. Letermovir is a novel antiviral recently approved for CMV prophylaxis following hematopoietic cell transplantation, but its efficacy in other settings is unknown. We recently used letermovir for salvage treatment in four solid organ transplant recipients with ganciclovir-resistant CMV retinitis. All patients improved clinically without known adverse drug events. However, three patients failed to maintain virologic suppression, including two patients who developed genotypically confirmed resistance to letermovir while on therapy.

Two-Phase Hospital-Associated Outbreak of Mycobacterium abscessus: Investigation and Mitigation.

BACKGROUND: Nontuberculous mycobacteria (NTM) commonly colonize municipal water supplies and cause healthcare-associated outbreaks. We investigated a biphasic outbreak of Mycobacterium abscessus at a tertiary care hospital. METHODS: Case patients had recent hospital exposure and laboratory-confirmed colonization or infection with M. abscessus from January 2013 through December 2015. We conducted a multidisciplinary epidemiologic, field, and laboratory investigation. RESULTS: The incidence rate of M. abscessus increased from 0.7 cases per 10000 patient-days during the baseline period (January 2013-July 2013) to 3.0 cases per 10000 patient-days during phase 1 of the outbreak (August 2013-May 2014) (incidence rate ratio, 4.6 [95% confidence interval, 2.3-8.8]; P < .001). Thirty-six of 71 (51%) phase 1 cases were lung transplant patients with positive respiratory cultures. We eliminated tap water exposure to the aerodigestive tract among high-risk patients, and the incidence rate decreased to baseline. Twelve of 24 (50%) phase 2 (December 2014-June 2015) cases occurred in cardiac surgery patients with invasive infections. Phase 2 resolved after we implemented an intensified disinfection protocol and used sterile water for heater-cooler units of cardiopulmonary bypass machines. Molecular fingerprinting of clinical isolates identified 2 clonal strains of M. abscessus; 1 clone was isolated from water sources at a new hospital addition. We made several water engineering interventions to improve water flow and increase disinfectant levels. CONCLUSIONS: We investigated and mitigated a 2-phase clonal outbreak of M. abscessus linked to hospital tap water. Healthcare facilities with endemic NTM should consider similar tap water avoidance and engineering strategies to decrease risk of NTM infection.

Real-World Experience With Maribavir for Treatment of Cytomegalovirus Infection in High-Risk Solid Organ Transplant Recipients.

We evaluated use of maribavir (MBV) for treatment of 15 episodes of refractory/resistant cytomegalovirus infection in 13 solid organ transplant recipients. Treatment failure due to treatment-emergent MBV resistance or early virological recurrence after MBV discontinuation occurred in 7 (47%) episodes. Sustained viral clearance was achieved in 6 (40%) episodes.

Clinical Utility of Plasma Microbial Cell-Free DNA Sequencing Among Immunocompromised Patients With Pneumonia.

Background: Plasma microbial cell-free DNA (mcfDNA) sequencing can establish the etiology of multiple infectious syndromes by identifying microbial DNA in plasma. However, data are needed to define the clinical scenarios where this tool offers the highest clinical benefit. Methods: We conducted a prospective multicenter observational study that evaluated the impact of plasma mcfDNA sequencing compared with usual care testing among adults with hematologic malignancies. This is a secondary analysis of an expanded cohort that evaluated the clinical utility of plasma mcfDNA sequencing across prespecified and adjudicated outcomes. We examined the percentage of participants for whom plasma mcfDNA sequencing identified a probable cause of pneumonia or clinically relevant nonpneumonia infection. We then assessed potential changes in antimicrobial therapy based on plasma mcfDNA sequencing results and the potential for early mcfDNA testing to avoid bronchoscopy and its associated adverse events. Results: Of 223 participants, at least 1 microbial detection by plasma mcfDNA sequencing was adjudicated as a probable cause of pneumonia in 57 (25.6%) and a clinically relevant nonpneumonia infection in 88 (39.5%). A probable cause of pneumonia was exclusively identified by plasma mcfDNA sequencing in 23 (10.3%) participants. Antimicrobial therapy would have changed for 41 (18.4%) participants had plasma mcfDNA results been available in real time. Among the 57 participants with a probable cause of pneumonia identified by plasma mcfDNA sequencing, bronchoscopy identified no additional probable cause of pneumonia in 52 (91.2%). Conclusions: Plasma mcfDNA sequencing could improve management of both pneumonia and other concurrent infections in immunocompromised patients with suspected pneumonia.

Real-world Experiences in the Transplantation of Hepatitis C-NAAT-positive Organs.

Background: Hepatitis C virus (HCV) nucleic acid amplification test (NAAT)-positive donors have increased the organ pool. Direct-acting antivirals (DAAs) have led to high rates of treatment success and sustained virologic response (SVR) in recipients with donor-derived HCV infection without significant adverse effects, although variability remains in the timing and duration of antivirals. Methods: This retrospective study analyzed all adult HCV-NAAT-negative transplant recipients who received an organ from HCV-NAAT-positive donors from November 24, 2018, to March 31, 2022, at Duke University Medical Center with protocolized delay of DAA initiation until after hospital discharge, with at least 180-d follow-up on all patients. Transplant and HCV-related outcomes were analyzed. Results: Two hundred eleven transplants (111 kidneys, 41 livers, 34 hearts, and 25 lungs) were performed from HCV-NAAT-positive donors to HCV-NAAT-negative recipients. Ninety percent of recipients became viremic within 7 d posttransplant. Ninety-nine percent of recipients were initiated on pangenotypic DAAs in the outpatient setting a median of 52 d posttransplant, most commonly with 12-wk courses of sofosbuvir-velpatasvir (lungs) and glecaprevir-pibrentasvir (heart, kidney, and liver). Ninety-seven percent of recipients had SVR after a first-line DAA; all ultimately achieved SVR at 12 wk after subsequent treatment courses. The median peak HCV RNA for all organ systems was 2 436 512 IU/mL; the median time from antiviral to undetectable RNA was 48 d, although differences were noted between organ groups. No patient deaths or graft losses were directly attributable to HCV infection. Conclusions: One hundred percent of transplant recipients of HCV-NAAT-positive organs ultimately developed SVR without significant adverse effects when HCV antivirals were initiated in the outpatient setting after transplant hospitalization, suggesting that this real-world treatment pathway is a viable option.

Cytomegalovirus prevention in thoracic organ transplantation: A single-center evaluation of letermovir prophylaxis.

BACKGROUND: Cytomegalovirus (CMV) infection is common following thoracic organ transplantation and causes substantial morbidity and mortality. Letermovir is a novel antiviral agent used off-label in this population for CMV prevention. Our goal was to understand patterns of letermovir use and effectiveness when applied for CMV prophylaxis after thoracic transplantation. METHODS: We retrospectively evaluated letermovir use among thoracic transplant recipients at an academic transplant center who initiated letermovir from January 2018 to October2019 for CMV prophylaxis. We analyzed indication, timing, and duration of prophylaxis; tolerability; and occurrence of breakthrough CMV DNAemia and disease. RESULTS: Forty-two episodes of letermovir prophylaxis occurred in 41 patients, including 37 lung and 4 heart transplant recipients. Primary prophylaxis (26/42, 61.9%) was utilized mainly due to myelosuppression (25/26, 96.2%) and was initiated a median of 315 days post-transplant (interquartile range [IQR] 125-1139 days). Sixteen episodes of secondary prophylaxis (16/42, 38.1%) were initiated a median of 695 days post-transplant (IQR 537-1156 days) due to myelosuppression (10/16, 62.5%) or prior CMV resistance (6/16, 37.5%). Median duration of letermovir prophylaxis was 282 days (IQR 131-433 days). Adverse effects required letermovir cessation in 5/42 (11.9%) episodes. Only one episode (2.4%) was complicated by clinically significant breakthrough CMV infection. Transient low-level CMV DNAemia (<450 IU/ml) occurred in 15 episodes (35.7%) but did not require letermovir cessation. CONCLUSIONS: Letermovir was well tolerated and effective during extended prophylactic courses with only one case of breakthrough CMV infection in this cohort of thoracic transplant recipients. Further prospective trials of letermovir prophylaxis in this population are warranted.

Bloodstream Infections in Hematologic Malignancy Patients With Fever and Neutropenia: Are Empirical Antibiotic Therapies in the United States Still Effective?

Background: Rising antimicrobial resistance rates may impact the efficacy of empirical antibiotic treatment for febrile neutropenia in high-risk cancer patients. Lacking contemporary data about the epidemiology, antibiotic resistance patterns, and clinical outcomes from bloodstream infections (BSIs) in US cancer patients, it is unclear if current guidelines remain relevant. Methods: In a cross-sectional study, 14 US cancer centers prospectively identified BSIs in high-risk febrile neutropenic (FN) patients, including those receiving chemotherapy for hematologic malignancies or hematopoietic stem cell transplantation. Results: Among 389 organisms causing BSI in 343 patients, there was an equal distribution of gram-negative (GN) and gram-positive (GP) bacteria, with variability across centers. Cefepime and piperacillin-tazobactam were the most commonly prescribed empirical antibiotics for FN, at 62% and 23%, respectively; a GP-directed agent was empirically included in nearly half of all FN episodes within the first 24 hours. Susceptibility to fluoroquinolones, cefepime, piperacillin-tazobactam, and carbapenems was 49%, 84%, 88%, and 96%, respectively, among GN isolates. Critical illness (CrI), defined as a new requirement for mechanical ventilation, vasopressor, or death within 30 days, occurred in 15% and did not correlate with fluoroquinolone prophylaxis, organism type, initial antibiotics, or adequacy of coverage. Only severity of illness at presentation, signified by a Pitt bacteremia score ≥2, predicted for critical illness within 30 days. Mortality was 4% by day 7 and 10% overall. Conclusions: In accordance with US guidelines, cefepime or piperacillin-tazobactam remain effective agents or empirical treatment for high-risk cancer patients with FN who are stable at presentation, maintaining high GN pathogen susceptibility and yielding excellent outcomes.

A randomized, double-blind, placebo-controlled clinical trial of fluconazole as early empiric treatment of coccidioidomycosis pneumonia (Valley Fever) in adults presenting with community-acquired pneumonia in endemic areas (FLEET-Valley Fever).

INTRODUCTION: Coccidioidomycosis is a fungal infection endemic in the southwestern United States (US). Primary pulmonary coccidioidomycosis (PPC) is a leading cause of community-acquired pneumonia (CAP) in this region, although its diagnosis is often delayed, leading to lag in antifungal treatment and subsequent morbidity. The impact of early empiric antifungal therapy as part of treatment for CAP in endemic areas on clinical outcomes is unknown. METHODS: Phase IV randomized, double-blind, placebo-controlled trial in individuals aged 18 years or older with CAP who met all eligibility criteria in Coccidioides endemic regions in the US. Eligible participants with CAP were randomized to receive either fluconazole (400 mg daily) or matching placebo for 42 days and were subsequently monitored for clinical resolution of their illness. OBJECTIVES: The primary objective was to assess the clinical response of early empiric antifungal therapy with fluconazole through Day 22 in subjects with PPC who were adherent to the study intervention. Secondary objectives included: assessments of the impact of early empiric antifungal therapy with fluconazole through Day 22 and 43 in subjects with PPC regardless of adherence, comparisons of the clinical response and its individual components over time by treatment group in subjects with PPC, assessments of days lost from work or school, hospitalization, and all-cause mortality. DISCUSSION: This trial was halted early due to slow enrollment (72 participants in one year, 33 received fluconazole and 39 received placebo). Of those enrolled, eight (11%) met the study definition of PPC. The study design and challenges are discussed.

The robust and rapid role of molecular testing in precision fungal diagnostics: A case report.

Diagnosis of invasive fungal disease remains an ongoing challenge for clinicians, while continuously evolving treatment regimens increase patient risk for invasive infection. This case highlights how molecular testing led to the diagnosis of co-infection with two fungal pathogens producing invasive disease in a hematopoietic stem cell transplant recipient with graft-versus-host disease (GVHD).

Disseminated Cryptococcosis With Brain Involvement in Patients With Chronic Lymphoid Malignancies on Ibrutinib.

We report 2 cases of disseminated cryptococcosis with central nervous system involvement in patients with chronic lymphoid malignancies occurring within 1 month of starting on ibrutinib. Characteristically, in both cases, no inflammation was seen in the cerebrospinal fluid. Central nervous system mycoses should be considered as a potential complication of ibrutinib.