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.

Use of Letermovir for Primary and Secondary Cytomegalovirus Prophylaxis in Abdominal Organ Transplantation: A Single Center Experience.

BACKGROUND: Cytomegalovirus (CMV) infection after abdominal organ transplantation is associated with increased morbidity and mortality. The use of valganciclovir for CMV prophylaxis is limited by drug-induced myelosuppression and potential emergence of resistance. Letermovir is approved for primary CMV prophylaxis in CMV seropositive allogeneic hematopoietic cell transplant recipients. However, it is increasingly used off-label for prophylaxis in solid organ transplant (SOT) recipients. METHODS: Based on pharmacy records, we examined retrospectively the use of letermovir for CMV prophylaxis in abdominal transplant recipients initiated on therapy at our center from January 1, 2018 through October 15, 2020. Data were summarized using descriptive statistics. RESULTS: Twelve episodes of letermovir prophylaxis occurred in ten patients. Four patients received primary and 6 patients received secondary prophylaxis during the study period, with 1 patient receiving letermovir secondary prophylaxis on 3 separate occasions. All patients receiving letermovir for primary prophylaxis had successful outcomes. However, letermovir secondary prophylaxis was unsuccessful in 5 of the 8 episodes (62.5%) due to breakthrough CMV DNAemia and/or disease. Only 1 patient discontinued therapy due to adverse effects. CONCLUSION: Although letermovir was generally well tolerated, the high rate of failure when used as secondary prophylaxis was noteworthy. Additional controlled clinical trials assessing the safety and efficacy of letermovir prophylaxis in SOT recipients are warranted.

Cytomegalovirus Therapy: Role of Letermovir in Prophylaxis and Treatment in Transplant Recipients.

Cytomegalovirus (CMV) is a common viral pathogen in the transplant population and is associated with significant morbidity and mortality. CMV prevention is paramount; however, selecting the best preventive strategy depends on many factors including donor-recipient CMV serostatus, transplant-specific risks, antiviral toxicities and cost. Novel CMV therapeutics such as letermovir (LTV) are desperately needed to optimize CMV management. Uniquely among CMV antiviral therapies, LTV inhibits the viral terminase complex in the CMV DNA synthesis pathway and disrupts viral genome packaging. Further, it lacks side effects frequently associated with other CMV antiviral therapies and evades common mechanisms of resistance. LTV is approved by the US Food and Drug Administration for CMV prevention in adult CMV-seropositive hematopoietic cell transplant recipients but is increasingly applied off-label for prophylaxis and treatment. This review summarizes important concepts of CMV management in transplantation, with a specific focus on LTV pharmacology and clinical experience to date alongside future prospects for its application.

Updates on Histoplasmosis in Solid Organ Transplantation.

Purpose of Review: Histoplasmosis remains a challenging infection in solid organ transplantation. This review provides a topic update with emphasis on the changing Histoplasma epidemiology, along with new diagnostic and treatment innovations. Recent Findings: Recent years have observed expanding Histoplasma geographic distribution due to climate change, environmental disruption, and host factors. Early clinical experience also suggests a relationship between COVID-19 infection and histoplasmosis, particularly among immunocompromised individuals. Advances in diagnostic methods, such as newer enzyme immunoassays and molecular techniques, have broadened the capability for expedient and highly specific pathogen identification. Novel drug innovations, including the development of new formulations of existing antifungal agents, extended-spectrum azoles and new antifungal drug classes have expanded therapeutic options. Summary: Advances in organ transplantation have largely outpaced those for histoplasmosis. However, these emerging insights enhance our understanding of this pathogen and management of clinical infection, particularly for transplant recipients with a higher incidence and severity of disease.

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.

Chlorhexidine Gluconate Bathing Reduces the Incidence of Bloodstream Infections in Adults Undergoing Inpatient Hematopoietic Cell Transplantation.

Bloodstream infections (BSIs) occur in 20% to 45% of inpatient autologous and allogeneic hematopoietic cell transplant (HCT) patients. Daily bathing with the antiseptic chlorhexidine gluconate (CHG) has been shown to reduce the incidence of BSIs in critically ill patients, although very few studies include HCT patients or have evaluated the impact of compliance on effectiveness. We conducted a prospective cohort study with historical controls to assess the impact of CHG bathing on the rate of BSIs and gut microbiota composition among adults undergoing inpatient HCT at the Duke University Medical Center. We present 1 year of data without CHG bathing (2016) and 2 years of data when CHG was used on the HCT unit (2017 and 2018). Because not all patients adhered to CHG, patients were grouped into four categories by rate of daily CHG usage: high (>75%), medium (50% to 75%), low (1% to 49%), and none (0%). Among 192 patients, univariate trend analysis demonstrated that increased CHG usage was associated with decreased incidence of clinically significant BSI, defined as any BSI requiring treatment by the medical team (high, 8% BSI; medium, 15.2%; low, 15.6%; no CHG, 30.3%; P = .003), laboratory-confirmed BSI (LCBI; P = .03), central line-associated BSI (P = .04), and mucosal barrier injury LCBI (MBI-LCBI; P = .002). Multivariate analysis confirmed a significant effect of CHG bathing on clinically significant BSI (P = .023) and MBI-LCBI (P = .007), without consistently impacting gut microbial diversity. Benefits of CHG bathing were most pronounced with >75% daily usage, and there were no adverse effects attributable to CHG. Adherence to daily CHG bathing significantly decreases the rate of bloodstream infection following HCT.

Update on Nocardia infections in solid-organ transplantation.

PURPOSE OF REVIEW: Nocardia is a ubiquitous pathogen associated with life-threatening opportunistic infections. Organ transplant recipients are uniquely predisposed to Nocardia infections due to their iatrogenic cell-mediated immune deficit necessary to maintain allograft function. This review aims to address recent updates in the epidemiology, clinical presentation, diagnostics, treatment, and outcomes of Nocardia infections in solid-organ transplant recipients. RECENT FINDINGS: The incidence of Nocardia infection depends on multiple patient and environmental factors. Among transplant recipients, lung recipients are most commonly affected. Species identification and antimicrobial susceptibility testing are critical for optimizing therapy as substantial variation occurs among and within Nocardia spp. This has been increasingly accomplished through advances in molecular methods leading to improved accuracy and wider accessibility to testing. There are emerging data applying novel therapeutics and short course therapy that may offer alternative management approaches for transplant associated nocardiosis to minimize drug toxicity and intolerance. SUMMARY: Further prospective, multicenter studies are needed to better characterize the epidemiology of Nocardia in transplant recipients, as well as evaluate the impact of diagnostic advancements and new treatment strategies.

Healthcare associated diarrhea, not Clostridioides difficile.

PURPOSE OF REVIEW: The aim of this article is to review the epidemiology, cause, diagnostic evaluation, and management of healthcare-associated diarrhea (HCAD) with particular attention to current epidemiology and recent developments in diagnostics. RECENT FINDINGS: Multiplex polymerase chain reaction gastrointestinal panels allow rapid detection of a wide array of potential enteropathogens but the role, yield, and utility of these tests have not been systematically assessed in patients with HCAD. Recent epidemiologic studies reaffirm that HCAD is predominantly a noninfectious condition most often caused by medications or underlying medical conditions, sometimes Clostridioides difficile, and occasionally viruses. Other infections are rare. SUMMARY: Clinical assessment remains fundamental to the evaluation of HCAD and targeted testing for C. difficile is sufficient in most patients. Multiplex gastrointestinal panels may have a role in immunocompromised patients but more study is needed. Medication-induced diarrhea is common and underappreciated and not limited to antibiotics, laxatives, and enemas.

Oral and Inhaled Ribavirin Treatment for Respiratory Syncytial Virus Infection in Lung Transplant Recipients.

BACKGROUND: Respiratory syncytial virus (RSV) infection in lung transplant recipients (LTRs) causes mortality rates of 10%-20% despite antiviral therapy. Ribavirin (RBV) has been used to treat RSV-infected LTRs with limited data. METHODS: A retrospective study including all LTRs at Duke Hospital during January 2013-May 2017 with positive RSV polymerase chain reaction respiratory specimens was performed. RESULTS: Fifty-six of 70 patients in the oral RBV group and 29 of 32 in the inhaled RBV group had symptomatic RSV infection. One patient receiving oral RBV had to prematurely stop drug due to significant nausea and vomiting. While unadjusted all-cause 1-year mortality was significantly higher in the inhaled RBV group (24.1% versus 7.1% [oral RBV], P = 0.03), adjusted hazard ratio (HR) for death and oral RBV use (compared to inhaled RBV), accounting for oxygen requirement and need for mechanical ventilation, showed the HR for death and oral RBV use was 0.38 ([0.10, 1.46], P = 0.38). The HR for death in patients with supplemental oxygen >2 L/min at diagnosis was 6.18 ([1.33, 26.83], P = 0.02). Kaplan-Meier curves showed patients with forced expiratory volume in 1 second decline ≥5% and ≥10% at 90 days post-RSV infection had a higher 1-year mortality (P = 0.004 and P = 0.001, respectively). CONCLUSIONS: Oral and inhaled RBV appear to be well tolerated in LTRs, and our data support the use of oral RBV as a safe alternative to inhaled ribavirin in LTRs. Oxygen requirement >2 L/min at diagnosis and forced expiratory volume in 1 second decline ≥5% postinfection may be markers for increased mortality.

Cytomegalovirus in Allogeneic Hematopoietic Transplantation: Impact on Costs and Clinical Outcomes Using a Preemptive Strategy.

Cytomegalovirus (CMV) results in significant morbidity and mortality following hematopoietic cell transplantation (HCT). Establishing the cost and clinical impact is imperative to the selection of appropriate CMV preventative strategies. This is a retrospective cohort study of consecutive patients undergoing their first allogeneic HCT between January 1, 2009, and December 31, 2013. Detailed clinical and institutional cost data were obtained from the start of conditioning through 1-year post-transplantation. Baseline characteristics, resource utilization, costs, and outcomes were compared between patients with and without clinically significant CMV infection (csCMVi). One hundred seventy out of 388 patients (44%) developed csCMVi within 1 year after HCT. Within the first year post-HCT, patients with csCMVi had a significantly longer transplantation-related length of stay (mean, 91.7 days versus 78.3 days; P < .0001) and more frequent and prolonged hospitalizations (mean, 2.4 versus 1.7 admissions [P < .0001]; mean, 39.1 versus 31.5 inpatient days [P = .001]) without significantly more admissions to the intensive care unit (28.2% versus 21.6%; P = .408). The use of granulocyte colony-stimulating factor was greater in patients with csCMVi (73.5% versus 54.1%; P = .0001), although no significant differences were demonstrated in mean platelet or red blood cell (RBC) transfusions. Total costs were also higher in patients with csCMVi (mean cost difference, $45,811; 95% CI, $26,385 to $67,544). However, the incidence of graft-versus-host disease (GVHD) and selected infectious complications was not significantly different between the 2 groups. There were no significant differences in 1-year and 5-year post-transplantation overall survival (OS) or nonrelapse mortality (NRM) between those with and those without csCMVi, although relapse of underlying disease was significantly lower in the csCMVi group. Overall, our data show that allogeneic HCT recipients with csCMVi had significantly greater medical resource utilization and costs than those without csCMVi. However, clinical outcomes, including GVHD, infections, and mortality, were similar in the 2 groups. Further study is needed to determine the cost-effectiveness of CMV preventive modalities.

Updates on Nocardia Skin and Soft Tissue Infections in Solid Organ Transplantation.

PURPOSE OF REVIEW: Due to their immunocompromised status, solid organ transplant (SOT) recipients are at risk for Nocardia infections. These infections often necessitate early invasive diagnostics alongside prolonged, often combination antimicrobial therapy. This review summarizes the importance of this pathogen in skin and soft tissue infections (SSTIs) in SOT recipients inclusive of recently reported cases in the literature and an update on the epidemiology, diagnostics, and management. RECENT FINDINGS: Six studies with 13 isolated SSTIs due to Nocardia have been published in the last 5 years in SOT recipients. The most common underlying type of transplant was kidney and time from transplantation to infection varied from 6 months to 16 years. Misdiagnosis was frequent. Available identified species included N. brasiliensis (2), N. farcinica (2), N. flavorosea (1), N. abscessus (1), N. anaemiae (1), N. asteroides (1), N. nova (1), and N. vinacea (1). Treatment choice and duration varied widely, and trimethoprim-sulfamethoxazole was utilized most often with no documented infection relapse. Nocardia SSTIs can occur both in isolation and as a component of a disseminated infection. Overall, isolated Nocardia SSTIs are uncommon in SOT recipients and are often initially misdiagnosed. They present multiple challenges to the clinician including evaluation for potential co-pathogens and/or non-infectious processes and ruling out the presence of disseminated infection. While trimethoprim-sulfamethoxazole remains the agent of choice for management of most isolated SSTIs, therapy must be tailored to the individual patient based on species-specific susceptibility patterns and formal susceptibility testing, site(s) of infection, and patient tolerability.

Brincidofovir (CMX001) Toxicity Associated With Epithelial Apoptosis and Crypt Drop Out in a Hematopoietic Cell Transplant Patient: Challenges in Distinguishing Drug Toxicity From GVHD.

Brincidofovir (CMX001) is an oral agent with activity against double-strand DNA viruses undergoing clinical trials in immunocompromised patients. We report a patient clinically diagnosed with brincidofovir-related gastrointestinal (GI) toxicity and his histologic findings. A 2-year-old boy with medulloblastoma undergoing autologous hematopoietic cell transplantation developed adenovirus viremia 9 days posttransplant. After initial treatment with intravenous cidofovir he was started on oral brincidofovir as part of a clinical trial. He developed hematochezia, anorexia, and emesis 11 weeks later. Sigmoid colon biopsy showed marked crypt drop out, moderate epithelial apoptosis, and lamina propria edema. The pathologic diagnosis was drug-related injury versus infection. Brincidofovir toxicity was diagnosed clinically and the drug was discontinued. His GI symptoms improved in 2 weeks with supportive care and octreotide. Brincidofovir causes GI toxicity and histologically demonstrates epithelial apoptosis and crypt injury, similar to graft versus host disease and mycophenolate mofetil toxicity.

Nocardia infections in the transplanted host.

BACKGROUND: Nocardia are uncommon pathogens that disproportionately afflict the immunocompromised host. Epidemiology and outcome data of Nocardia infections in transplant recipients are limited. METHODS: We performed a retrospective chart review of all patients at Duke University Hospital with a history of solid organ transplant (SOT) or hematopoietic cell transplant (HCT) and at least one positive culture for Nocardia between 1996 and 2013. Our aim was to describe the epidemiology and outcomes of Nocardia infections in the transplanted host. RESULTS: During the 18-year study period, 51 patients (14 HCT and 37 SOT recipients) had Nocardia infection. Nocardia incidence was stable during the study period in all populations except heart transplants, whose incidence declined. Infection occurred earlier in the HCT group than the SOT group (median time to diagnosis of 153 and 370 days, respectively). In both groups, the most common site involved was the lung. Outcomes were overall poor, especially in the HCT group with a cure rate of 29%. Heart transplant recipients had significantly better overall survival (P < .05) than other patients. Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis did not provide complete protection from Nocardia infections, nor did it appear to select for resistant Nocardia isolates. CONCLUSIONS: Infections with Nocardia are typically a late post-transplant complication. The use of TMP-SMX prophylaxis was not associated with TMP-SMX-resistant Nocardia. Overall outcomes remain poor.

Increasing Nocardia Incidence Associated with Bronchiectasis at a Tertiary Care Center.

RATIONALE: Nocardia is a genus of pathogens that most commonly afflict immunocompromised hosts but may be an emerging infection among persons with bronchiectasis. OBJECTIVES: To examine the epidemiology and clinical presentation of adult patients with Nocardia and bronchiectasis relative to other patient groups. METHODS: We examined a retrospectively assembled cohort of adults at Duke University Hospital in Durham, North Carolina with at least one positive culture from a bodily fluid or tissue specimen for Nocardia between January 1996 and December 2013. Denominator data for key populations (e.g., bronchiectasis, transplant) were obtained using International Classification of Diseases, Ninth Revision codes. In addition, we performed a case-control analysis to examine the relationship between inhaled corticosteroid use and Nocardia lung infection among otherwise immunocompetent patients with bronchiectasis. MEASUREMENTS AND MAIN RESULTS: We identified 183 patients with one or more cultures positive for Nocardia: 44 from 1996 to 2001, 64 from 2002 to 2007, and 75 from 2008 to 2013. Immune compromise was common (56%), particularly solid organ or hematopoietic cell transplant (30%). Infection usually was confined to the lungs (62%), followed by skin (10%), other sites (6%), brain (2%), and multiple sites (17%). Non-cystic fibrosis bronchiectasis was common among both immunocompetent (38%) and immunocompromised (10%) patients. Nocardia incidence in patients with bronchiectasis increased significantly over time, but there was no significant change in Nocardia incidence in hematopoietic cell or solid organ transplant recipients (our largest immunocompromised population). Among patients with bronchiectasis, Nocardia was positively but nonsignificantly associated with use of inhaled corticosteroids (odds ratio, 1.8; 95% confidence interval, 0.7-4.4). CONCLUSIONS: The increasing incidence of Nocardia infections at our medical center appears to be driven by increased incidence in patients with bronchiectasis rather than increases in immunocompromised populations. It is unclear whether increased environmental exposures, microbiologic surveillance, or other factors account for the increased incidence of Nocardia in our patients with bronchiectasis.