Building a successful transplant research center: Blueprints and barriers.

A successful multidisciplinary research center depends on the quality of the science being conducted and the quality of the center's design, culture, infrastructure, and institutional support. In this perspective, we describe our experience building and maintaining a multidisciplinary transplant research center with a large focus on transplant infectious diseases. We identify principles that we believe contributed to our success including: taking inventory, defining culture, creating a multidisciplinary shared leadership model, establishing expertise in a multiple method approach, investing in operations and management, building and sharing resources, and securing institutional support. We share our experience putting these principles into practice and highlight potential roadblocks.

Geographical distribution of the Cryptococcus gattii species complex: a systematic review.

The taxonomy of the Cryptococcus gattii species complex continues to evolve, and has been divided into five pathogenic species. The objective of this systematic review was to summarise the geographical distribution of the C gattii species complex and the species within the C gattii species complex. We searched PubMed for articles related to human, animal, ecological, or laboratory-based studies of C gattii species complex isolates with traceable geographical origin published from January, 1970, until September, 2021. Having extracted their geographical origin, we used ArcMap to construct maps according to the highest degree of resolution allowed by their reported taxonomy, to reflect the most likely area of transmission on the basis of published reports of human isolates. 604 such articles were included in the study. This review indicated that although C gattii species complex isolates have been reported globally, understanding their heterogeneous geographical distribution by species can have implications for researchers and clinicians in formulating research questions and considering diagnostic quandaries.

Minimizing risk while maximizing opportunity: The infectious disease organ offer process survey.

BACKGROUND: The purpose of this study was to understand how transplant infectious disease (TID) physicians assess a potential donor with known or suspected infection and describe posttransplant management. METHODS: We designed a survey of 10 organ offer scenarios and asked questions pertaining to organ acceptability for transplantation and management posttransplant. The survey was distributed to TID clinicians via transplant society listservs and email. Responses were recorded in REDCap, and descriptive statistics were employed. RESULTS: One hundred thirteen infectious disease physicians responded to the survey, of whom 85 completed all cases. Respondents were generally in agreement regarding organ acceptability, although some divergence was seen when evaluating lungs from donors with influenza, tuberculosis, or multidrug-resistant Acinetobacter infection. Posttransplant management showed more variation. Areas of optimization were identified: (1) Further understanding of where risk-mitigation strategies within the donor offer process may improve donor acceptability and therefore organ utilization; (2) importance of recipient considerations in assessing degree of infectious risk; and (3) gaps in evidenced-based data regarding optimal posttransplant management of recipients. CONCLUSION: Evaluation of donor offers by TID clinicians is a complex process. Although the survey does not itself serve to make recommendations regarding best practices, it highlights areas where generation of data to inform acceptance and management practices may allow for improved organ utilization and recipient management.

The Burden of Invasive Fungal Disease Following Chimeric Antigen Receptor T-Cell Therapy and Strategies for Prevention.

Chimeric antigen receptor (CAR) T-cell therapy is a novel immunotherapy approved for the treatment of hematologic malignancies. This therapy leads to a variety of immunologic deficits that could place patients at risk for invasive fungal disease (IFD). Studies assessing IFD in this setting are limited by inconsistent definitions and heterogeneity in prophylaxis use, although the incidence of IFD after CAR T-cell therapy, particularly for lymphoma and myeloma, appears to be low. This review evaluates the incidence of IFD after CAR T-cell therapy, and discusses optimal approaches to prevention, highlighting areas that require further study as well as future applications of cellular therapy that may impact IFD risk. As the use of CAR T-cell therapy continues to expand for hematologic malignancies, solid tumors, and most recently to include non-oncologic diseases, understanding the risk for IFD in this uniquely immunosuppressed population is imperative to prevent morbidity and mortality.

Infectious Diseases Physician Management of Cryptococcal Meningitis in North America-Is Single High-Dose Liposomal Amphotericin B Being Used?

Background: Several recent randomized trials have been conducted in resource-limited settings for cryptococcal meningitis that have rapidly innovated international guidelines. The 2010 Infectious Diseases Society of America (IDSA) cryptococcal meningitis guideline has not been updated with recent trials. The 2022 AMBITION-cm trial found that a single 10-mg/kg dose of liposomal amphotericin B plus daily flucytosine and fluconazole for 2 weeks was noninferior to 1 week of amphotericin B deoxycholate with flucytosine. It is unknown whether physicians in high-resource settings are using this regimen or more traditional regimens. Methods: We developed an electronic survey in June 2023 to better understand whether physician members of the IDSA Emerging Infections Network (EIN) and Mycoses Study Group Education and Research Consortium (MSG-ERC) had used the AMBITION-cm induction regimen, would use the regimen in hypothetical clinical scenarios, and what perceived barriers to use existed. Results: A total of 242 of 561 (43%) physicians responded to the survey, of whom 205 provided care for persons with cryptococcal meningitis in the last year. Overall, 29 (14%) had used the AMBITION-cm regimen, and 176 (86%) had not. In various hypothetical clinical scenarios, only ∼10% of 209 respondents selected the AMBITION-cm regimen as preferred. Perceived barriers to uptake included the applicability of trials performed in low-resource settings to high-resource settings, that the regimen is not recommended in the 2010 IDSA guidelines, and the applicability to persons without HIV. Conclusions: Most respondents had not used the single-dose liposomal amphotericin B regimen, but the regimen is being used. Further study of this regimen in other patient populations and settings is necessary.

Long-term outcomes after COVID-19 infection in transplant recipients.

BACKGROUND: Long-term outcomes after COVID-19 infection unique to solid organ transplant recipients (SOTR) are not published. We describe outcomes including readmission, allograft rejection, allograft dysfunction, allograft failure, and death. METHODS: We conducted a retrospective cohort study of mostly unvaccinated SOTR with COVID-19 from March 2020 to November 2021. Disease severity was assigned by NIH criteria. Data included demographics, clinical features, treatment, and outcomes and are presented as mean ± standard deviation or median (range). RESULTS: One hundred and thirty-eight SOTR were diagnosed with COVID-19 at a median of 5 (IQR 3-8) years post-transplant with a mean age of 57 ± 12 years at diagnosis. Forty-one recovered at home; 97 were admitted. 12/32 (37.5%) SOTR with critical disease expired during initial admission. Among those who recovered, 48/126 (38.0%) had asymptomatic or mild infection, 31/126 (24.6%) had moderate, 27/126 (21.4%) severe, and 20/126 (15.9%) critical infection. 38/85 (44.7%) of SOTR who survived initial admission had 74 readmissions within 180 days (Figure 1). The 6-month mortality rate among those who survived infection was 4/126 (3.2%). The mean time from initial infection to death was 32 ± 66 days in inpatient deaths and 95 ± 39 days in those who were discharged or never admitted. Six-month graft dysfunction occurred in 18/125 (14.4%) and graft failure in 9/126 (7.2%); five failures were deaths with function. CONCLUSION: Readmissions after COVID-19 infection were frequent after the index admission. Rejection was relatively infrequent; graft dysfunction at 6 months post-infection was more common than rejection. Six-month mortality following COVID-19 recovery in SOTR was significant; close follow-up of patients is warranted.

Consensus position statement on advancing the standardised reporting of infection events in immunocompromised patients.

Patients can be immunocompromised from a diverse range of disease and treatment factors, including malignancies, autoimmune disorders and their treatments, and organ and stem-cell transplantation. Infections are a leading cause of morbidity and mortality in immunocompromised patients, and the disease treatment landscape is continually evolving. Despite being a critical but preventable and curable adverse event, the reporting of infection events in randomised trials lacks sufficient detail while inconsistency of categorisation and definition of infections in observational and registry studies limits comparability and future pooling of data. A core reporting dataset consisting of category, site, severity, organism, and endpoints was developed as a minimum standard for reporting of infection events in immunocompromised patients across study types. Further additional information is recommended depending on study type. The standardised reporting of infectious events and attributable complications in immunocompromised patients will improve diagnostic, treatment, and prevention approaches and facilitate future research in this patient group.

Lung and sinus fungal infection imaging in immunocompromised patients.

BACKGROUND: Imaging is a key diagnostic modality for suspected invasive pulmonary or sinus fungal disease and may help to direct testing and treatment. Fungal diagnostic guidelines have been developed and emphasize the role of imaging in this setting. We review and summarize evidence regarding imaging for fungal pulmonary and sinus disease (in particular invasive aspergillosis, mucormycosis and pneumocystosis) in immunocompromised patients. OBJECTIVES: We reviewed data on imaging modalities and findings used for diagnosis of invasive fungal pulmonary and sinus disease. SOURCES: References for this review were identified by searches of PubMed, Google Scholar, Embase and Web of Science through 1 April 1 2023. CONTENT: Computed tomography imaging is the method of choice for the evaluation of suspected lung or sinus fungal disease. Although no computed tomography radiologic pattern is pathognomonic of pulmonary invasive fungal disease (IFD) the halo sign firstly suggests an angio-invasive pulmonary aspergillosis while the Reversed Halo Sign is more suggestive of pulmonary mucormycosis in an appropriate clinical setting. The air crescent sign is uncommon, occurring in the later stages of invasive aspergillosis in neutropenic patients. In contrast, new cavitary lesions should suggest IFD in moderately immunocompromised patients. Regarding sinus site, bony erosion, peri-antral fat or septal ulceration are reasonably predictive of IFD. IMPLICATIONS: Imaging assessment of the lung and sinuses is an important component of the diagnostic work-up and management of IFD in immunocompromised patients. However, radiological features signs have sensitivity and specificity that often vary according to underlying disease states. Periodic review of imaging studies and diagnostic guidelines characterizing imaging findings may help clinicians to consider fungal infections in clinical care thereby leading to an earlier confirmation and treatment of IFD.

Clinical Testing Guidance for Coccidioidomycosis, Histoplasmosis, and Blastomycosis in Patients with Community-Acquired Pneumonia for Primary and Urgent Care Providers.

Coccidioidomycosis, histoplasmosis, and blastomycosis are underrecognized and frequently misdiagnosed fungal infections that can clinically resemble bacterial and viral community-acquired pneumonia (CAP). This guidance is intended to help clinicians in outpatient settings test for these fungal diseases in patients with CAP to reduce misdiagnoses, unnecessary antibacterial use, and poor outcomes.

Fungal Endocarditis: Pathophysiology, Epidemiology, Clinical Presentation, Diagnosis, and Management.

Fungal endocarditis accounts for 1% to 3% of all infective endocarditis cases, is associated with high morbidity and mortality (>70%), and presents numerous challenges during clinical care. Candida spp. are the most common causes of fungal endocarditis, implicated in over 50% of cases, followed by Aspergillus and Histoplasma spp. Important risk factors for fungal endocarditis include prosthetic valves, prior heart surgery, and injection drug use. The signs and symptoms of fungal endocarditis are nonspecific, and a high degree of clinical suspicion coupled with the judicious use of diagnostic tests is required for diagnosis. In addition to microbiological diagnostics (e.g., blood culture for Candida spp. or galactomannan testing and PCR for Aspergillus spp.), echocardiography remains critical for evaluation of potential infective endocarditis, although radionuclide imaging modalities such as 18F-fluorodeoxyglucose positron emission tomography/computed tomography are increasingly being used. A multimodal treatment approach is necessary: surgery is usually required and should be accompanied by long-term systemic antifungal therapy, such as echinocandin therapy for Candida endocarditis or voriconazole therapy for Aspergillus endocarditis.

Is diagnostic stewardship possible in solid organ transplantation?

BACKGROUND: Diagnostic stewardship in solid organ transplant (SOT) recipients has the potential to help these vulnerable patients at risk for over-testing and overtreatment. METHODS: Herein, we review potential targets for diagnostic stewardship in SOT, such as Clostridioides difficile testing, urine cultures, molecular diagnostics, as well as novel areas of diagnostic stewardship. RESULTS: Bundled interventions focused on appropriate C. difficile testing can result in a significant decrease in testing and clinical diagnosis of C. difficile infection without any harms related to delay in diagnosis. In otherwise stable renal transplant recipients after the first month of transplant, screening urine cultures have not been shown to improve outcomes. Novel targets that require additional study in the SOT population include noninvasive fungal diagnostics and cytomegalovirus testing strategies CONCLUSIONS: Diagnostic stewardship is an innovative approach to improve diagnosis and limit unnecessary antimicrobial use. While there has been little direct exploration of diagnostic stewardship in the SOT population, there is great potential for benefit given frequent testing with diagnostics that have imperfect sensitivity and specificity, and sometimes great cost. Diagnostic stewardship in the SOT population is indeed possible but will require a multidisciplinary effort to ensure that appropriates tests and benefits are realized.

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.

Management of Histoplasmosis by Infectious Disease Physicians.

Background: The Infectious Diseases Society of America (IDSA) guidelines for the management of histoplasmosis were last revised 15 years ago. Since those guidelines were compiled, new antifungal treatment options have been developed. Furthermore, the ongoing development of immunomodulatory therapies has increased the population at increased risk to develop histoplasmosis. Methods: An electronic survey about the management practices of histoplasmosis was distributed to the adult infectious disease (ID) physician members of the IDSA's Emerging Infections Network. Results: The survey response rate was 37% (551/1477). Only 46% (253/551) of respondents reported seeing patients with histoplasmosis. Regions considered endemic had 82% (158/193) of physicians report seeing patients with histoplasmosis compared to 27% (95/358) of physicians in regions not classically considered endemic (P < 0.001). Most ID physicians follow IDSA treatment guidelines recommending itraconazole for acute pulmonary (189/253 [75%]), mild-moderate disseminated (189/253 [75%]), and as step-down therapy for severe disseminated histoplasmosis with (232/253 [92%]) and without (145/253 [57%]) central nervous system involvement. There were no consensus recommendations observed for survey questions regarding immunocompromised patients. Conclusions: Though there are increased reports of histoplasmosis diagnoses outside regions classically considered endemic, a majority of ID physicians reported not seeing patients with histoplasmosis. Most respondents reported adherence to IDSA guidelines recommending itraconazole in each clinical situation. New histoplasmosis guidelines need to reflect the growing need for updated general guidance, particularly for immunocompromised populations.

Clinical utility of antifungal susceptibility testing.

Invasive fungal diseases cause significant morbidity and mortality, in particular affecting immunocompromised patients. Resistant organisms are of increasing importance, yet there are many notable differences in the ability to both perform and interpret antifungal susceptibility testing compared with bacteria. In this review, we will highlight the strengths and limitations of resistance data of pathogenic yeasts and moulds that may be used to guide treatment and predict clinical outcomes.

Overview of COVID-19-Associated Invasive Fungal Infection.

Purpose of Review: Invasive fungal infections are a complication of COVID-19 disease. This article reviews literature characterizing invasive fungal infections associated with COVID-19. Recent Findings: Multiple invasive fungal infections including aspergillosis, candidiasis, pneumocystosis, other non-Aspergillus molds, and endemic fungi have been reported in patients with COVID-19. Risk factors for COVID-19-associated fungal disease include underlying lung disease, diabetes, steroid or immunomodulator use, leukopenia, and malignancy. COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM) are the most common fungal infections described. However, there is variability in the reported incidences related to use of differing diagnostic algorithms. Summary: Fungal pathogens are important cause of infection in patients with COVID-19, and the diagnostic strategies continue to evolve. Mortality in these patients is increased, and providers should operate with a high index of suspicion. Further studies will be required to elucidate the associations and pathogenesis of these diseases and best management and prevention strategies.

Frequency and Duration of, and Risk Factors for, Diagnostic Delays Associated with Histoplasmosis.

Histoplasmosis is often confused with other diseases leading to diagnostic delays. We estimated the incidence, length of, and risk factors for, diagnostic delays associated with histoplasmosis. Using data from IBM Marketscan, 2001-2017, we found all patients with a histoplasmosis diagnosis. We calculated the number of visits that occurred prior to the histoplasmosis diagnosis and the number of visits with symptomatically similar diagnoses (SSDs). Next, we estimated the number of visits that represented a delay using a simulation-based approach. We also computed the number of potential opportunities for diagnosis that were missed for each patient and the length of time between the first opportunity and the diagnosis. Finally, we identified risk factors for diagnostic delays using a logistic regression model. The number of SSD-related visits increased significantly in the 97 days prior to the histoplasmosis diagnosis. During this period, 97.4% of patients had a visit, and 90.1% had at least one SSD visit. We estimate that 82.9% of patients with histoplasmosis experienced at least one missed diagnostic opportunity. The average delay was 39.5 days with an average of 4.0 missed opportunities. Risk factors for diagnostic delays included prior antibiotic use, history of other pulmonary diseases, and emergency department and outpatient visits, especially during weekends. New diagnostic approaches for histoplasmosis are needed.

Clinical characteristics of COVID-19 in solid organ transplant recipients following COVID-19 vaccination: A multicenter case series.

BACKGROUND: Solid organ transplant recipients (SOTR) have diminished humoral immune responses to COVID-19 vaccination and higher rates of COVID-19 vaccine breakthrough infection than the general population. Little is known about COVID-19 disease severity in SOTR with COVID-19 vaccine breakthrough infections. METHODS: Between 4/7/21 and 6/21/21, we requested case reports via the Emerging Infections Network (EIN) listserv of SARS-CoV-2 infection following COVID-19 vaccination in SOTR. Online data collection included patient demographics, dates of COVID-19 vaccine administration, and clinical data related to COVID-19. We performed a descriptive analysis of patient factors and evaluated variables contributing to critical disease or need for hospitalization. RESULTS: Sixty-six cases of SARS-CoV-2 infection after vaccination in SOTR were collected. COVID-19 occurred after the second vaccine dose in 52 (78.8%) cases, of which 43 (82.7%) occurred ≥14 days post-vaccination. There were six deaths, three occurring in fully vaccinated individuals (7.0%, n = 3/43). There was no difference in the percentage of patients who recovered from COVID-19 (70.7% vs. 72.2%, p = .90) among fully and partially vaccinated individuals. We did not identify any differences in hospitalization (60.5% vs. 55.6%, p = .72) or critical disease (20.9% vs. 33.3%, p = .30) among those who were fully versus partially vaccinated. CONCLUSIONS: SOTR vaccinated against COVID-19 can still develop severe, and even critical, COVID-19 disease. Two doses of mRNA COVID-19 vaccine may be insufficient to protect against severe disease and mortality in SOTR. Future studies to define correlates of protection in SOTR are needed.