Delabeling penicillin and other antibiotic allergies in solid organ transplantation patients - Ham, Young Yoon; Joshi, Shyam; Sukerman, Ellie (Transplant Infectious Disease, 2022)
Background Immunocompromised populations including solid organ transplant (SOT) recipients have a high likelihood of need for antibiotic therapy for treatment of infection as well as for prophylaxis. Antibiotic allergy is commonly reported and often leads to the use of alternative, second-line antibiotics, which have been associated with poor outcomes, increased adverse effects, and higher cost. Formal allergy assessment and allergy testing can serve as an important antimicrobial stewardship tool in optimizing antibiotic regimens for this patient population. Methods A PubMed search with relevant keywords was performed. Review of relevant professional society guidelines was also performed. Results Documented penicillin and sulfonamide allergies are common impediments to the treatment and prophylaxis of immunocompromised populations, but are rarely formally evaluated in practice; however, there is evidence that most patients with documented allergy to these antibiotics can, in fact, tolerate penicillins and sulfonamide antibiotics. Implementation of an antibiotic allergy evaluation and testing program has been shown to increase the use of first-line antibiotics and can be cost saving. Conclusion Antibiotic allergies have significant clinical consequences, especially in immunocompromised populations. Evaluation of these allergies to prevent the avoidance of first-line antibiotics should be a standard part of the workflow for these patients, prior to transplant. Programs can be tailored to the available personnel and resources of the organization.
Keywords: allergy; antibiotic; delabeling; organ transplant

COVID-19 therapeutics and outcomes among solid organ transplant recipients during the Omicron BA.1 era - Hedvat, Jessica; Lange, Nicholas W.; Salerno, David M.; DeFilippis, Ersilia M.; Kovac, Danielle; Corbo, Heather; Chen, Justin K.; Choe, Jason Y.; Lee, Jennifer H.; Anamisis, Anastasia; Jennings, Douglas L.; Codispodo, Giovanna; et al. (American Journal of Transplantation, 2022)
Treatment outcomes associated with the use of novel COVID-19 therapeutics in solid organ transplant recipients (SOTR) are not well described in the literature. The objective of this analysis was to characterize 30-day hospitalization and other key secondary endpoints experienced by outpatient SOTR with mild–moderate COVID-19 treated with nirmatrelvir/ritonavir (NR), sotrovimab, or no SARS-CoV-2 specific treatment. This IRB-approved, retrospective study included 154 SOTR with a documented positive SARS-CoV-2 infection between December 16, 2021 and January 19, 2022 (a predominant Omicron BA.1 period in New York City). Patients who received NR (N = 28) or sotrovimab (N = 51) experienced a lower rate of 30-day hospitalization or death as compared to those who received no specific treatment (N = 75) (p = .009). A total of three deaths occurred, all among patients who initially received no specific treatment prior to hospitalization. These results suggest a role for SARS-CoV-2 specific agents in the treatment of SOTR with COVID-19, and that there does not appear to be any difference in effectiveness when comparing NR versus sotrovimab.

Incidence of sexually transmitted infections is lower among kidney transplant recipients compared to the general population—A nationwide cohort study - Helanterä, Ilkka; Gissler, Mika; Kanerva, Mari; Rimhanen-Finne, Ruska; Lempinen, Marko; Finne, Patrik (Transplant Infectious Disease, 2022)
Aim The burden of sexually transmitted infections (STI) among solid-organ transplant recipients is currently unknown. We studied the risk of STIs among kidney transplant recipients compared with the general population in a nationwide cohort. Methods Between 2002 and 2019, all microbiological findings of Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum (syphilis), and human immunodeficiency virus among kidney transplant recipients <65 years and transplanted between 1995 and 2017 in our country were captured from statutory national registries. Data from the general population of Finland, population 5.5 million, were used for comparisons. Incidence of STIs and age and sex-adjusted standardized incidence ratios (SIR) were calculated. Results Altogether 3612 transplantations, with a total follow-up of 27 069 person-years were included. A total of 30 STIs microbiological findings of STI were confirmed in 25 patients: C. trachomatis (N = 27), N. gonorrhoeae (N = 2), and syphilis (N = 1). No hospitalizations associated with STIs were detected. The risk of STI after kidney transplantation was significantly lower compared to the general population (SIR, 0.57, 95% CI 0.39–0.80). The lower risk of STIs was more pronounced in female patients (SIR 0.40, 95% CI 0.20–0.74), whereas in male patients the difference was statistically not significant (SIR 0.69, 95% CI 0.44–1.04). Of the confirmed STI cases, 30% were detected in patients who received their transplants during adolescence. Conclusions Within the Finnish kidney transplant population, the age and sex-adjusted incidence of sexually transmitted infections is not higher compared to the general population. Highest frequency of infections was seen among patients transplanted during adolescence.
Keywords: Chlamydia trachomatis; Neisseria gonorrhoeae; kidney transplantation; sexually transmitted infections; syphilis

HIV D+/R+ heart/kidney transplantation: First case report - Hemmige, Vagish; Saeed, Omar; Puius, Yoram A.; Azzi, Yorg; Colovai, Adriana; Borgi, Jamil; Goldstein, Daniel J.; Rahmanian, Marjan; Carlese, Anthony; Jorde, Ulrich P.; Patel, Snehal (The Journal of Heart and Lung Transplantation, 2022)

Sphingosine-1 Phosphate Receptor Modulators - Herrera, Sabina; Bodro, Marta (Infectious Complications in Biologic and Targeted Therapies, 2022)
Sphingosine-1-phosphate receptor (S1PR) modulators have and are being evaluated for numerous conditions. To date, the main indication of this group of drugs is for multiple sclerosis (MS). Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and neurodegeneration. Therapeutic approaches are focused on both inflammation and neurodegeneration that are present from early stages of the disease. Sphingosine-1-phosphate receptor (S1PR) modulators, like Fingolimod, seem to target both scenarios and have demonstrated to be able to reduce disease activity or progression in multiple sclerosis. They act as functional antagonists of sphingosine by blockade of the S1PR signaling pathway. Their action results in naïve and memory T and B lymphocytes being stacked at the lymph node, but still allowing the circulation of effector memory lymphocytes.
Keywords: Fingolimod; Multiple sclerosis; Sphingosine-1-phosphate receptor (S1PR); Varicella-zoster

COVID-19-associated fungal infections - Hoenigl, Martin; Seidel, Danila; Sprute, Rosanne; Cunha, Cristina; Oliverio, Matteo; Goldman, Gustavo H.; Ibrahim, Ashraf S.; Carvalho, Agostinho (Nature Microbiology, 2022)
Coronavirus disease 2019 (COVID-19)-associated invasive fungal infections are an important complication in a substantial number of critically ill, hospitalized patients with COVID-19. Three groups of fungal pathogens cause co-infections in COVID-19: Aspergillus, Mucorales and Candida species, including Candida auris. Here we review the incidence of COVID-19-associated invasive fungal infections caused by these fungi in low-, middle- and high-income countries. By evaluating the epidemiology, clinical risk factors, predisposing features of the host environment and immunological mechanisms that underlie the pathogenesis of these co-infections, we set the scene for future research and development of clinical guidance., Hoenigl and colleagues review the epidemiology, immunology and clinical risk factors contributing to COVID-19-associated fungal infections.
Keywords: Fungal infection; Risk factors

Current state of antimicrobial stewardship in solid organ transplantation in Israel - Hoffman, Tomer; Atamna, Alaa; Katchman, Eugene; Orenbuch-Harroch, Efrat; Nesher, Lior; Bitterman, Roni; Yahav, Dafna; Nutman, Amir (Transplant Infectious Disease, 2022)
Background We aimed to review the current state, challenges, and needs of antimicrobial stewardship programs (ASPs) in adult solid organ transplantation (SOT) centers in Israel. Methods We conducted a survey using electronic questionnaires sent during February 2022 to infectious disease (ID) consultants of SOT centers, encompassing general and organ-specific ASP issues. Results All six centers performing adult SOTs in Israel participated. The institutional ASPs in all centers included SOT recipients, and five centers had specific stewardship activities targeting SOT recipients. ASP activities were performed by ID consultants in all centers, with clinical pharmacists in most. ASP protocols and activity scope were highly variable. Formulary restriction with pre-authorization was used in all centers. Antibiotic allergy was addressed in ASP guidelines in half of the centers. Peri-transplantation antibiotic, antifungal, and antiviral prophylactic regimens varied based on center, transplanted organ, and patient risk group. Approaches to surveillance cultures, diagnosis and treatment of various graft infections were also variable. ASP outcome measurement was not performed in all centers. The main challenges and barriers to successful ASP implementation were difficulty in defining appropriate durations of therapy for certain infections, high rates of antimicrobial resistance (AMR), and lack of dedicated ASP teams. Conclusion Antimicrobial stewardship in SOT centers in Israel is performed by ID consultants and practices vary. Challenges are related to high AMR rates, insufficient evidence to support practices, lack of dedicated ASP teams, and lack of outcome measurement. There is an urgent need to establish a national collaborative program including all SOT centers.
Keywords: Israel; antimicrobial stewardship; national survey; solid organ transplantation

Organ transplant and Covid-19 vaccination: Considering the ethics of denying transplant to unvaccinated patients - Hurst, Daniel J.; Potter, Jordan; Padilla, Luz A. (Clinical Transplantation, 2022)
Recently, a number of organ transplant centers in the United States have proposed to only allow patients who have received the Covid-19 vaccination to be active on their transplant waiting list. This raises numerous ethical issues. This analysis utilizes current empirical data and the guidelines on the ethics of organ allocation published by the Organ Procurement and Transplant Network to guide our ethical reasoning. We conclude that it would be permissible to mandate Covid-19 vaccination as a condition of being listed for an organ transplant at a transplant center and offer recommendations for how to do so.
Keywords: Covid-19; ethics; transplant

Is diagnostic stewardship possible in solid organ transplantation? - Husson, Jennifer; Bork, Jacqueline T.; Morgan, Daniel; Baddley, John W. (Transplant Infectious Disease, 2022)
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.
Keywords: C difficile; CMV; diagnostic stewardship; solid organ transplant

Real-time Transcription Polymerase Chain Reaction Cycle Threshold Values as Criteria for Utilization of Incidental COVID-19 Positive Lung Donors - Hwang, Josephine; Yuen, Alexander; Rhoades, Joshua; Barnes, Darina; Zakowski, Phillip; Megna, Dominick J; Catarino, Pedro; Zaffiri, Lorenzo; Rampolla, Reinaldo (The Journal of Heart and Lung Transplantation, 2022)

Shorter is better: The case for short antibiotic courses for common infections in solid organ transplant recipients - Imlay, Hannah; Spellberg, Brad (Transplant Infectious Disease, 2022)
Background Prolonged antibiotics are associated with toxicity, selection for resistant organisms, and secondary infections such as Clostridioides difficile colitis. Emerging clinical data suggest that short courses of antibiotics can be used for common bacterial infections among immune competent patients, but for many randomized controlled trials (RCTs), immunocompromised patients, including solid organ transplant recipients (SOTRs), have been excluded. Methods Peer-reviewed publications were identified through PubMed and Embase searches. Results We review data examining shorter antibiotic courses among immunocompetent and immunocompromised patients and the rationale for use of short antibiotic courses in SOTRs. Conclusion There are known harms associated with antibiotics and, when studied, existing data do not demonstrate harm associated with shorter courses of antibiotics among SOTRs. Furthermore, several RCTs did include some immune compromised patients and found shorter therapy to result in similar clinical efficacy with diminished adverse effects. Shorter antibiotic durations should be considered in SOTRs, and questions of antibiotic duration among SOTRs should be prioritized for study in clinical trials.
Keywords: antibiotic course; antibiotic duration; antimicrobial stewardship; bacterial infection; organ transplantation

Importance of antimicrobial stewardship in solid organ transplant recipients: An ESCMID perspective - Ioannou, Petros; Karakonstantis, Stamatis; Schouten, Jeroen; Kostyanev, Tomislav; Charani, Esmita; Vlahovic-Palcevski, Vera; Kofteridis, Diamantis P.; Esgap, Supported by the ESCMID Study Group for Antimicrobial Stewardship- (Transplant Infectious Disease, 2022)
Background In the last decades, solid organ transplantation (SOT) has emerged as an important method in the management of chronic kidney, liver, heart, and lung failure. Antimicrobial use has led to a significant reduction of morbidity and mortality due to infectious complications among patients with SOT; however, it can lead to adverse events and drive the development of antimicrobial resistance; thus, antimicrobial stewardship is of extreme importance. Even though there are ongoing efforts of transplant societies to implement principles of antimicrobial stewardship in everyday practice in SOT, there is still a lack of guidelines in this patient population. Aim The aim of this study was to review the status of antimicrobial stewardship in patients with SOT, highlight its importance from the perspective of an ongoing vivid dialogue among ESCMID experts in the field of antimicrobial stewardship, and depict opportunities for future study in the field. Review Antimicrobial stewardship programs are important in order to allow appropriate initiation and termination of antimicrobials in SOT recipients, and also aid in the most appropriate dosing and choosing of the route of administration of antimicrobials. Application of already known antimicrobial stewardship principles and application of currently used biomarkers and newly developed molecular rapid diagnostic testing tools can aid to the rationalization of antimicrobial prescribing and to a more targeted treatment of infections. Finally, physicians caring for SOT recipients should be actively involved in antimicrobial stewardship in order to assure optimization of antimicrobial prescribing and become familiar with the principles of antimicrobial stewardship.
Keywords: antibiotics; antimicrobial resistance; antimicrobial stewardship; transplantation

COVID-19 in the Immunocompromised Host, Including People with Human Immunodeficiency Virus - Jakharia, Niyati; Subramanian, Aruna K.; Shapiro, Adrienne E. (Infectious Disease Clinics of North America, 2022)

Cytomegalovirus antiviral stewardship in solid organ transplant recipients: A new gold standard - Jorgenson, Margaret R.; Descourouez, Jillian L.; Kleiboeker, Hanna; Goldrosen, Kerry; Schulz, Lucas; Rice, John P.; Odorico, Jon S.; Mandelbrot, Didier A.; Smith, Jeannina A.; Saddler, Christopher M. (Transplant Infectious Disease, 2022)
Purpose Antimicrobial stewardship programs (ASPs) are essential entities that promote the appropriate use of antimicrobials, leading to improved patient outcomes and reduced resistance. Application to the immunocompromised host is a natural progression for expansion. Cytomegalovirus (CMV) infection is a common complication following solid organ transplant with significant implications on graft survival, making it an attractive ASP target. The aim of this piece is to review our center-specific experience with the development, implementation, and maintenance of a CMV stewardship initiative at a large transplant center. Methods Our CMV stewardship initiative began in 2018. Herein, we review 3 years’ experience and quality-related improvement that occurred from initiation to present state and share our stewardship algorithms. Special attention is paid to the impact of the program as well as our increased understanding of the complex interplay between prevention, treatment, and host development of CMV-specific cell-mediated immunity (CMI). Results We found our stewardship initiative not only reduced the incidence of ganciclovir resistance but also streamlined care via a centralized and structured approach. This objective, protocolized program has resulted in a significant shift away from a reactive to a proactive state and in turn, reduced CMV treatment rates (26% at initiation to 12% in the current state, p = .012). Conclusion A dedicated multidisciplinary team focused on CMV stewardship is imperative in providing a patient-centered approach focused on development of CMV-specific CMI, and as a result prevention of CMV disease. We believe these programs will be the new gold standard for CMV management.
Keywords: cytomegalovirus; immunity; optimization; prevention; treatment

α4-Integrin (and Other Leukocyte Integrin)-Targeting Agents - Kampouri, Eleftheria E.; Tschopp, Jonathan; Manuel, Oriol (Infectious Complications in Biologic and Targeted Therapies, 2022)
Integrins are transmembrane receptors that play a key role in cell adhesion and intracellular signaling. Leukocyte integrins are essential for the recruitment of leukocytes from the vasculature to the tissues and are used as therapeutic targets to modulate inflammation. The monoclonal antibody natalizumab targets the α4 subunit of α4β1 and α4β7 integrins, implicated in the entry of lymphocytes in the central nervous system (CNS) and the gut mucosa, respectively. These integrins are involved in the pathogenesis of multiple sclerosis (MS) and inflammatory bowel disease (IBD) which represent the two approved indications for the use of natalizumab. Vedolizumab selectively targets α4β7 integrin and is approved for the treatment of IBD. Progressive multifocal leukoencephalopathy (PML) is the main infectious complication observed with natalizumab, due to the blockade of α4β1-mediated entry of T lymphocytes in the CNS, leading to decreased immunosurveillance against JC virus (JCV). PML is not observed with vedolizumab, which has no effect on leukocyte trafficking to the CNS. The risk of PML development, a life-threatening disease, is associated with the patient’s JCV serostatus, the use of previous immunosuppression, and treatment duration. No specific treatment exists for PML, and therefore stringent risk stratification and prevention strategies are required during natalizumab therapy.
Keywords: Anti-JCV IgG antibody index; Etrolizumab; Infectious complications; JC virus; Leukocyte integrins; Natalizumab; Prevention; Progressive multifocal leukoencephalopathy; Vedolizumab; α4-Integrin antagonists

Cytomegalovirus-related Complications and Management in Facial Vascularized Composite Allotransplantation: An International Multicenter Retrospective Cohort Study - Kauke-Navarro, Martin; Panayi, Adriana C.; Formica, Richard; Marty, Francisco; Parikh, Neil; Foroutanjazi, Sina; Safi, Ali-Farid; Mardini, Samir; Razonable, Raymund R.; Morelon, Emmanuel; Gelb, Bruce; Rodriguez, Eduardo; et al. (Transplantation, 2022)

Outpatient and peri-operative antibiotic stewardship in solid organ transplantation - Kinn, Patrick Michael; Ince, Dilek (Transplant Infectious Disease, 2022)
Background The consequences of inappropriate antimicrobial use including resistance are increasingly recognized as a global public health threat and many steps have been taken over the last few decades to advance antimicrobial stewardship initiatives with most organ transplant centers currently part of institutions with active antimicrobial stewardship programs. Methods A review of the literature was conducted and articles were categorized according to the topic and relevance in the judgment of the two authors. Results A summary review of the currently available literature was created with a focus on periprocedural and outpatient antimicrobial stewardship. Limitations in the data were significant and discussed in the review. Conclusion The principles of antimicrobial stewardship remain important throughout all phases starting with periprocedural prophylactic antimicrobial selection all the way through to discharge and subsequent healthcare encounters. Despite the broad advances in stewardship initiatives and the rapidly progressing supportive data overall there continue to be significant opportunities for additional research within various special patient populations including recipients of solid organ transplantation (SOT). The recent white paper published in the American Journal of Transplantation called to action the transplant and stewardship communities to have an increased focus and awareness of the issues that antimicrobial overuse can present in the SOT patient population. This is an important step that will hopefully generate more data in this group of patients that arguably faces the greatest vulnerability to the consequences of increased antimicrobial resistance.
Keywords: outpatient stewardship; peri-operative stewardship surgical prophylaxis; solid organ transplant; transitions of care

Antimicrobial stewardship in pediatric solid organ transplantation: Is it possible? - Kitano, Taito; Allen, Upton (Transplant Infectious Disease, 2022)
Background Solid organ transplant (SOT) recipients are at increased risk of severe outcomes associated with antimicrobial resistance (AMR). Antimicrobial stewardship programs (ASPs) play a vital role in mitigating the negative impacts of AMR. Pediatric evidence regarding ASP for SOT recipients is scarce, although many pediatric SOT centers have implemented different forms of ASP. Methods This article summarized the available evidence relating to AMR among pediatric SOT recipients and discussed key strategies for the successful implementation of ASP among this population. The focus is primarily on antibacterial and secondarily on antifungal management. Results The development of multidisciplinary antimicrobial stewardship teams for pediatric SOT recipients is essential for successful stewardship implementation. Key stakeholders may include but are not limited to SOT recipients and their caregivers, primary SOT teams (transplant physicians, transplant pharmacists, transplant unit nurses, and transplant outpatient care team), transplant surgery teams, transplant infectious diseases teams, hospital AST, microbiology teams, infection prevention teams, quality improvement teams, and information technology teams. Conclusion As the evidence for optimal ASP in pediatric SOT is still evolving, it is important to measure the impact of implemented interventions.
Keywords: antimicrobial resistance; antimicrobial stewardship; immunocompromised hosts; pediatrics; solid organ transplant

Japan perspective on antimicrobial stewardship and solid organ transplantation - Kitaura, Satoshi; Jindai, Kazuaki; Okamoto, Koh (Transplant Infectious Disease, 2022)
Background The current situation, challenges, and opportunities related to antimicrobial stewardship for solid organ transplantations (SOTs) patients in Japan are not well known. Methods We searched English and Japanese literature using Pubmed and Ichushi-Web (the Japanese medical literature search system provided by the Japan Medical Abstract Society) with relevant keywords including solid organ transplant, antimicrobial stewardship, and Japan. Hand searches of the references from the retrieved literature, including conference proceedings of The Japanese Association for Infectious Diseases, were conducted. Results The Japanese National Action Plan for antimicrobial resistance has brought attention to the importance of antimicrobial stewardship programs (ASPs) in Japan. According to national surveillance, the proportion of methicillin resistance among Staphylococcus aureus was 48%, while the proportion of vancomycin-resistance among Enterococcus faecium was 1.5% in 2019. Resistance against imipenem in Escherichia coli and Klebsiella pneumoniae in 2019 were 0.1% and 0.2%, respectively. Exploration of SOT-specific data on antimicrobial usage and drug resistance are warranted. A large questionnaire survey revealed a low proportion of hospitals with >500 beds implementing ASP toward immunocompromised patients. While the annual number of SOT in Japan has increased, the implementation of SOT-specific ASP varies among institutions. Conclusion A coordinated ASP and exploration of the burden of antimicrobial resistance are needed for SOT patients in Japan. Promoting both intrainstitutional and interinstitutional collaboration is vital to the advancement of SOT-specific ASP in Japan.
Keywords: antimicrobial resistance; antimicrobial stewardship; solid organ transplantation

Antifungal stewardship in solid organ transplantation - Kriegl, Lisa; Boyer, Johannes; Egger, Matthias; Hoenigl, Martin (Transplant Infectious Disease, 2022)
Background Antifungal stewardship (AFS) has emerged as an important component of quality in managing invasive fungal infections (IFIs), and cost-benefit calculations suggest regular training in AFS is well worth the effort. Methods This review will discuss the most common IFIs in solid organ transplantation (SOT)-recipients, how to diagnose them, and current recommendations for antifungal treatment and prophylaxis before demonstrating key takeaway points of AFS in this high-risk population. Results Effective AFS starts before a patient is admitted for SOT, through education and regular interactions of the interdisciplinary clinical team involved in patient management, considering local factors such as epidemiological data and knowledge of diagnostic options including local turnaround times. Understanding the spectrum of antifungal agents, their efficacy and safety profiles, and pharmacokinetics, as well as duration of therapy is hereby essential. The most frequent IFIs in SOT recipients are caused by Candida species, followed by Aspergillus species, both with increasing resistance rates. Diagnosis of IFI can be challenging due to unspecific clinical presentation and difficult interpretation of microbiological findings and biomarkers. Prophylactic strategies, such as those for invasive aspergillosis in lung transplantation or invasive candidiasis (IC) in certain liver transplant settings, as well as the selection of the appropriate therapeutic agents require detailed knowledge on the pharmacokinetics and drug–drug interactions of antifungals. Conclusions Here in this review, we address what constitutes good AFS in this heterogeneous field of solid organ transplant recipients.
Keywords: antifungal prophylaxis; antifungal stewardship; appropriate use of antifungals; invasive fungal infection; solid organ transplantation

The EBMT/EHA CAR-T Cell Handbook - Kröger, Nicolaus; Gribben, John; Chabannon, Christian; Yakoub-Agha, Ibrahim; Einsele, Hermann (Springer International Publishing, 2022)

Neutralization against Omicron variant in transplant recipients after three doses of mRNA vaccine - Kumar, Deepali; Hu, Queenie; Samson, Reuben; Ferreira, Victor H.; Hall, Victoria G.; Ierullo, Matthew; Majchrzak-Kita, Beata; Hardy, William; Gingras, Anne-Claude; Humar, Atul (American Journal of Transplantation, 2022)
The SARS-CoV-2 virus Omicron variant has now supplanted wild-type virus as the dominant circulating strain globally. Three doses of mRNA COVID-19 vaccine are recommended for transplant recipients as their primary vaccine series. However, the immunogenicity of mRNA vaccines as they specifically relate to the Omicron variant are not well studied. We analyzed Omicron-specific neutralization in transplant recipients after three-doses of mRNA-1273 vaccine. Neutralization was determined using a SARS-CoV-2 spike pseudotyped lentivirus assay with constructs for Omicron and Delta variants. A total of 60 transplant patients (kidney, kidney-pancreas, lung, heart, liver) were analyzed 1 month and 3 months after completion of three doses of mRNA-1273. At 1 month, 11/60 (18.3%) patients had detectable neutralizing antibody responses to Omicron (log10ID50 of 2.38 [range 1.34–3.57]). At 3 months, 8/51 (15.7%) were positive (median log10ID50 [1.68; range 1.12–3.61; approximate fivefold reduction over time]). The proportion of positive patients was lower for Omicron versus wild-type, and Omicron vs. Delta (p < .001). No demographic variables were found to be significantly associated with Omicron response. Many patients with a positive anti-RBD response still had undetectable Omicron-specific neutralizing antibody. In conclusion, three doses of mRNA vaccine results in poor neutralizing responses against the Omicron variant in transplant patients.
Keywords: infection and infectious agents—viral: SARS-CoV-2/COVID-19; infectious disease; translational research/science; vaccine

Immune Checkpoint Inhibitors - Lau, Keith C. K.; Weyant, Benson; Cervera, Carlos (Infectious Complications in Biologic and Targeted Therapies, 2022)
Immune costimulatory checkpoints are crucial in regulating both lymphocyte activation and function. They also serve a major role in foreign antigen specificity and self-tolerance. The two major families of checkpoint inhibitors target the CTLA-4/B7s and the PD-1/PD-L1 axis. Inhibition of either of these two pathways intends to enhance the antitumor activity of lymphocytes. The risk of infections associated with checkpoint inhibition can be explained by two major mechanisms: the use of corticosteroids for the treatment of autoimmune inflammatory reactions and immune-mediated cytopenia. The overall risk of infections with immune checkpoint inhibitors is considered to be low, with bacterial infections being most frequent. For this reason, no prophylaxis is recommended with the use of checkpoint inhibitors. Recent research suggests that these drugs may be efficacious in treating specific infectious syndromes (such as sepsis, HIV infection, progressive multifocal leukoencephalopathy, hepatitis B, fungal infections, and COVID-19) but more data is needed to recommend its use.
Keywords: CTLA-4; Immune checkpoints; Ipilimumab; Nivolumab; PD-1/PD-L1; Pembrolizumab; Tremelimumab

Efficacy of anti-fungal agents for invasive fungal infection prophylaxis in liver transplant recipients: A network meta-analysis - Liu, Yusi; Lan, Chunhai; Qin, Sibei; Qin, Zhuo; Zhang, Zhiqiang; Zhang, Peng; Cao, Weiling (Mycoses, 2022)
At present, there is still a lack of effective invasive fungal prophylaxis therapy in liver transplant recipients (LTRs). This study aimed to analysis the latest evidence on efficacy of current prophylactic anti-fungal therapy, and systematically compare between anti-fungal agents and placebo by a fixed-effects meta-analysis in all randomised controlled trials. A network meta-analysis was performed for invasive fungal infection (IFI) among different agents in 14 randomised controlled trials, in which 10 anti-fungal approaches were identified. Overall, anti-fungal prophylaxis reduced the rate of IFI (RR 0.30, 95% CI 0.18–0.52) and proven IFI (RR 0.27, 95% CI 0.14–0.53) when compared to placebo. In the network meta-analysis, an equivalent reduction in the rate of IFI was observed in fluconazole (OR 4.70, 95% CI 1.22–18.10), itraconazole (OR 5.82, 95% CI 1.10–30.71) and Liposomal amphotericin B (LAmB, OR 5.74, 95% CI 1.29–25.58) groups when compared with placebo. Anidulafungin might be the most effective agents in IFI prevention; however, this superiority did not meet statistically significance. Our study indicated that fluconazole, echinocandins and LAmB are equivalent in efficacy. Of which, fluconazole is recommended for the prevention of IFI in LTRs due to its efficacy, economics and compliance.
Keywords: anti-fungal agents; invasive fungal infection; liver transplant recipients; network meta-analysis

Driveline Infection in Left Ventricular Assist Device Patients: Effect of Standardized Protocols, Pathogen Type, and Treatment Strategy - Lumish, Heidi S.; Cagliostro, Barbara; Braghieri, Lorenzo; Bohn, Bruno; Mondellini, Giulio M.; Antler, Karen; Feldman, Vivian; Kleet, Audrey; Murphy, Jennifer; Tiburcio, Melie; Fidlow, Kathryn; Jennings, Douglas; et al. (ASAIO Journal, 2022)

Impact of belatacept and tacrolimus on cytomegalovirus viral load control and relapse in moderate and high-risk cytomegalovirus serostatus kidney transplant recipients - Magua, Wairimu; Johnson, Aileen C.; Karadkhele, Geeta M.; Badell, Idelberto R.; Vasanth, Payaswini; Mehta, Aneesh K.; Easley, Kirk A.; Newell, Kenneth A.; Rickert, Joseph B.; Larsen, Christian P. (Transplant Infectious Disease, 2022)
Background Belatacept improves long-term graft survival, but control of some primary viral infections may be impaired. We evaluated the impact of belatacept and tacrolimus on cytomegalovirus (CMV) viral control, remission and relapse in CMV high-risk and moderate-risk recipients. Methods Using a multistate Markov model, we evaluated viral load state transitions of 173 kidney transplant recipients with at least one episode of viremia within 1 year after transplant: state 1, undetectable/low viral load; state 2, moderate viremia; and state 3, severe viremia. Results Among high-risk recipients, belatacept-treated recipients exhibited a significantly higher probability of entering moderate viremia (.36; 95% CI = .31, .41) than tacrolimus-treated recipients (.20; 95% CI = .13, .29). The expected number of days in viremic states differed. High-risk belatacept-treated recipients persisted in moderate viremia for significantly longer (128 days, 95% CI = 110, 146) than did tacrolimus-treated recipients (70.0 days, 95% CI = 45.2, 100) and showed a trend of shorter duration in low/undetectable viral load state (172 days, 95% CI = 148, 195) than did tacrolimus-treated recipients (239 days, 95% CI = 195, 277). Moderate-risk recipients showed better viral load control and with no differences by immunosuppression. Conclusion High-risk belatacept-treated recipients showed defects in sustaining viral control relative to tacrolimus-treated recipients. Avoidance of initial use belatacept in high-risk recipients or development of modified management protocols should be considered.
Keywords: CMV bidirectional viral load state transitions; CMV control; CMV high-risk; CMV management strategies; CMV moderate-risk; CMV relapse; CMV serostatus risk; CMV viral infection and infectious agents; CMV viral load dynamics; CMV viral load volatility; Markov multistate; belatacept; clinical research/practice; cytomegalovirus; immunosuppression/immune modulation; immunosuppressive regimens—maintenance; infectious disease; kidney (allograft) function/disfunction; kidney transplant; length of stay in viral load state; tacrolimus; viral load trajectory; viremia

Donor-derived tuberculosis among solid organ transplant recipients in the United States—2008 to 2018 - Malinis, Maricar; La Hoz, Ricardo M.; Vece, Gabriel; Annambhotla, Pallavi; Aslam, Saima; Basavaraju, Sridhar V.; Bucio, Jamie; Danziger-Isakov, Lara; Florescu, Diana F.; Jones, Jefferson M.; Rana, Meenakshi; Wolfe, Cameron R.; et al. (Transplant Infectious Disease, 2022)
Mycobacterium tuberculosis can be transmitted via organ donation and result in severe outcomes. To better understand donor-derived tuberculosis (DDTB), all potential transmissions reported to the Organ Procurement and Transplantation Network (OPTN) Ad Hoc Disease Transmission Advisory Committee between 2008 and 2018 were analyzed. Among 51 total reports, nine (17%) (9 donors/35 recipients) had ≥ 1 recipient with proven/probable disease transmission. Of these, eight were reported due to recipient disease, and one was reported due to a positive donor result. Proven/probable DDTB transmissions were reported in six lung and five nonlung recipients. The median time to diagnosis was 104 days posttransplant (range 0–165 days). Pulmonary TB, extrapulmonary TB, pulmonary plus extrapulmonary TB, and asymptomatic TB infection with positive interferon-gamma release assay were present in five, three, one, and two recipients, respectively. All recipients received treatment and survived except for one whose death was not attributed to TB. All donors associated with proven/probable DDTB had ≥ 1 TB risk factor. Six were born in a TB-endemic country, five had traveled to a TB-endemic country, three had been incarcerated, and three had latent TB infection. These cases highlight the importance of evaluating donors for TB based on risk factors. Early posttransplant TB in organ recipients of donors with TB risk factors requires prompt reporting to OPTN to identify other potential affected recipients and implement timely treatment interventions.
Keywords: donor-derived infections; transplant; tuberculosis

Antifungal prophylaxis in adult lung transplant recipients: Uncertainty despite 30 years of experience. A systematic review of the literature and network meta-analysis - Marinelli, Tina; Davoudi, Setareh; Foroutan, Farid; Orchanian-Cheff, Ani; Husain, Shahid (Transplant Infectious Disease, 2022)
Background Invasive fungal infections (IFI), particularly invasive aspergillosis (IA), cause significant morbidity and mortality in lung transplant (LTx) recipients. The optimum strategy and antifungal agents for prevention are unclear. Methods We performed a comprehensive literature search, systematic review, and network meta-analysis using a frequentist framework to compare the efficacy of various antifungal drugs on the incidence of IA/IFI in the setting of universal prophylaxis or no prophylaxis following lung transplantation. Results We included 13 eligible studies comprising of 1515 LTx recipients and 12 different prophylaxis strategies/antifungal combinations. The greatest number of direct comparisons were between the inhaled amphotericin formulations. The top three ranked treatments were inhaled liposomal amphotericin B (L-AmB), inhaled amphotericin deoxycholate (AmBd), and itraconazole plus inhaled amphotericin B (AmB). Among the azoles, isavuconazole ranked highest. The certainty of the evidence, assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework, was very low. Conclusion Although universal antifungal prophylaxis post lung transplantation is commonly used, robust data from randomized controlled trials (RCTs) to inform the choice of antifungal agent and prophylaxis strategy are lacking. This exploratory network meta-analysis provides insight into the probable relative effectiveness of various antifungal agents in preventing IA, and this analysis should serve as a guide when selecting antifungals to be assessed in a RCT.
Keywords: antifungal; lung transplant; prophylaxis

Infectious complications of targeted drugs and biotherapies in acute leukemia. Clinical practice guidelines by the European Conference on Infections in Leukemia (ECIL), a joint venture of the European Group for Blood and Marrow Transplantation (EBMT), the European Organization for Research and Treatment of Cancer (EORTC), the International Immunocompromised Host Society (ICHS) and the European Leukemia Net (ELN) - Maschmeyer, Georg; Bullinger, Lars; Garcia-Vidal, Carolina; Herbrecht, Raoul; Maertens, Johan; Menna, Pierantonio; Pagano, Livio; Thiebaut-Bertrand, Anne; Calandra, Thierry (Leukemia, 2022)
The 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated with more recently approved immunotherapeutic agents and molecular targeted drugs for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Novel antibody based treatment approaches (inotuzumab ozogamicin, gemtuzumab ozogamicin, flotetuzumab), isocitrate dehydrogenases inhibitors (ivosidenib, enasidenib, olutasidenib), FLT3 kinase inhibitors (gilteritinib, midostaurin, quizartinib), a hedgehog inhibitor (glasdegib) as well as a BCL2 inhibitor (venetoclax) were reviewed with respect to their mode of action, their immunosuppressive potential, their current approval and the infectious complications and febrile neutropenia reported from clinical studies. Evidence-based recommendations for prevention and management of infectious complications and specific alerts regarding the potential for drug-drug interactions were developed and discussed in a plenary session with the panel of experts until consensus was reached. The set of recommendations was posted on the ECIL website for a month for comments from members of EBMT, EORTC, ICHS and ELN before final approval by the panelists. While a majority of these agents are not associated with a significantly increased risk when used as monotherapy, caution is required with combination therapy such as venetoclax plus hypomethylating agents, gemtuzumab ozogamicin plus cytotoxic drugs or midostaurin added to conventional AML chemotherapy.

CD19, CD20 and CD52 - Mikulska, Malgorzata; Averbuch, Diana (Infectious Complications in Biologic and Targeted Therapies, 2022)
Agents targeting the CD19, CD20 and CD52 surface antigens on lymphoid cells have been increasingly used in the past three decades in various haematologic, rheumatologic and autoimmune diseases. The impact these agents have on the immune system and their consequent infectious complications depend on the agent, dose, underlying disease and concomitant or previous immunosuppressive treatments.
Keywords: Alemtuzumab; Anti-CD20 monoclonal antibodies; B-cell depletion; Blinatumomab; CD19; CD52; Hepatitis B virus; Inebilizumab; Infection; Multiple sclerosis; Obinutuzumab; Ocrelizumab; Rituximab

Effects of reported beta‐lactam allergies on pneumonia outcomes in lung transplant recipients - Motzer, Andrew R.; Holaday, Eric; Axelrod, Peter; Mishkin, Aaron (Transplant Infectious Disease, 2022)

Bcl-2, JAK and mTOR Inhibitors - Mueller, Nicolas J.; Burkhard, Sara H. (Infectious Complications in Biologic and Targeted Therapies, 2022)
Small-molecule inhibitors have revolutionized the treatment of cancer and autoimmune disease. Inhibitors of the mammalian target of rapamycin (mTOR), Janus kinases (JAK), and B-cell lymphoma-2 (BCL-2) are three of the most successful therapeutics developed. They target intracellular signaling pathways involved in cell survival, proliferation, and metabolism, processes that are frequently dysregulated in autoimmunity and neoplasia. The inhibition of such pathways also affects physiological processes in various tissues, including mucosal linings and immune cells. Thus, the cost of such treatment often entails higher rates of infectious complications, which holds true for mTOR and JAK inhibition. In addition, JAK inhibitors specifically elevate the risk for herpes zoster, while mTOR inhibitors uniquely reduce the frequency of cytomegalovirus infection. The mechanism that links these inhibitors to particular infections is not yet fully elucidated, and a multitude of factors are likely involved. BCL-2 inhibitors were recently approved and have not been directly associated with infectious complications. Due to the paucity of trials aiming to study infectious adverse events, future research may still unveil infections linked to BCL-2 inhibition.
Keywords: BCL-2; Infectious adverse event; JAK; Opportunistic infection; Small-molecule inhibitor; mTOR

Polyoma BK Virus in Kidney Transplant Recipients: Screening, Monitoring, and Management - Myint, Thida Maung; Chong, Chanel H. Y.; Wyld, Melanie; Nankivell, Brian; Kable, Kathy; Wong, Germaine (Transplantation, 2022)
Polyomavirus BK virus (BKPyV) infection is an important complication of kidney transplantation and allograft failure. The prevalence of viremia is 10%–15%, compared with BK-associated nephropathy (BKPyVAN) at 3%–5%. Given that there are no effective antiviral prophylaxis or treatment strategies for BKPyVAN, active screening to detect BKPyV viremia is recommended, particularly during the early posttransplant period. Immunosuppression reduction to allow viral clearance may avoid progression to severe and irreversible allograft damage. The frequency and duration of screening are highly variable between transplant centers because the evidence is reliant largely on observational data. While the primary treatment goals center on achieving viral clearance through immunosuppression reduction, prevention of subsequent acute rejection, premature graft loss, and return to dialysis remain as major challenges. Treatment strategies for BKPyV infection should be individualized to the recipient’s underlying immunological risk and severity of the allograft infection. Efficacy data for adjuvant therapies including intravenous immunoglobulin and cidofovir are sparse. Future well-powered and high-quality randomized controlled trials are needed to inform evidence-based clinical practice for the management of BKPy infection.

Moving xenotransplantation from bench to bedside: Managing infectious risk - Nellore, Anoma; Walker, Jeremey; Kahn, Mauricio J.; Fishman, Jay A. (Transplant Infectious Disease, 2022)
Xenotransplantation of organs from swine in immunosuppressed human recipients poses many of the same challenges of allotransplantation relative to the risk for infection, malignancy, or graft rejection in proportion to the degree of immunosuppression and epidemiologic exposures. The unique features of xenotransplantation from pigs relative to infectious risk center on the potential for unusual organisms derived from swine causing productive infection, “xenosis” or “xenozoonosis,” in the host. Based on experience in allotransplantation, the greatest hazard is due to viruses, due to the relative lack of information regarding the behavior of these potential pathogens in humans, the absence of validated serologic and molecular assays for swine-derived pathogens, and uncertainty regarding the efficacy of therapeutic agents for these organisms. Other known, potential pathogens (i.e., bacteria, fungi, parasites) tend to be comparable to those of humans. Concerns remain for unknown organisms in swine that may replicate in immunosuppressed humans. Clinical trials of genetically modified organs sourced from swine in immunosuppressed humans with organ failure are under development. Such trials require informed consent regarding potential infectious risks to the recipient, determination of breeding characteristics of swine, assessments of potential risks to the public and healthcare providers, consideration of ethical issues posed by this novel therapy, and defined strategies to monitor and address infectious episodes that may be encountered by healthcare teams. Clinical trials in xenotransplantation will allow improved definition of potential infectious risks.
Keywords: CRISPR; designated pathogen free; immunosuppression; infection control; porcine cytomegalovirus; xenografts

Consensus recommendations for use of maintenance immunosuppression in solid organ transplantation: Endorsed by the American College of Clinical Pharmacy, American Society of Transplantation, and the International Society for Heart and Lung Transplantation - Nelson, Joelle; Alvey, Nicole; Bowman, Lyndsey; Schulte, Jamie; Segovia, Maria Cristina; McDermott, Jennifer; Te, Helen S.; Kapila, Nikhil; Levine, Deborah Jo; Gottlieb, Robert L.; Oberholzer, Jose; Campara, Maya (Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 2022)
Advances in maintenance immunosuppression over the past three decades have improved solid organ transplantation outcomes dramatically. Uninterrupted access to immunosuppression is paramount to minimize rejection and maintain allograft and patient survival. There is no standardized approach to maintenance immunosuppression management. Agents used vary based on transplanted organ, center-specific protocol, provider expertise, insurance formularies, ability to cover co-pays, recipient characteristics and tolerability. Published data reflects this heterogeneity. Despite this limitation, maintenance immunosuppression usage cross pollinates between organ groups with standard of care agents often being used off-label, making medication access a challenge for many transplant recipients. A multidisciplinary panel of American transplant clinicians was formed to review published literature on maintenance immunosuppression with the goal to formulate consensus recommendations for their use in specific organ groups. These consensus recommendations are intended to provide transplant clinicians with a summary of literature on maintenance immunosuppression in the modern era and to support transplant team members working to secure medication access for patients.
Keywords: drug approval; immunosuppression therapy; immunosuppressive agents; organ transplantation

Comparative clinical manifestations and immune effects of cytomegalovirus infections following distinct types of immunosuppression - Ong, David S.Y.; Chong, Ga-Lai M.; Chemaly, Roy F.; Cremer, Olaf L. (Clinical Microbiology and Infection, 2022)

Antiviral Therapeutics in Pediatric Transplant Recipients - Otto, William R.; Green, Abby (Infectious Disease Clinics of North America, 2022)

Evaluation of cytomegalovirus “Blips” in high-risk kidney/kidney-pancreas transplant recipients - Payne, Alexandra T.; Lindner, Brian K.; Gilbert, Alexander J.; Kumar, Rebecca N.; Thomas, Beje S.; Timpone, Joseph G. (Transplant Infectious Disease, 2022)
Background Cytomegalovirus (CMV) is a significant cause of morbidity and mortality after solid organ transplantation. While guidelines suggest using highly sensitive QNAT assays for CMV detection, there is no defined viral load to guide initiation of preemptive therapy. This study evaluates the progression to quantifiable CMV (DNAemia) following a CMV “blip” in high-risk (D+/R) kidney/kidney-pancreas (KP) transplant recipients. Methods This is a single center, retrospective study. A CMV “blip” was defined as the first positive QNAT assay below the level of quantification (<1.37 × 102 IU/ml or <200 viral copies). Subsequent CMV QNAT assays were followed to assess the progression from blip to CMV DNAemia for 1 year following transplant. Results A total of 134 patients were included in the study. Fifty-three (39.6%) patients had their first positive CMV QNAT value below the level of quantification, a “CMV blip.” Of these 53 patients, 69.8% (n = 37) progressed to DNAemia while 30.2% (n = 16) did not. The median time from transplant to the first CMV blip was 68 (46–97) days and most patients with viral blips (71.1%) were on prophylaxis. No differences in patient characteristics were found among those who progressed from blip to DNAemia and those who only had a blip. Conclusions In CMV high-risk kidney/KP transplant recipients, CMV blips progressed to CMV DNAemia in the majority of cases. This progression typically occurred 2–3 weeks following the initial blip. CMV blips are common early posttransplant despite prophylaxis and likely represent an early marker of CMV infection.
Keywords: CMV DNAemia; cytomegalovirus; kidney transplant; kidney-pancreas transplant; viral blip

Fungal infection and colonization in lung transplant recipients with chronic lung allograft dysfunction - Pennington, Kelly M.; Aversa, Meghan; Martinu, Tereza; Johnson, Bradley; Husain, Shahid (Transplant Infectious Disease, 2022)
Background The incidence and impact of de novo fungal airway colonization and infection in lung transplant recipients (LTRs) with known chronic lung allograft dysfunction (CLAD) has not been established. We aimed to determine the 1-year cumulative incidence and risk factors of de novo fungal colonization or infection in LTRs with CLAD and assess the impact of colonization or infection on post-CLAD survival. Methods Prospectively collected Toronto Lung Transplant Program database and chart review were used for double-LTRs who were diagnosed with CLAD from January 1, 2016 to January 1, 2020 and who were free of airway fungi within 1 year prior to CLAD onset. International Society for Heart and Lung Transplantation definitions were used to define clinical syndromes. Cox-Proportional Hazards Models were used for risk-factor analysis. Survival analysis could not be completed secondary to low number of fungal events; therefore, descriptive statistics were employed for survival outcomes. Results We found 186 LTRs diagnosed with CLAD meeting our inclusion criteria. The 1-year cumulative incidence for any fungal event was 11.8% (7.0% for infection and 4.8% for colonization). Aspergillus fumigatus was a causative pathogen in eight of 13 (61.5%) patients with infection and six of nine (66.7%) patients with colonization. No patients with fungal colonization post-CLAD developed fungal infection. Peri-CLAD diagnosis (3 months prior or 1 month after) methylprednisolone bolus (hazards ratio: 8.84, p = .001) increased the risk of fungal events. Most patients diagnosed with fungal infections (53.8%) died within 1-year of CLAD onset. Conclusion De novo IFIs and fungal colonization following CLAD onset were not common. Fungal colonization did not lead to fungal infection. Methylprednisolone bolus was a significant risk factors for post-CLAD fungal events.
Keywords: Aspergillus; chronic lung allograft dysfunction; fungal infections; lung transplant

Epidemiology and outcomes of bone and joint infections in solid organ transplant recipients - Pham, Truong‐Thanh; Andrey, Diego O.; Stampf, Susanne; Burkhard, Sara H.; Hirzel, Cédric; Tschopp, Johnathan; Ullrich, Kathrin; Strahm, Carol; Schreiber, Peter W.; Boillat‐Blanco, Noémie; Garzoni, Christian; Khanna, Nina; et al. (American Journal of Transplantation, 2022)

Risk factors of invasive fungal infections in liver transplant recipients: A systematic review and meta-analysis - Phoompoung, Pakpoom; Herrera, Sabina; Pérez Cortés Villalobos, Armelle; Foroutan, Farid; Orchanian-Cheff, Ani; Husain, Shahid (American Journal of Transplantation, 2022)

Brazilian perspective: antimicrobial stewardship in solid organ transplant - Porto, Ana Paula Matos; Tavares, Bruno de Melo; de Assis, Denise Brandão; Mendes, Elisa Teixeira; Girão, Evelyne Santana; Perdigão Neto, Lauro Vieira; Falcão, Maria Alice Pimentel; de Oliveira, Maura Salaroli; Freire, Maristela Pinheiro; Guimaraes, Thais; Arantes, Tiago; Levin, Anna Sara; et al. (Transplant Infectious Disease, 2022)
Background The incidence of multidrug resistant organisms (MDROs) infections among solid organ transplant (SOT) patients is very high in Brazil. Methods This review will discuss antimicrobial use and resistance in SOT in Brazil, highlighting the main barriers and facilitators for implementation of an antimicrobial stewardship programme (ASP). Results The most common group of MDROs is carbapenem-resistant Gram-negative bacteria and vancomycin-resistant Enterococcus. Carbapenem-resistant Enterobacterales (CREs) are the most frequent MDROs and have been reported as donor-derived as well. Although ASPs are mandatory in the country, there is a lack of information regarding ASPs in SOT recipients. The main barriers for the implementation of ASPs in Brazilian hospitals are lack of electronic medical records, absence of national guidelines specific to SOT recipients, lack of recommendations on surveillance culture to evaluate colonization and transmission of donor-derived MDROs, limited availability of rapid diagnostic tests, and insufficient pharmacist and clinician time allocated to ASP activities in some SOT centers. Conclusions The incidence of MDRO infections caused mainly by VREs and CREs is very high in the country. There is limited data regarding antimicrobial use among SOT recipients in Brazil. The absence of antimicrobial stewardship national guidelines specific to SOT recipients is one of the main barriers for the implementation of ASPs in Brazilian hospitals.
Keywords: Brazil; antimicrobial resistance; antimicrobial stewardship; solid organ transplant

Infection Associated with the Use of CAR T Cells - Puerta-Alcalde, Pedro; Garcia-Pouton, Nicole; Garcia-Vidal, Carolina (Infectious Complications in Biologic and Targeted Therapies, 2022)
Chimeric antigen receptor (CAR) T cells targeting the B-cell-specific antigen, CD19, has revolutionized the management and prognosis of patients with relapsing/refractory B-cell malignancies. Such patients often present immunosuppressed due to previous treatments and baseline malignancy. Lymphodepletion chemotherapy is administered prior to CAR T therapy, causing profound cytopenias and mucositis. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are frequent complications, as is B-cell aplasia, prolonged hypogammaglobulinemia, and cytopenia. Infections in the first year after CAR T therapy are seen in up to 63% of patients with most infections being moderate or severe and occurring in the first month. Bacterial infections are most frequent, followed by viral and fungal infections. Risk factors for infection relate to both host and procedure factors such as secondary neutropenia, hypogammaglobulinemia, and secondary CRS/ICANS with their respective immunosuppressive treatments including corticosteroids and anti-inflammatory monoclonal antibodies.
Keywords: CAR T cells; Cytokine release syndrome; Hematology; Infection; Neutropenia; Risk

Dematiaceous fungal infections in solid organ transplantation: Systematic review and Bayesian meta-analysis - Radcliffe, Christopher; Radcliffe, Andrew J.; Azar, Marwan M.; Grant, Matthew (Transplant Infectious Disease, 2022)
Background Dematiaceous fungi cause a number of infectious syndromes referred to as phaeohyphomycosis among both immunocompetent and immunocompromised hosts. We performed a systematic review to characterize these infections in solid organ transplant recipients (SOTR). Methods We searched PubMed database (last searched 1/6/2022) for English-language reports on dematiaceous fungal infections in SOTR. Included reports needed individualized demographic, treatment, and outcome data; pediatric reports were excluded. A universally applicable bias assessment was performed on reports. Models for infection type and outcome were created using the Bayesian paradigm. Results We included 149 reports on 201 cases of dematiaceous fungal infections in SOTR. The mean age was 54 years, 72% were men, and kidney recipients accounted for 61% of cases. Skin and soft tissue infection (SSTI) was the most common infectious syndrome (73%). Death from infection occurred in 7% of cases (14/201), with disseminated (32%) cases having the highest mortality. Our model for infection type predicted the relative probability of central nervous system infection to be highest in liver recipients. Across all transplant types, higher relative probabilities of disseminated and pulmonary infections occur in the early post-transplant period, and the predicted probabilities for these infection types decreased after 100 months post-transplantation. Discussion We identified SSTI as the most common dematiaceous fungal infections in SOTR. Disseminated infections carried the worst prognosis. The evidence in this review is limited by the heterogeneity of included cases. No funding source was used, and this review's protocol was not registered.
Keywords: Alternaria; Exophiala; dematiaceous fungi; phaeohyphomycosis; solid organ transplant

Antimicrobial stewardship in solid organ transplant recipients: Current challenges and proposed metrics - Raglow, Zoe; Advani, Sonali D.; Aitken, Samuel L.; Patel, Payal K. (Transplant Infectious Disease, 2022)
Background Solid organ transplant (SOT) recipients are challenging populations for antimicrobial stewardship interventions due to a variety of reasons, including immunosuppression, consequent risk of opportunistic and donor-derived infections, high rates of infection with multi-drug resistant organisms (MDROs), Clostridioides difficile, and need for prolonged antimicrobial prophylaxis. Despite this, data on stewardship interventions and metrics that address the distinct needs of these patients are limited. Methods We performed a narrative review of the current state of antimicrobial stewardship in SOT recipients, existing interventions and metrics in this population, and considerations for implementation of transplant-specific stewardship programs. Results Antimicrobial stewardship metrics are evolving even in the general patient population. Data on metrics applicable to the SOT population are even more limited. Standard process, outcomes, and balancing metrics may not always apply to the SOT population. A successful stewardship program for SOT recipients requires reviewing existing data, applying general stewardship principles, and understanding the nuances of SOT patients. Conclusion As antimicrobial stewardship interventions are being implemented in SOT recipients; new metrics are needed to assess their impact. In conclusion, SOT patients present a challenging but important opportunity for antimicrobial stewards. Abbreviations SOT, antimicrobial stewardship program, MDRO, Clostridioides difficile infection, Centers for Disease Control and Prevention, Infectious Diseases Society of America, prospective audit and feedback, hematopoietic cell transplant, cytomegalovirus, trimethoprim-sulfamethoxazole, surgical site infections, nucleic acid amplification testing, days of therapy, defined daily dose, and length of stay.
Keywords: antimicrobial stewardship; interventions; metrics; solid organ transplant

Management of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) - Rees, Jeremy H. (The EBMT/EHA CAR-T Cell Handbook, 2022)
A common and challenging side effect associated with CAR-T cell therapy is immune cell-associated neurotoxicity syndrome (ICANS), which occurs in 20–60% of patients, of whom 12–30% have severe (≥ grade 3) symptoms.

Management of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) - Rees, Jeremy H. (The EBMT/EHA CAR-T Cell Handbook, 2022)
Abstract A common and challenging side effect associated with CAR-T cell therapy is immune cell-associated neurotoxicity syndrome (ICANS), which occurs in 20–60% of patients, of whom 12–30% have severe (≥ grade 3) symptoms.

Interleukin-6 Targeted Agents - Rinaldi, Matteo; Ferraro, Giuseppe; Giannella, Maddalena (Infectious Complications in Biologic and Targeted Therapies, 2022)
IL-6 has a key role in supporting immunocompetent responses to all type of infections, especially bacterial events. Agents targeting IL-6 and/or its receptor may result in severe and potentially life-threatening infections with significant discrepancy in both clinical and laboratory markers. Current evidence on the infection risk associated with the use of IL-6 or IL-6R-targeted agents consists mostly of studies including patients treated for a chronic autoimmune condition, such as rheumatoid arthritis (RA). Recently, a huge amount of data on these agents has been obtained from its use in hospitalized patients for COVID-19. The incidence of severe (secondary) infections in observational studies was higher than that observed in randomized controlled trials for both conditions. For patients with RA, such incidence seems to be similar or slightly higher than that associated with the use of other immunomodulatory drugs, in particular anti-TNF-α agents. However, a systematic active search or surveillance screening for infectious disease during or after treatment with IL-6 or IL-6R-targeted agents has not yet been performed.
Keywords: Bacterial infections; Interleukin-6; Interleukin-6 receptor; Monoclonal antibodies; Opportunistic infections

Azole-resistant Aspergillus fumigatus as an emerging worldwide pathogen - Rivelli Zea, Sofia Marisel; Toyotome, Takahito (Microbiology and Immunology, 2022)
Aspergillus fumigatus, a ubiquitous pathogen, causes aspergillosis in humans, especially in immunodeficient patients. Azoles are frontline antifungal drugs for treating aspergillosis. The recent global emergence of azole resistance in A. fumigatus has become a serious problem worldwide. It has arisen through two routes: long-term azole medical therapy, called the patient route, and the use of azole fungicides in its habitats especially for agricultural activities, called the environmental route. Resistant strains developed through the latter route show cross-resistance to medical azoles because of the identical molecular target Cyp51A between azole compounds used for medical treatment and agricultural disease control. In azole-resistant strains arising through the environmental route, A. fumigatus is observed frequently to possess mutations in the cyp51A gene linked to tandem repeats in the promoter region such as TR34/L98H and TR46/Y121F/T289A. The results of microsatellite genotyping analyses of resistant A. fumigatus strains have suggested a transboundary spread of this microorganism in many countries. Diverse actors are involved in the global highway of transmission. Therefore, the matter must be addressed as a “One Health” issue. This review presents a background of azole resistance in A. fumigatus and introduces newly discovered difficulties generated as this pathogen spreads worldwide.
Keywords: Aspergillus fumigatus; One Health; azole; drug resistance

Maribavir does not significantly influence tacrolimus dose requirements in solid organ transplant recipients - Sabatino, David C.; Hedvat, Jessica; Salerno, David M.; Lange, Nicholas W. (Transplant Infectious Disease, 2022)

Utilization and outcomes of deceased donor SARS-CoV-2–positive organs for solid organ transplantation in the United States - Schold, Jesse D.; Koval, Christine E.; Wee, Alvin; Eltemamy, Mohamed; Poggio, Emilio D. (American Journal of Transplantation, 2022)
Coronavirus disease-19 has had a marked impact on the transplant population and processes of care for transplant centers and organ allocation. Several single-center studies have reported successful utilization of deceased donors with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests. Our aims were to characterize testing, organ utilization, and transplant outcomes with donor SARS-CoV-2 status in the United States. We used Scientific Registry of Transplant Recipients data from March 12, 2020 to August 31, 2021 including a custom file with SARS-CoV-2 testing data. There were 35 347 donor specimen SARS-CoV-2 tests, 77.5% upper respiratory samples, 94.6% polymerase chain reaction tests, and 1.2% SARS-CoV-2–positive tests. Donor age, gender, history of hypertension, and diabetes were similar by SARS-CoV-2 status, while positive SARS-CoV-2 donors were more likely African-American, Hispanic, and donors after cardiac death (p-values <.01). Recipient demographic characteristics were similar by donor SARS CoV-2 status. Adjusted donor kidney discard (odds ratio = 2.08, 95% confidence interval [CI] 1.66–2.61) was higher for SARS-CoV-2–positive donors while donor liver (odds ratio = 0.44, 95% CI 0.33–0.60) and heart recovery (odds ratio = 0.44, 95% CI 0.31–0.63) were significantly reduced. Overall post-transplant graft survival for kidney, liver, and heart recipients was comparable by donor SARS-CoV-2 status. Cumulatively, there has been significantly lower utilization of SARS-CoV-2 donors with no evidence of reduced recipient graft survival with variations in practice over time.
Keywords: clinical research/practice; donors and donation: donor evaluation; epidemiology; graft survival; health services and outcomes research; infection and infectious agents; infection and infectious agents—viral: SARS-CoV-2/COVID-19; infectious disease; organ procurement and allocation; organ transplantation in general

Non-invasive diagnosis of Pneumocystis jirovecii pneumonia: a systematic review and meta-analysis - Senécal, Julien; Smyth, Elizabeth; Del Corpo, Olivier; Hsu, Jimmy M.; Amar-Zifkin, Alexandre; Bergeron, Amy; Cheng, Matthew P.; Butler-Laporte, Guillaume; McDonald, Emily G.; Lee, Todd C. (Clinical Microbiology and Infection, 2022)
Background: Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection commonly affecting immunocompromised people. Diagnosis usually requires invasive techniques to obtain respiratory specimens. Minimally invasive detection tests have been proposed, but their operating characteristics are poorly described. Objectives: To systematically review and meta-analyse the performance of minimally invasive PCP detection tests to inform diagnostic algorithms. Data sources: Medline, Embase, Cochrane Library (inception to 15 October 2020). Study eligibility criteria: Studies of minimally invasive PCP detection tests were included if they contained a minimum of ten PCP cases. Participants: Adults at risk of PCP. Tests: Non-invasive PCP detection tests. Reference standard: Diagnosis using the combination of clinical and radiographical features with invasive sampling. Assessment of risk bias: Using the QUADAS-2 tool. Methods: We used bivariate and, when necessary, univariate analysis models to estimate diagnostic test sensitivity and speciﬁcity. Results: Fifty-two studies were included; most studies (40) comprised exclusively human immunodeﬁciency virus (HIV) -infected individuals; nine were mixed (HIV and non-HIV), two were non-HIV and one study did not report HIV status. Sampling sites included induced sputum, nasopharyngeal aspirate, oral wash and blood. The four testing modalities evaluated were cytological staining, ﬂuorescent antibody, PCR and lactate dehydrogenase. Induced sputum had the most data available; this modality was both highly sensitive at 99% (95% CI 51%e100%) and speciﬁc at 96% (95% CI 88%e99%). Induced sputum cytological staining had moderate sensitivity at 50% (95% CI 39%e61%) and high speciﬁcity at 100% (95% CI 100%e100%), as did ﬂuorescent antibody testing with sensitivity 74% (95% CI 62%e87%) and speciﬁcity 100% (95% CI 91%e100%). Conclusion: There are several promising minimally invasive PCP diagnostic tests available, some of which may reduce the need for invasive respiratory sampling. Understanding the operating characteristics of these tests can augment current diagnostic strategies and help establish a more conﬁdent clinical diagnosis of PCP. Further studies in non-HIV infected populations are needed. Julien Sene cal, Clin Microbiol Infect 2022;28:23 © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Outcomes after lung resection in renal transplant patients with pulmonary mucormycosis - Seth, Abhinav; Patil, Shivakumar S.; Axelrod, David; Singh, Harkant; Sharma, Ashish; Kenwar, Deepesh Benjamin; Vaiphei, Kim; Mandwar, Milind; Rally, Sahil; Singh, Sarbpreet (Clinical Transplantation, 2022)
Background Pulmonary mucormycosis has been associated with high mortality (reported up to 100%) in renal transplant recipients. Methods This was a retrospective analysis of renal transplant patients with pulmonary mucormycosis between April 2014 and March 2020, who underwent surgical resection of the affected lung along with liposomal amphotericin therapy. Patients with lower respiratory illness features underwent chest X-ray, high-resolution computed tomography of the chest, and those with suspicious findings underwent analysis of bronchioloalveolar fluid and transbronchial lung biopsy. Patients with histological or microbiological evidence of mucormycosis were started on liposomal Amphotericin B. Tacrolimus and mycophenolate mofetil were stopped at the time of diagnosis. Result Ten patients underwent combined management, while five patients were managed medically. At last follow up, seven out of ten patients (70%) who underwent combined management and two of the five patients (40%) who were managed medically, had a mean survival of 28.86 months (sd = 15.71, median = 25) and 14.17 months (sd = 12.21, median = 18), respectively, post-diagnosis of pulmonary mucormycosis. Conclusion Surgical resection combined with antifungals in the perioperative period and decreased immunosuppression may improve the outcomes in renal transplant patients with pulmonary mucormycosis.
Keywords: Pulmonary mucormycosis; amphotericin; graft and patient survival outcomes; pulmonary mucormycosis; renal transplant patients; surgical resection

Infective hyperammonaemic encephalopathy after allogeneic stem cell transplant - Shipton, Michael J.; Kinsella, Paul M.; Davis, Thomas; Azzato, Francesca; Taiaroa, George; Szer, Jeff; Routledge, David; Smibert, Olivia (Bone Marrow Transplantation, 2022)

Transplant surgeons’ perspective on antimicrobial stewardship: Experience with TransQIP - Shwaartz, Chaya; Reichman, Trevor W. (Transplant Infectious Disease, 2022)
Antimicrobial stewardship programs (ASPs) have been shown to reduce the rates of antimicrobial resistance and improve morbidity and mortality in surgical patients. ASPs have largely been underutilized in solid organ transplant programs, and the current state of ASPs in transplantation is reviewed. Continued implementation of ASPs would likely significantly benefit transplant patients. Furthermore, coupling ASPs with robust programmatic metrics (such as transplant-specific NSQIP) will hopefully lead to improved outcomes including morbidity and mortality of solid organ transplant recipients.
Keywords: Clostridioides difficile; organ transplant outcomes; surgical Quality

Current state of antimicrobial stewardship and organ transplantation in Spain - Silva, Jose Tiago; Aguado, José María (Transplant Infectious Disease, 2022)
Introduction Solid-organ transplantation (SOT) remains the best therapeutic option for end-stage organ disease. Regrettably, SOT recipients are disproportionately affected by nosocomial infections produced by multidrug-resistant (MDR) microorganisms and antimicrobial adverse events. Both have a negative impact on the patient´s outcome. Methods Description of data concerning the antimicrobial stewardship program (ASP) in SOT recipients of the University Hospital “12 de Octubre”, and review of other Spanish ASPs. Results From May 2017 to December 2021, the ASP issued 2.785 recommendations. Approximately, 4.9% were aimed at improving the antimicrobial treatment administered to SOT recipients. Treatment discontinuation or change to a better therapeutic regimen was recommended in 51.8% and 26.3% of cases, respectively. The acceptance rate of the recommendations was close to 92%. Between June 2015 and March 2016, a quasi-experimental study consisting of a joint ASP and hospital-acquired infection control (HAIC) initiative, which included kidney transplant recipients, reported a significant reduction in the consumption of meropenem, vancomycin and ciprofloxacin, and a reduction in the incidence of global bacterial infections, upper urinary tract infections, and cystitis. Although Spain has several robust regional ASPs (e.g., VINCat and PIRASOA), data specifically concerning SOT patients is lacking. Conclusion ASP coupled with HAIC programs have proven to be effective in SOT, and should be implemented in centers that perform transplantation. Since data is scarce, Spanish centers which have ASP should report their experience in SOT. Understanding the efficacy and safety of the Spanish ASP´s intervention in the SOT population is essential and deserves further study.
Keywords: antibiotic; antimicrobial stewardship; prophylactic therapy; solid-organ transplantation

Antibiotics and the transplant patient: The good, the bad, and the ugly - Silverstein, Amy (Transplant Infectious Disease, 2022)
As a heart transplant recipient for 34 years, I have been asked to write an experience-based opinion on antibiotic stewardship programs (ASPs) in the transplant setting. The aim of this piece is to provide real-life examples—the good, the bad, and the ugly—to help contextualize the potential impact of an effective transplant-specific ASP model. The exigency of transplant ASPs is illuminated, and suggested changes that can help patients right away are provided.
Keywords: Clostridioides difficile; infection in transplant recipients; patient advocacy; transplant antibiotic stewardship

White paper on antimicrobial stewardship in solid organ transplant recipients - So, Miranda; Hand, Jonathan; Forrest, Graeme; Pouch, Stephanie M.; Te, Helen; Ardura, Monica I.; Bartash, Rachel M.; Dadhania, Darshana M.; Edelman, Jeffrey; Ince, Dilek; Jorgenson, Margaret R.; Kabbani, Sarah; et al. (American Journal of Transplantation, 2022)
Antimicrobial stewardship programs (ASPs) have made immense strides in optimizing antibiotic, antifungal, and antiviral use in clinical settings. However, although ASPs are required institutionally by regulatory agencies in the United States and Canada, they are not mandated for transplant centers or programs specifically. Despite the fact that solid organ transplant recipients in particular are at increased risk of infections from multidrug-resistant organisms, due to host and donor factors and immunosuppressive therapy, there currently are little rigorous data regarding stewardship practices in solid organ transplant populations, and thus, no transplant-specific requirements currently exist. Further complicating matters, transplant patients have a wide range of variability regarding their susceptibility to infection, as factors such as surgery of transplant, intensity of immunosuppression, and presence of drains or catheters in situ may modify the risk of infection. As such, it is not feasible to have a “one-size-fits- all” style of stewardship for this patient population. The objective of this white paper is to identify opportunities, risk factors, and ASP strategies that should be assessed with solid organ transplant recipients to optimize antimicrobial use, while producing an overall improvement in patient outcomes. We hope it may serve as a springboard for development of future guidance and identification of research opportunities.

Auditing tools for antimicrobial prescribing in solid organ transplant recipients: The why, the how, and an assessment of current options - So, Miranda; Nakamachi, Yoshiko; Thursky, Karin (Transplant Infectious Disease, 2022)
Background Antimicrobial stewardship (AMS) aims to optimize antimicrobial use. Auditing and reporting of antimicrobial prescribing are essential. Auditing tools for solid organ transplant (SOT) patients should tailor to their needs. Methods We reviewed published data describing auditing tools in the general and SOT population. Results We focused on three internationally or nationally available auditing tools. The National Antimicrobial Prescribing Survey (NAPS) is web-based tool to report antimicrobial consumption and assess appropriateness using standardized definitions based on consensus guidelines. In the absence of guidelines, adjudication is based on AMS principles. An automated dashboard, analyses by indication or antimicrobial, and benchmarking reports are available. The National Healthcare Safety Network Antimicrobial Use/Resistance module was developed by the Centers for Disease Control and Prevention for hospitals to upload monthly data, which are standardized for benchmarking. It does not assess appropriateness or address SOT wards. The Global-Point Prevalence Survey from bioMérieux collects data on antimicrobial regimen, indication and microbial resistance. Variables unique to SOT include comorbidities and devices. Assessment of appropriateness is limited to guideline adherence, and benchmarking may require prearrangement with bioMérieux. Benchmarking requires prearrangement. Advances in electronic health record systems and clinical decision support tools can improve the efficiency of the auditing process. Conclusion Each AMS auditing tool has unique features for SOT patients. Capturing immunosuppression, source control, organ dysfunction, donor-derived infection, serology, and colonization status will enhance their applicability.
Keywords: antimicrobial resistance; antimicrobial use; appropriateness; auditing tool; benchmarking; indication

Bring it on: Top five antimicrobial stewardship challenges in transplant infectious diseases and practical strategies to address them - So, Miranda; Tsai, Helen; Swaminathan, Neeraja; Bartash, Rachel (Antimicrobial Stewardship & Healthcare Epidemiology, 2022)
Antimicrobial therapies are essential tools for transplant recipients who are at high risk for infectious complications. However, judicious use of antimicrobials is critical to preventing the development of antimicrobial resistance. Treatment of multidrug-resistant organisms is challenging and potentially leads to therapies with higher toxicities, intravenous access, and intensive drug monitoring for interactions. Antimicrobial stewardship programs are crucial in the prevention of antimicrobial resistance, though balancing these strategies with the need for early and frequent antibiotic therapy in these immunocompromised patients can be challenging. In this review, we summarize 5 frequently encountered transplant infectious disease stewardship challenges, and we suggest strategies to improve practices for each clinical syndrome. These 5 challenging areas are: asymptomatic bacteriuria in kidney transplant recipients, febrile neutropenia in hematopoietic stem cell transplantation, antifungal prophylaxis in liver and lung transplantation, treatment of left-ventricular assist device infections, and Clostridioides difficile infection in solid-organ and hematopoietic stem-cell transplant recipients. Common themes contributing to these challenges include limited data specific to transplant patients, shortcomings in diagnostic testing, and uncertainties in pharmacotherapy.

An Australian perspective on antimicrobial stewardship programs and transplantation - Stewart, Adam G.; Isler, Burcu; Paterson, David L. (Transplant Infectious Disease, 2022)
Background Over 1000 solid-organ and close to 2000 stem-cell transplants are performed annually in Australia. Methods Antimicrobial stewardship activities in transplant units in Australia were reviewed. Results All health service organizations, and thus all transplant centers, in Australia are required to have an antimicrobial stewardship program. Despite this, in one recent survey, 23.5% of hospital antibiotic prescriptions were inappropriate. Vigorous efforts are being made to implement antifungal stewardship in Australian transplant programs, with guidelines for implementation published in December 2021. These guidelines include therapeutic antifungal drug monitoring and diagnostic stewardship as it pertains to the investigation of suspected invasive fungal infections. Conclusions Infections with multidrug resistant pathogens and invasive fungi are sporadic issues in Australian transplant units, but stewardship efforts can optimize patient outcomes.
Keywords: Australia; Klebsiella; antifungal; antimicrobial resistance; multiple drug resistance

Management of Myelotoxicity (Aplasia) and Infectious Complications - Subklewe, Marion; Benjamin, Reuben (The EBMT/EHA CAR-T Cell Handbook, 2022)
Haematologic toxicity is the most common adverse event after CAR-T cell therapy, with a cumulative 1-year incidence of 58% (CTCAE grade ≥ 3) in the real-world setting (Wudhikarn et al., Blood Advances 2020). It is characterized by a biphasic temporal course and is often prolonged (Fried et al., Bone Marrow Transplant 2019, Rejeski et al., Blood et al. 2021a, b, Fig. 29.1). In a report of Axi-Cel-treated patients, only 30% demonstrated a neutrophil count >1 × 109/L and 50% showed a platelet count >50 × 109/L at 30 days following CAR-T cell treatment (Jain et al., Blood Advances 2020). In a long-term follow-up study of patients with ongoing CR and an absence of MDS, 16% of patients experienced prolonged significant cytopenias that lasted up to 22 months after CAR-T cell treatment (Cordeiro et al., Biol Blood Marrow Transplant 2020). These findings highlight that cytopenia can present long after lymphodepletion and the resolution of acute CRS. Risk factors include severe CRS/ICANS, cytopenia prior to initiation of lymphodepleting chemotherapy, and prior allogeneic stem cell transplantation (Jain et al., Blood Advances 2020, Fried et al., BMT, 2019). Importantly, cytopenia predisposes patients to severe infectious complications, which are the most frequent cause of non-relapse mortality (Nastoupil et al., JCO 2020).

QuantiFERON-cytomegalovirus to predict clinically significant cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation - Thompson, Grace; Boan, Peter; Purtill, Duncan; Cooney, Julian; Cannell, Paul; Wright, Matthew; John, Mina (Transplant Infectious Disease, 2022)
Background Controlling cytomegalovirus (CMV) infection through prophylaxis or pre-emptive therapy remains an important contributor to outcomes after allogeneic hematopoetic stem cell transplant (alloHCT). Predicting clinically significant CMV infection (csCMVi) after day 100 remains a challenge. Methods We examined the abilty of the QuantiFERON-CMV assay (QFN-CMV) at day 100 (d100) and day 150 (d150) after alloHCT to predict csCMVi after these time points, with median follow-up of 3.1 years (range 1.3–4.3 years). Results In 46 transplants (donor seropositive (D+) recipient seronegative (R-) = 12, D+R+ = 25, D-R+ = 9; matched related = 13, unrelated donor = 32, haploidentical = 1), for the prediction of freedom from csCMVi >d100, QFN-CMVd100 (positive compared to negative/indeterminate) had sensitivity 62% (23/37), specificity 100% (9/9), positive predictive value 100% (23/23), and negative predictive value 39% (9/23). For the prediction of freedom from csCMVi >d150, QFN-CMVd150 (positive compared to negative/indeterminate) had sensitivity 62% (18/29), specificity 83% (5/6), positive predictive value 95% (18/19), and negative predictive value 31% (5/16). Conclusion Positive QFN-CMV at d100 and d150 strongly predicted freedom from csCMVi after these time points. QFN-CMV could be utilized to predict the need for pre-emptive therapy and CMV viral load monitoring after day 100 post-alloHCT.
Keywords: QuantiFERON; T-cell immunity; bone marrow transplant; cytomegalovirus; interferon gamma release assay; quantiferon; stem cell transplant

Secondary Prophylaxis With Inhaled Colistin to Prevent Recurrence of Pseudomonas aeruginosa and Extended-spectrum β-lactamase-producing Enterobacterales Pneumonia in ICU After Lung Transplantation: A Before-and-after Retrospective Cohort Analysis - Tran-Dinh, Alexy; Slassi, Lina; De Tymowski, Christian; Assadi, Maksud; Tanaka, Sébastien; Zappella, Nathalie; Lortat Jacob, Brice; Jean-Baptiste, Sylvain; Atchade, Enora; Castier, Yves; Mal, Hervé; Mordant, Pierre; et al. (Transplantation, 2022)
Background. Early pneumonia is an independent risk factor for 1-y mortality after lung transplantation (LTx). Pseudomonas aeruginosa is the most common isolate in early pneumonia and is also associated with an increased risk of chronic lung allograft dysfunction. The aim of our study was to evaluate the efficacy of secondary prophylaxis with inhaled colistin (IC) in preventing the recurrence of P aeruginosa or extended-spectrum β-lactamase-producing Enterobacterales (ESBL-PE) pneumonia in the postoperative period in the intensive care unit after LTx. Methods. We conducted a before-and-after retrospective cohort study by including all patients who underwent LTx between January 2015 and December 2020 in our center. Secondary prophylaxis with IC was instituted in January 2018 (observation period from January 2015 to December 2017, intervention period from January 2018 to December 2020). Results. A total of 271 lung transplants were included (125 in the observation period and 146 in the intervention period). The patients were predominately male (64.2%) with a median age of 57 y and received double LTx (67.9%) for chronic obstructive pulmonary disease/emphysema (36.2%) or interstitial lung disease (48.3%). The proportion of patients who experienced at least 1 recurrence of P aeruginosa or ESBL-PE pneumonia was significantly lower in the intervention period than in the observation period (0.7% versus 7.2%, P = 0.007). Conclusions. Our study suggests a potential benefit of secondary prophylaxis with IC to prevent the recurrence of P aeruginosa or ESBL-PE pneumonia in the intensive care unit after LTx.

Rapid molecular testing for antimicrobial stewardship and solid organ transplantation - Vega, Ana D.; Abbo, Lilian M. (Transplant Infectious Disease, 2022)
Background Several molecular platforms now exist for early detection of infectious pathogens. In this review, we present the currently available literature summarizing clinical outcomes using rapid diagnostic tests (RDTs) in the solid organ transplant (SOT) population. We also present potential benefits and drawbacks of these technologies for SOT patients. Methods We completed a PubMed search querying for 31 specific RDTs AND (“SOT”). We also queried PubMed for studies on RDT outcomes in the general population. References of the resulting relevant studies were reviewed and incorporated if the study population included at least one SOT patient. All culture specimen types were included. Only full-text peer-reviewed publications in English were examined. Results Our search yielded eleven studies. Across these studies, integrating RDTs with ASP intervention led to faster species identification and susceptibility results, faster time-to-optimal therapy, decreased hospital length-of-stay and costs, and decreased mortality. Potential drawbacks of RDTs in the SOT population included: overdiagnosis due to increased sensitivity (i.e., Clostridium difficile), decreased yield of tests for respiratory pathogens, and lack of identification of important pathogens in this population such as, Aspergillus species. Conclusions Although there is a scarcity of studies involving SOT patients, current available data suggests that the use of RDTs helps improve patient outcomes and minimizes inappropriate antimicrobial use when coupled with proactive ASPs. Future studies should focus on clinical outcomes in SOT patients specifically, as well as how to optimize the use of RDTs in conjunction with traditional microbiology methods.
Keywords: antimicrobial stewardship; diagnostic stewardship; molecular testing; rapid diagnostics; solid organ transplantation

Incidence and risk factors for the development of cytomegalovirus viremia in a steroid sparing liver transplant center - Viehl, Emily; Lichvar, Alicia; Chan, Christine; Choi, David (Transplant Infectious Disease, 2022)
Background Cytomegalovirus (CMV) is a common opportunistic infection in patients after liver transplant (LT). Guidelines recommend 900 mg daily of valganciclovir; however, valganciclovir commonly causes dose-dependent hematologic toxicities. Use of a low-dose valganciclovir (450 mg) has been used to prevent these adverse effects, but the data regarding this dosing strategy are not as robust in a steroid sparing LT center. Methods Retrospective chart review of adult LT recipients between January 1, 2008 and June 30, 2019. All patients received low-dose valganciclovir 450 mg PO daily for CMV prophylaxis. Primary outcome was the incidence of CMV viremia in LT recipients at 12 months post-LT. Secondary outcomes include time to CMV viremia, risk factors for the development of CMV viremia, and incidence of breakthrough CMV viremia while on valganciclovir prophylaxis. Results A total of 266 patients were included. Overall, the majority were male (63.2%) and Caucasian (45.5%). The most common indication for transplant was decompensated cirrhosis (82%). The incidence of CMV at 1 year posttransplant was 7.9%. Independent risk factors included high risk status (OR 5.97, 95% CI 2.14–16.61, p = .001) as well as having an episode of rejection (OR 5.99, 95% CI 2.16–16.66, p = .001). Conclusion Low-dose valganciclovir can be effective in the prevention of CMV viremia in LT patients and may be a beneficial strategy for CMV prophylaxis in a steroid-sparing transplant center. Further studies may be needed to determine appropriate length of prophylaxis therapy for different risk groups.
Keywords: CMV; LIVER transplant; cytomegalovirus; immunosuppression; viremia

Antibiotic allergy labels in immunocompromised populations - Waldron, Jamie L.; Trubiano, Jason A. (Transplant Infectious Disease, 2022)
Antibiotic allergy labels (AALs) are commonly reported, with well-defined prevalence in the general population; several studies have now focused efforts on immunocompromised hosts. Understanding the prevalence of reported allergy labels and methods of antibiotic allergy evaluation and delabeling strategies has the potential to improve prescribing practices and clinical outcomes in this high-antibiotic use group. In this review, we will discuss the current literature on the prevalence, impact, and evaluations of AALs in immunocompromised hosts with a focus on beta-lactam (penicillin) allergy and sulfa-antibiotic (antimicrobial sulfurs) allergy labels.

Effect of nirmatrelvir/ritonavir on calcineurin inhibitor levels: Early experience in four SARS-CoV-2 infected kidney transplant recipients - Wang, Aileen X.; Koff, Alan; Hao, Diana; Tuznik, Natascha M.; Huang, Yihung (American Journal of Transplantation, 2022)
Keywords: clinical research/practice; drug interaction; immunosuppressant - calcineurin inhibitor (CNI); infection and infectious agents—viral: SARS-CoV-2/COVID-19; infectious disease; pharmacology; solid organ transplantation

Antifungal stewardship in solid-organ transplantation: What is needed? - Whitney, Laura; Armstrong-James, Darius; Lyster, Haifa S.; Reed, Anna K.; Dunning, John; Nwankwo, Lisa; Cheong, Jamie (Transplant Infectious Disease, 2022)
Background Antifungal stewardship (AFS) lags behind antimicrobial stewardship (AMS) in terms of implementation, evidence base, and workforce experience. Solid-organ transplantation (SOT) carries a significant risk of invasive fungal infection, with high associated mortality, and is therefore associated with significant opportunities to optimize antifungal use. Methods A literature search for the terms “antifungal stewardship” and “solid-organ transplant” revealed a small evidence base to support AFS programs in this patient group. Results There is significant overlap in the methodology used in AMS and AFS programs, with notable differences in diagnostics, which are discussed in detail. The primary AFS interventions tested in SOT recipients are implementation of clinical guidelines and care bundles, digital enablers of AFS, and post-prescription review/audit and feedback. Conclusion There is an urgent need for further research to support effective AFS strategies in this highly susceptible population.
Keywords: antifungal stewardship; fungal infections; prescribing optimization; solid-organ transplantation

Measles Outbreak Guide - WHO (World Health Organization, 2022)
Intro -- Acknowledgements -- Abbreviations -- Executive summary -- Introduction -- 1.3 Summary of objectives -- 1.4 Disease characteristics -- 1.4.1 Measles -- 1.4.2 Rubella -- 1.5 Measles outbreak characteristics -- Preparedness -- 2.3 Contingency finance -- 2.4 Surveillance -- 2.5 Standard operating procedures -- 2.6 Risk communication and community engagement -- 2.7 Health workforce -- 2.8 Health structures -- 2.9 Logistics and supply chain -- 2.10 Partner engagement -- Detecting and confirming measles outbreaks -- 3.2 Case definitions and case classifications -- 3.3 Laboratory confirmation -- Investigating measles outbreaks -- 4.2 Outbreak investigation -- 4.2.1 Initial field investigation -- 4.2.2 Confirming suspected measles cases -- 4.2.3 Additional case finding -- 4.3 Descriptive epidemiology -- Responding to measles outbreaks -- 5.2 Outbreak response immunization -- 5.2.1 Outbreak response immunization strategies -- 5.2.2 Reinforcement of routine immunization activities -- 5.2.3 Implementation of selective vaccination activities -- 5.2.4 Implementation of non-selective mass vaccination campaigns -- 5.3 Coordination -- 5.4 Determine the risk of spread -- 5.5 Intensification of surveillance -- 5.5.1 Approaches to measles case-based surveillance during outbreaks -- 5.5.2 Focus on the response when outbreaks become too large -- 5.6 Clinical case management -- 5.6.1 Immediate administration of vitamin A -- 5.6.2 Preventing and managing complications -- 5.7 Infection prevention and control -- 5.8 Contact tracing and management -- 5.8.1 Managing contacts -- 5.9 Managing measles exposures in health settings -- 5.10 Special considerations -- 5.11 Risk communications, social mobilization and community engagement -- 5.11.1 Ways to communicate with the public -- 5.11.2 Addressing vaccine concerns

Emerging Fungal Infections: New Species, New Names, and Antifungal Resistance - Wiederhold, Nathan P. (Clinical Chemistry, 2021)
BACKGROUND: Infections caused by fungi can be important causes of morbidity and mortality in certain patient populations, including those who are highly immunocompromised or critically ill. Invasive mycoses can be caused by well-known species, as well as emerging pathogens, including those that are resistant to clinically available antifungals. CONTENT: This review highlights emerging fungal infections, including newly described species, such as Candida auris, and those that having undergone taxonomic classification and were previously known by other names, including Blastomyces and Emergomyces species, members of the Rasamsonia argillacea species complex, Sporothrix brasiliensis, and Trichophyton indotinae. Antifungal resistance also is highlighted in several of these emerging species, as well as in the well-known opportunistic pathogen Aspergillus fumigatus. Finally, the increased recognition and importance of fungal co-infections with respiratory pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is discussed. SUMMARY: Both clinicians and clinical microbiology laboratories should remain vigilant regarding emerging fungal infections. These may be difficult both to diagnose and treat due to the lack of experience of clinicians and laboratory personnel with these organisms and the infections they may cause. Many of these fungal infections have been associated with poor clinical outcomes, either due to inappropriate therapy or the development of antifungal resistance.
Keywords: Antifungal Agents; Aspergillus; COVID-19; Candida auris; Communicable Diseases, Emerging; Drug Resistance, Fungal; Fungi; Humans; Mycoses; antifungal resistance; emerging fungal infections; mucormycosis; mycosis

Distribution of Aspergillus Species and Prevalence of Azole Resistance in Respiratory Samples From Swiss Tertiary Care Hospitals - Ragozzino, Silvio; Goldenberger, Daniel; Wright, Patrick R; Zimmerli, Stefan; Mühlethaler, Konrad; Neofytos, Dionysios; Riat, Arnaud; Boggian, Katia; Nolte, Oliver; Conen, Anna; Fankhauser, Hans; Schreiber, Peter W; et al. (Open Forum Infectious Diseases, 2021)
Among 400 Aspergillus species from respiratory samples in Switzerland, Aspergillus fumigatus was the most frequent species. Non-fumigatus Aspergillus spp were more prevalent among solid organ transplant recipients and after azole exposure. Azole resistance was detected in 4 A fumigatus isolates, 3 of them with the “environmental” mutation TR34/L98H in the cyp51A gene.

CDC - Cryptosporidiosis - Fact Sheets - Infection - Immunocompromised Persons - CDC (2021)
Crypto and Cryptosporidium Infection fact sheets for Immunocompromised Persons

Fungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond - Bastos, Rafael W.; Rossato, Luana; Goldman, Gustavo H.; Santos, Daniel A. (PLOS Pathogens, 2021)
Fungal infections are underestimated threats that affect over 1 billion people, and Candida spp., Cryptococcus spp., and Aspergillus spp. are the 3 most fatal fungi. The treatment of these infections is performed with a limited arsenal of antifungal drugs, and the class of the azoles is the most used. Although these drugs present low toxicity for the host, there is an emergence of therapeutic failure due to azole resistance. Drug resistance normally develops in patients undergoing azole long-term therapy, when the fungus in contact with the drug can adapt and survive. Conversely, several reports have been showing that resistant isolates are also recovered from patients with no prior history of azole therapy, suggesting that other routes might be driving antifungal resistance. Intriguingly, antifungal resistance also happens in the environment since resistant strains have been isolated from plant materials, soil, decomposing matter, and compost, where important human fungal pathogens live. As the resistant fungi can be isolated from the environment, in places where agrochemicals are extensively used in agriculture and wood industry, the hypothesis that fungicides could be driving and selecting resistance mechanism in nature, before the contact of the fungus with the host, has gained more attention. The effects of fungicide exposure on fungal resistance have been extensively studied in Aspergillus fumigatus and less investigated in other human fungal pathogens. Here, we discuss not only classic and recent studies showing that environmental azole exposure selects cross-resistance to medical azoles in A . fumigatus , but also how this phenomenon affects Candida and Cryptococcus , other 2 important human fungal pathogens found in the environment. We also examine data showing that fungicide exposure can select relevant changes in the morphophysiology and virulence of those pathogens, suggesting that its effect goes beyond the cross-resistance.

Impact of decreasing vancomycin exposure on acute kidney injury in stem cell transplant recipients - Hambrick, Horace Rhodes; Greco, Kimberly F.; Weller, Edie; Ganapathi, Lakshmi; Lehmann, Leslie E.; Sandora, Thomas J. (Infection Control & Hospital Epidemiology, 2021)
Objective: To evaluate the change in vancomycin days of therapy (DOT) and vancomycin-associated acute kidney injury (AKI) after an antimicrobial stewardship program (ASP) intervention to decrease vancomycin use in stable patients after hematopoietic stem cell transplantation (HSCT). Design: Retrospective cohort study and quasi-experimental interrupted time series analysis. Change in unit-level vancomycin DOT per 1,000 inpatient days after the intervention was assessed using segmented Poisson regression. Subject-specific risk of vancomycin-associated AKI was evaluated using a random intercept logistic regression model with mediation analysis. Setting: HSCT unit at a single quaternary-care pediatric hospital. Participants: Inpatients aged 3 months and older who underwent HSCT between January 1, 2015, and March 31, 2019 (27 months before and after the intervention) who received any dose of vancomycin. Intervention: An ASP intervention in April 2017 creating a new practice guideline to decrease prolonged (>72 hours) vancomycin courses for stable HSCT patients with febrile neutropenia. Results: Overall, 439 vancomycin exposures (234 before the intervention and 205 after the intervention) occurring across 300 transplants and 259 subjects were included. The mean vancomycin DOT was 307 per 1,000 inpatient days (95% confidence interval [CI], 272–342) and decreased after the intervention to 207 per 1,000 inpatient days (95% CI, 173–240). In multivariable analyses, the odds of AKI in the postintervention period were 37% lower than in the preintervention period (adjusted OR, 0.63; 95% CI, 0.42–0.95; P = .0268); 56% of the excess risk was mediated by vancomycin DOT. Conclusions: An ASP intervention successfully decreased vancomycin use after HSCT and resulted in a decrease in AKI. Reducing empiric antibiotic exposure for stable patients after HSCT can improve clinical outcomes.

Beta-D-Glucan in Patients with Haematological Malignancies - Mikulska, Malgorzata; Balletto, Elisa; Castagnola, Elio; Mularoni, Alessandra (Journal of Fungi, 2021)
(1-3)-beta-D-glucan (BDG) is an almost panfungal marker (absent in zygomycetes and most cryptococci), which can be successfully used in screening and diagnostic testing in patients with haematological malignancies if its advantages and limitations are known. The aim of this review is to report the data, particularly from the last 5 years, on the use of BDG in haematological population. Published data report mainly on the performance of the Fungitell™ assay, although several others are currently available, and they vary in method and cut-off of positivity. The sensitivity of BDG for invasive fungal disease (IFD) in haematology patients seems lower than in other populations, possibly because of the type of IFD (lower sensitivity was found in case of aspergillosis compared to candidiasis and pneumocystosis) or the use of prophylaxis. The specificity of the test can be improved by using two consecutive positive assays and avoiding testing in the case of the concomitant presence of factors associated with false positive results. BDG should be used in combination with clinical assessment and other diagnostic tests, both radiological and mycological, to provide maximum information. Good performance of BDG in cerebrospinal fluid (CSF) has been reported. BDG is a useful diagnostic method in haematology patients, particularly for pneumocystosis or initial diagnosis of invasive fungal infections.

Letermovir treatment for CMV infection in kidney and pancreas transplantation: A valuable option for complicated cases - Ortiz, Fernanda; Lempinen, Marko; Aaltonen, Sari; Koivuviita, Niina; Helanterä, Ilkka (Clinical Transplantation, 2021)
Cytomegalovirus (CMV) infection remains a major challenge in solid organ transplantation. Ganciclovir has changed the prognosis, but with the expense of possible viral resistance. New antiviral drugs, such as letermovir, have not been studied sufficiently in kidney and pancreas transplant recipients. We reviewed abdominal organ transplants recipients with CMV infection from the national transplant registry and identified patients treated with letermovir from electronic medical records. We report on letermovir treatment in one kidney and three simultaneous pancreas and kidney (SPK) transplant patients with refractory or ganciclovir-resistant CMV infection (UL54/ UL97 mutation). In SPK patients, persistent leukopenia undermined immunosuppressive and antiviral treatment, favoring life-threatening bacterial infections or ganciclovir resistance. All patients achieved viral clearance after letermovir monotherapy of 1.5–6 months. Letermovir was well tolerated and leukopenia resolved. Adjustments of calcineurin inhibitor doses were challenging. One acute rejection occurred because of under immunosuppression. After the end of treatment, recurrent low-grade CMV-DNAemia was common requiring reinitiating antiviral therapy to achieve viral clearance. To conclude, letermovir was a well-tolerated valuable option for the treatment of refractory or resistant CMV infection in kidney and pancreas transplantation.

Coronavirus Disease 2019–Associated Invasive Fungal Infection - Baddley, John W; Thompson, George R; Chen, Sharon C -A; White, P Lewis; Johnson, Melissa D; Nguyen, M Hong; Schwartz, Ilan S; Spec, Andrej; Ostrosky-Zeichner, Luis; Jackson, Brendan R; Patterson, Thomas F; Pappas, Peter G (Open Forum Infectious Diseases, 2021)
Abstract Coronavirus disease 2019 (COVID-19) can become complicated by secondary invasive fungal infections (IFIs), stemming primarily from severe lung damage and immunologic deficits associated with the virus or immunomodulatory therapy. Other risk factors include poorly controlled diabetes, structural lung disease and/or other comorbidities, and fungal colonization. Opportunistic IFI following severe respiratory viral illness has been increasingly recognized, most notably with severe influenza. There have been many reports of fungal infections associated with COVID-19, initially predominated by pulmonary aspergillosis, but with recent emergence of mucormycosis, candidiasis, and endemic mycoses. These infections can be challenging to diagnose and are associated with poor outcomes. The reported incidence of IFI has varied, often related to heterogeneity in patient populations, surveillance protocols, and definitions used for classification of fungal infections. Herein, we review IFI complicating COVID-19 and address knowledge gaps related to epidemiology, diagnosis, and management of COVID-19–associated fungal infections.

Liquid Biopsy for Invasive Mold Infections in Hematopoietic Cell Transplant Recipients With Pneumonia Through Next-Generation Sequencing of Microbial Cell-Free DNA in Plasma - Hill, Joshua A; Dalai, Sudeb C; Hong, David K; Ahmed, Asim A; Ho, Carine; Hollemon, Desiree; Blair, Lily; Maalouf, Joyce; Keane-Candib, Jacob; Stevens-Ayers, Terry; Boeckh, Michael; Blauwkamp, Timothy A; et al. (Clinical Infectious Diseases, 2021)
Noninvasive diagnostic options are limited for invasive mold infections (IMIs). We evaluated the performance of a plasma microbial cell-free DNA sequencing (mcfDNA-Seq) test for diagnosing pulmonary IMI after hematopoietic cell transplant (HCT). We retrospectively assessed the diagnostic performance of plasma mcfDNA-Seq next-generation sequencing in 114 HCT recipients with pneumonia after HCT who had stored plasma obtained within 14 days of diagnosis of proven/probable Aspergillus IMI (n = 51), proven/probable non-Aspergillus IMI (n = 24), possible IMI (n = 20), and non-IMI controls (n = 19). Sequences were aligned to a database including >400 fungi. Organisms above a fixed significance threshold were reported. Among 75 patients with proven/probable pulmonary IMI, mcfDNA-Seq detected ≥1 pathogenic mold in 38 patients (sensitivity, 51% [95% confidence interval CI, 39%–62%]). When restricted to samples obtained within 3 days of diagnosis, sensitivity increased to 61%. McfDNA-Seq had higher sensitivity for proven/probable non-Aspergillus IMI (sensitivity, 79% [95% CI, 56%–93%]) compared with Aspergillus IMI (sensitivity, 31% [95% CI, 19%–46%]). McfDNA-Seq also identified non-Aspergillus molds in an additional 7 patients in the Aspergillus subgroup and Aspergillus in 1 patient with possible IMI. Among 19 non-IMI pneumonia controls, mcfDNA-Seq was negative in all samples, suggesting a high specificity (95% CI, 82%–100%) and up to 100% positive predictive value (PPV) with estimated negative predictive values (NPVs) of 81%–99%. The mcfDNA-Seq assay was complementary to serum galactomannan index testing; in combination, they were positive in 84% of individuals with proven/probable pulmonary IMI. Noninvasive mcfDNA-Seq had moderate sensitivity and high specificity, NPV, and PPV for pulmonary IMI after HCT, particularly for non-Aspergillus species.

State of the CAR-T: Risk of Infections with Chimeric Antigen Receptor T-Cell Therapy and Determinants of SARS-CoV-2 Vaccine Responses - Meir, Juliet; Abid, Muhammad Abbas; Abid, Muhammad Bilal (Transplantation and Cellular Therapy, Official Publication of the American Society for Transplantation and Cellular Therapy, 2021)
Keywords: CAR-T therapy; COVID-19; Cellular immunity; Hematopoietic cell transplantation; Humoral immunity; Immunocompromised; Neutralizing antibodies; SARS-CoV-2; Vaccine response; mRNA vaccine

Global guideline for the diagnosis and management of the endemic mycoses: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology - Thompson, George R.; Le, Thuy; Chindamporn, Ariya; Kauffman, Carol A.; Alastruey-Izquierdo, Ana; Ampel, Neil M.; Andes, David R.; Armstrong-James, Darius; Ayanlowo, Olusola; Baddley, John W.; Barker, Bridget M.; Bezerra, Leila Lopes; et al. (The Lancet Infectious Diseases, 2021)

Evaluation of prognostic scores for respiratory syncytial virus infection in a French multicentre cohort of allogeneic haematopoietic stem cell transplantation recipients - Houist, Anne-Laure; Bondeelle, Louise; Salmona, Maud; LeGoff, Jérôme; de Latour, Régis Peffault; Rivière, Frédéric; Soler, Charles; Houdouin, Véronique; Dalle, Jean-Hugues; Robin, Christine; Fourati, Slim; Griscelli, Franck; et al. (Bone Marrow Transplantation, 2021)
Haematopoietic stem cell transplantation (HSCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. Two prognostic scores have been proposed to predict the risk of progression from upper respiratory tract infection (URTI) to lower respiratory tract infection (LRTI) and death. This was a multicentre study of allogeneic HSCT recipients diagnosed with an RSV infection between 2010 and 2019 who were retrospectively stratified by the immunodeficiency scoring index (ISI) and the severe immunodeficiency (SID) score. Endpoints were overall survival, RSV-attributable mortality and progression to LRTI after URTI. Prognostic analyses were performed using Cox regression models. We included 147 consecutive patients, including 94 (63.9%) initially diagnosed with URTI and 53 (36.1%) with LRTI. At 90 days, 14 patients had died (survival rate, 90.5%; 95% CI: 85.9–95.3), and nine deaths were attributable to RSV (attributable mortality rate, 5.4%; 95% CI: 2.5–10.0). The cumulative 90-day incidence of LRTI after URTI was 13.8% (95% CI: 7.8–21.6). Neither score showed prognostic value for mortality, while the ISI allowed the prediction of progression to LRTI (p = 0.0008). Our results do not fully replicate the results previously reported in cohorts of HSCT recipients. This may reflect the recent epidemiology of RSV infections in this HSCT cohort.
Keywords: Haematological diseases; Infectious diseases

Liver transplantation from active COVID‐19 donors: A lifesaving opportunity worth grasping? - Romagnoli, Renato; Gruttadauria, Salvatore; Tisone, Giuseppe; Ettorre, Giuseppe Maria; Carlis, Luciano De; Martini, Silvia; Tandoi, Francesco; Trapani, Silvia; Saracco, Margherita; Luca, Angelo; Manzia, Tommaso Maria; Comandini, Ubaldo Visco; et al. (American Journal of Transplantation, 2021)
COVID‐19 pandemic dramatically impacted transplantation landscape. Scientific societies recommend against the use of donors with active SARS‐CoV‐2 infection. Italian Transplant Authority recommended to test recipients/donors for ...

Impact of empirical antibiotic regimens on mortality in neutropenic patients with bloodstream infection presenting with septic shock - Chumbita, Mariana; Puerta-Alcalde, Pedro; Gudiol, Carlota; Garcia-Pouton, Nicole; Laporte-Amargós, Júlia; Ladino, Andrea; Albasanz-Puig, Adaia; Helguera, Cristina; Bergas, Alba; Grafia, Ignacio; Sastre, Enric; Suárez-Lledó, María; et al. (Antimicrobial Agents and Chemotherapy, 2021)
Objectives: We analyzed risk factors for mortality in febrile neutropenic patients with bloodstream infections (BSI) presenting with septic shock and assessed the impact of empirical antibiotic regimens. Methods: Multicenter retrospective study (2010-2019) of two prospective cohorts comparing BSI episodes in patients with or without septic shock. Multivariate analysis was performed to identify independent risk factors for mortality in episodes with septic shock. Results: Of 1563 patients with BSI, 257 (16%) presented with septic shock. Those patients with septic shock had higher mortality than those without septic shock (55% vs 15%, p<0.001). Gram-negative bacilli caused 81% of episodes with septic shock; gram-positive cocci, 22%; and Candida species 5%. Inappropriate empirical antibiotic treatment (IEAT) was administered in 17.5% of septic shock episodes. Empirical β-lactam combined with other active antibiotics was associated with the lowest mortality observed. When amikacin was the only active antibiotic, mortality was 90%. Addition of empirical specific gram-positive coverage had no impact on mortality. Mortality was higher when IEAT was administered (76% vs 51%, p=0.002). Age >70 years (OR 2.3, 95% CI 1.2-4.7), IEAT for Candida spp. or gram-negative bacilli (OR 3.8, 1.3-11.1), acute kidney injury (OR 2.6, 1.4-4.9) and amikacin as the only active antibiotic (OR 15.2, 1.7-134.5) were independent risk factors for mortality, while combination of β-lactam and amikacin was protective (OR 0.32, 0.18-0.57). Conclusions: Septic shock in febrile neutropenic patients with BSI is associated with extremely high mortality, especially when IEAT is administered. Combination therapy including an active β-lactam and amikacin results in the best outcomes.

HOPE in action: A prospective multicenter pilot study of liver transplantation from donors with HIV to recipients with HIV - Durand, Christine M.; Florman, Sander; Motter, Jennifer D.; Brown, Diane; Ostrander, Darin; Yu, Sile; Liang, Tao; Werbel, William A.; Cameron, Andrew; Ottmann, Shane; Hamilton, James P.; Redd, Andrew D.; et al. (American Journal of Transplantation, 2021)

Adenovirus Infection and Transplantation - Al-Heeti, Omar M.; Cathro, Helen P.; Ison, Michael G. (Transplantation, 2021)
Adenoviruses result in a wide array of clinical presentations, including primarily respiratory, gastrointestinal, genitourinary, or systemic infections. Although adenovirus causes mild disease limited to a single organ system in immunocompetent individuals, severe and life-threatening infections do rarely occur. Disseminated disease and severe localized disease resulting in significant morbidity and mortality have been well described in the immunocompromised populations. Although asymptomatic viremia, respiratory tract, and gastrointestinal infections are the most common disease in most transplant patients, renal transplant patients more commonly experience urinary tract infections, including hemorrhagic cystitis or nephritis. Diagnosis requires astute clinical awareness of the patient’s clinical presentation that would be compatible with adenovirus combined with cultures, molecular testing, polymerase chain reaction, and tissue sampling. There is no Food and Drug Administration–approved treatment for adenovirus; however, several studies have evaluated therapeutic options including cidofovir, brincidofovir, and immunotherapy. This article will summarize our current understanding of adenovirus in the transplant population.

Return to School and COVID-19 Vaccination for Pediatric Solid Organ Transplant Recipients in the United States: Expert Opinion for 2021-2022 - Downes, Kevin J; Statler, Victoria A; Orscheln, Rachel C; Cousino, Melissa K; Green, Michael; Michaels, Marian G; Muller, William J; Sharma, Tanvi S; Danziger-Isakov, Lara A; Ardura, Monica I (Journal of the Pediatric Infectious Diseases Society, 2021)
Abstract The COVID-19 pandemic continues to generate challenges for pediatric solid organ transplant (SOT) recipients and their families. As rates of COVID-19 fluctuate, new SARS-CoV-2 variants emerge, and adherence to and implementation of mitigation strategies vary from community to community, questions remain about the best and safest practices to prevent COVID-19 in vulnerable patients. Notably, decisions about returning to school remain difficult. We assembled a team of specialists in pediatric infectious diseases, transplant infectious diseases, public health, transplant psychology, and infection prevention and control to re-address concerns about school re-entry, as well as COVID-19 vaccines, for pediatric SOT recipients in the United States in 2021. Based on available literature and guidance from national organizations, we generated expert statements specific to pediatric SOT recipients focused on school attendance in 2021.

Specimen Submission Form | Submitting Specimens to CDC | Infectious Diseases Laboratories | CDC (2021)
CDC Form 50.34

Clavulanate combinations with mecillinam, cefixime or cefpodoxime against ESBL-producing Enterobacterales frequently associated with blaOXA-1 in a paediatric population with febrile urinary tract infections - Birgy, André; Madhi, Fouad; Jung, Camille; Levy, Corinne; Cointe, Aurélie; Bidet, Philippe; Hobson, Claire Amaris; Bechet, Stéphane; Sobral, Elsa; Vuthien, Hoang; Ferroni, Agnès; Aberrane, Saïd; et al. (Journal of Antimicrobial Chemotherapy, 2021)
Oral treatment of febrile urinary tract infections (FUTIs) can be impaired by MDR Enterobacterales often combining ESBL and inhibitor-resistant genes. We studied the impact of β-lactamases and Enterobacterales’ genotypes on the cefixime, cefpodoxime and mecillinam ± amoxicillin/clavulanate MICs.In this multicentric study, we included 251 previously whole-genome-sequenced ESBL-producing Enterobacterales, isolated in French children with FUTIs. The MICs of cefixime, cefpodoxime, mecillinam alone and combined with amoxicillin/clavulanate were determined and analysed with respect to genomic data. We focused especially on the isolates’ ST and their type of β-lactamases. Clinical outcomes of patients who received cefixime + amoxicillin/clavulanate were also analysed.All isolates were cefixime and cefpodoxime resistant. Disparities depending on blaCTX-M variants were observed for cefixime. The addition of amoxicillin/clavulanate restored susceptibility for cefixime and cefpodoxime in 97.2% (MIC50/90 of 0.38/0.75 mg/L) and 55.4% (MIC50/90 of 1/2 mg/L) of isolates, respectively, whatever the ST, the blaCTX-M variants or the association with inhibitor-resistant β-lactamases (34.2%). All isolates were susceptible to mecillinam + amoxicillin/clavulanate with MIC50/90 of 0.19/0.25 mg/L, respectively. Neither therapeutic failure nor any subsequent positive control urine culture were reported for patients who received cefixime + amoxicillin/clavulanate as an oral relay therapy (n = 54).Despite the frequent association of ESBL genes with inhibitor-resistant β-lactamases, the cefixime + amoxicillin/clavulanate MICs remain low. The in vivo efficacy of this combination was satisfying even when first-line treatment was ineffective. Considering the MIC distributions and pharmacokinetic parameters, mecillinam + amoxicillin/clavulanate should also be an alternative to consider when treating FUTIs in children.

Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation - Leard, Lorriana E.; Holm, Are M.; Valapour, Maryam; Glanville, Allan R.; Attawar, Sandeep; Aversa, Meghan; Campos, Silvia V.; Christon, Lillian M.; Cypel, Marcelo; Dellgren, Göran; Hartwig, Matthew G.; Kapnadak, Siddhartha G.; et al. (The Journal of Heart and Lung Transplantation, 2021)
Keywords: chronic obstructive pulmonary disease; consensus; cystic fibrosis; emphysema; ethics; interstitial lung disease; lung transplant; pulmonary hypertension; risk factor

Impact of Screening and Treatment of Ureaplasma species on Hyperammonemia Syndrome in Lung Transplant Recipients: A Single Center Experience - Roberts, Scott C; Bharat, Ankit; Kurihara, Chitaru; Tomic, Rade; Ison, Michael G (Clinical Infectious Diseases, 2021)
Infection with Ureaplasma species (spp) has been linked to fatal hyperammonemia syndrome (HS) in lung transplant recipients. We sought to characterize the epidemiology of Ureaplasma spp in candidates and donors and describe outcomes of antimicrobial therapy in preventing and treating HS.Candidate testing for Ureaplasma spp was performed with urine culture and polymerase chain reaction (PCR) pretransplant. Positive candidates were treated with levofloxacin. Donor testing was performed with bronchoalveolar lavage (BAL) culture and PCR intraoperatively. From 7/2014 to 2/2017 patients were treated according to results; from 2/2017 to 10/2018 recipients received empiric levofloxacin and azithromycin at transplant until testing returned negative. HS was defined as new onset altered mental status after transplant with ammonia > 200 µmol/L.In total, 60 patients who underwent lung transplant were included. And 80% (n = 48) of patients had negative screening tests in donor and candidate pre-lung transplant, 8.3% (n = 5) of recipients had positive Ureaplasma spp testing in urine pre-transplant, and 13.3% (n = 8) had positive donor BAL testing at the time of lung transplant. Three patients developed HS a median of 7 days posttransplant; 2 died of HS. Recipients of organs with Ureaplasma spp who received empiric therapy did not develop HS. Donors with Ureaplasma spp were younger and more sexually active.Donor-derived Ureaplasma spp in lung transplant was associated with HS. Screening lung donors for Ureaplasma spp might allow for targeted therapy to reduce risk for development of HS, but future confirmatory studies are needed.

Antifungal Susceptibility Testing: A Primer for Clinicians - Wiederhold, Nathan P (Open Forum Infectious Diseases, 2021)
Abstract Clinicians treating patients with fungal infections may turn to susceptibility testing to obtain information regarding the activity of different antifungals against a specific fungus that has been cultured. These results may then be used to make decisions regarding a patient’s therapy. However, for many fungal species that are capable of causing invasive infections, clinical breakpoints have not been established. Thus, interpretations of susceptible or resistant cannot be provided by clinical laboratories, and this is especially true for many molds capable of causing severe mycoses. The purpose of this review is to provide an overview of susceptibility testing for clinicians, including the methods used to perform these assays, their limitations, how clinical breakpoints are established, and how the results may be put into context in the absence of interpretive criteria. Examples of when susceptibility testing is not warranted are also provided.

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021 - Evans, Laura; Rhodes, Andrew; Alhazzani, Waleed; Antonelli, Massimo; Coopersmith, Craig M.; French, Craig; Machado, Flávia R.; Mcintyre, Lauralyn; Ostermann, Marlies; Prescott, Hallie C.; Schorr, Christa; Simpson, Steven; et al. (Critical Care Medicine, 2021)
An abstract is unavailable.

Refractory and Resistant Cytomegalovirus After Hematopoietic Cell Transplant in the Letermovir Primary Prophylaxis Era - Sassine, Joseph; Khawaja, Fareed; Shigle, Terri Lynn; Handy, Victoria; Foolad, Farnaz; Aitken, Samuel L; Jiang, Ying; Champlin, Richard; Shpall, Elizabeth; Rezvani, Katy; Ariza-Heredia, Ella J; Chemaly, Roy F (Clinical Infectious Diseases, 2021)
Background.  Cytomegalovirus (CMV) reactivation is one of the most common infectious complications after allogeneic hematopoietic cell transplant (HCT) and may result in significant morbidity and mortality. Primary prophylaxis with letermovir demonstrated a reduction in clinically significant CMV infections (CS-CMVi) in clinical trials of CMV-seropositive HCT recipients. This study aims at exploring the effect of primary letermovir prophylaxis in this population on the incidence and outcomes of refractory or resistant CMV infections. Methods.  This is a single-center, retrospective cohort study of 537 consecutive CMV-seropositive allogeneic HCT recipients cared for between March 2016 and October 2018. Baseline demographics, HCT characteristics, CMV infections, treatment, and mortality data were collected from the electronic medical record. CMV outcomes were defined according to the recently standardized definitions for clinical trials. Characteristics and outcomes were assessed according to receipt of primary letermovir prophylaxis. Results.  Of 537 patients identified, 123 received letermovir for primary prophylaxis during the first 100 days after HCT; 414 did not. In a multivariate analysis, primary prophylaxis with letermovir was associated with reductions in CS-CMVi (hazard ratio [HR] 0.26; 95% confidence interval [CI], 0.16–0.41), CMV end-organ disease (HR 0.23; 95% CI, 0.10–0.52), refractory or resistant CMV infection (HR 0.15; 95% CI, 0.04–0.52), and nonrelapse mortality at week 48 (HR 0.55; 95% CI, 0.32–0.93). There was neither resistant CMV nor CMV-related mortality in the primary letermovir prophylaxis group. Conclusions.  Primary letermovir prophylaxis effectively prevents refractory or resistant CMV infections and decreases nonrelapse mortality at week 48, as well as CS-CMVi and CMV disease after allogeneic HCT.
Keywords: cytomegalovirus; hematopoietic cell transplant; letermovir; mortality; refractory and resistant cytomegalovirus

High Clinical Impact of Broad-Range Fungal PCR in Suspected Fungal Sinusitis - Lieberman, Joshua A.; Bryan, Andrew; Mays, James A.; Stephens, Karen; Kurosawa, Kyoko; Mathias, Patrick C.; SenGupta, Dhruba; Bourassa, Lori; Salipante, Stephen J.; Cookson, Brad T. (Journal of Clinical Microbiology, 2021)
Broad-range fungal PCR is a powerful tool for identifying pathogens directly from patient specimens; however, reported estimates of clinical utility vary and costs discourage universal testing. We investigated the diagnostic and clinical utility of broad-range fungal PCR by examining 9 years of results from sinonasal specimens, hypothesizing that this anatomic location would identify immunocompromised patients at high risk for invasive fungal disease. We retrospectively identiﬁed 644 PCRs and 1,446 fungal cultures from sinus sites. To determine the relative performance of each testing modality, we performed chart review on 52 patients having specimens submitted for culture and PCR on the same day. Positivity rates were signiﬁcantly higher for PCR (37.1%) than culture (13.7%) but similar for formalin-ﬁxed and fresh tissues (42.3% versus 34.6%). Relative to culture, PCR had signiﬁcantly faster turnaround time to both preliminary (94.5 versus 108.8 h) and ﬁnal positive (137.9 versus 278.5 h) results. Among chartreviewed patients, 88% were immunocompromised, 65% had proven or probable fungal disease, and testing sensitivities for culture and PCR (67.5% and 85.0%) were not statistically different. Nevertheless, PCR identiﬁed pathogens not recovered by culture in 14.9% of cases and informed clinical decision-making in 16.7% of all reviewed cases, and sensitivity of PCR combined with culture (90.0%) was higher than that of culture alone. We conclude that broad-range fungal PCR is frequently informative for patients at risk of serious fungal disease and is complementary to and has faster turnaround time than culture. Formalin-ﬁxed tissue does not adversely affect diagnostic yield, but anatomic site may impact assay positivity rates.

Enfermedades transmitidas en aguas recreativas | Healthy Swimming | Healthy Water | CDC - CDC (2021)

Immunosuppressive Agents and Infectious Risk in Transplantation: Managing the “Net State of Immunosuppression” - Roberts, Matthew B; Fishman, Jay A (Clinical Infectious Diseases, 2021)
Abstract Successful solid organ transplantation reflects meticulous attention to the details of immunosuppression, balancing risks for graft rejection against risks for infection. The “net state of immune suppression” is a conceptual framework of all factors contributing to infectious risk. Assays that measure immune function in the immunosuppressed transplant recipient relative to infectious risk and allograft function are lacking. The best measures of integrated immune function may be quantitative viral loads to assess the individual’s ability to control latent viral infections. Few studies address adjustment of immunosuppression during active infections; thus, confronted with infection in solid organ recipients, the management of immunosuppression is based largely on clinical experience. This review examines known measures of immune function and the immunologic effects of common immunosuppressive drugs and available studies reporting modification of drug regimens for specific infections. These data provide a conceptual framework for the management of immunosuppression during infection in organ recipients.

Expanding the Donor Pool: First Use of Hepatitis B Virus Nat Positive Solid Organ Allografts Into Seronegative Recipients - Delman, Aaron M.; Turner, Kevin M.; Safdar, Kamran; Anwar, Nadeem; Silski, Latifa S.; Lee, Tiffany C.; Luckett, Keith; Cuffy, Madison C.; Quillin, Ralph C.; Schoech, Michael; Kaiser, Tiffany E.; Govil, Amit; et al. (Annals of Surgery, 2021)
OBJECTIVES: The aim of this study was to assess the 1-year safety and effectiveness of HBV Nucleic Acid Test positive (HBV NAT+) allografts in seronegative kidney transplant (KT) and liver transplant (LT) recipients. SUMMARY BACKGROUND DATA: Despite an ongoing organ shortage, the utilization of HBV NAT+ allografts into seronegative recipients has not been investigated. METHODS: From January 2017 to October 2020, a prospective cohort study was conducted among consecutive KT and LT recipients at a single institution. Primary endpoints were post-transplant HBV viremia, graft and patient survival. RESULTS: With median follow-up of 1-year, there were no HBV-related complications in the 89 HBV NAT+ recipients. Only 9 of 56 KTs (16.1%) and 9 of 33 LTs (27.3%) experienced post-transplant HBV viremia at a median of 185 (KT) and 269 (LT) days postoperatively. Overall, viremic episodes resolved to undetected HBV DNA after a median of 80 days of entecavir therapy in 16 of 18 recipients. Presently, 100% of KT recipients and 93.9% of LT recipients are HBV NAT- with median follow-up of 13 months, whereas 0 KT and 8 LT (24.2%) recipients are HBV surface antigen positive indicating chronic infection. KT and LT patient and allograft survival were not different between HBV NAT+ and HBV NAT- recipients (P > 0.05), whereas HBV NAT+ KT recipients had decreased waitlist time and pretransplant duration on dialysis (P < 0.01). CONCLUSIONS: This is the largest series describing the transplantation of HBV NAT+ kidney and liver allografts into HBV seronegative recipients without chronic HBV viremia or decreased 1-year patient and graft survival. Increasing the utilization of HBV NAT+ organs in nonviremic recipients can play a role in decreasing the national organ shortage.
Keywords: Adult; Aged; Allografts; Donor Selection; End Stage Liver Disease; Female; Graft Survival; Hepatitis B; Humans; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Survival Rate; Treatment Outcome

Identification of Predictive Markers and Outcomes of Late-onset Pneumocystis jirovecii Pneumonia in Kidney Transplant Recipients - Kaminski, Hannah; Belliere, Julie; Burguet, Laure; Del Bello, Arnaud; Taton, Benjamin; Poirot-Mazères, Stéphane; Accoceberry, Isabelle; Delhaes, Laurence; Visentin, Jonathan; Gregori, Marco; Iriart, Xavier; Charpentier, Elena; et al. (Clinical Infectious Diseases, 2021)
In the era of prophylaxis, Pneumocystis pneumonia (PCP) has become a late-onset opportunistic infection requiring indications for prolonged prophylaxis to be defined. The primary objective of our study was therefore to evaluate risk factors associated with late-onset PCP. The secondary objective was to assess the impact of this infection on graft and patient survival.We conducted a French case-control study in Bordeaux and Toulouse center by matching 1 case to 1–2 controls from the same center based on the transplant date and the type of induction treatment.Seventy cases and 134 controls were included. PCP occurred at a median of 3 years after transplantation. The total lymphocyte count and CD4+ and CD8+ T-lymphocyte values were lower in the cases than in their matched controls on the day of infection and annually up to 4 years earlier. The covariables independently associated with PCP were the total lymphocyte count 1 year before Pneumocystis, mTOR inhibitors used as maintenance immunosuppressive drugs, and the administration of corticosteroid boluses used in acute rejection. A total lymphocyte count threshold <1000/µL offered the best predictive value for infection occurrence. PCP was associated with high incidence of graft loss and patient death (30% and 17% respectively, 3 years after PCP).Pneumocystis pneumonia has dramatic consequences in kidney transplant recipients; a targeted prophylaxis based on simple criteria, such as chronic lymphopenia and/or history of corticosteroid boluses, could be useful to avoid life-threatening complications.
Keywords: corticosteroid boluses; kidney transplantation; lymphopenia; pneumocystis pneumonia

Significance of Asymptomatic Pyelonephritis Found on Kidney Transplant Biopsy - Aziz, Fahad; Saddler, Christopher; Jorgenson, Margaret; Alstott, James; Swanson, Kurt; Parajuli, Sandesh; Garg, Neetika; Djamali, Arjang; Mandelbrot, Didier (Transplantation Direct, 2021)
Background. The clinical significance and appropriate management of graft pyelonephritis diagnosed by biopsy are poorly understood. Methods. We analyzed data from all patients with pyelonephritis on transplant kidney biopsy from January 1998 to December 2019. Patients were divided into 2 groups: those whose urinalysis was positive for urinary tract infection (UA+) and those whose urinalysis was negative (UA–). Results. There were a total of 101 patients with the diagnosis of pyelonephritis by biopsy during the study period. The mean time from transplant to pyelonephritis diagnosis was 3.3 ± 4 y. Thirty-six (35.6%) of the patients with pyelonephritis on biopsy had a negative UA. Out of 65 patients in the UA+ group, 54 (83%) received antibiotics. Only 12 of the UA– patients (33%) received antibiotics. The use of antibiotics in both the UA+ (P = 0.03) and UA– groups (P = 0.02) compared with no use of antibiotics was associated with better death-censored graft survival. On multivariate analysis, the use of antibiotics (hazard ratio = 0.22, P = 0.001, 95% confidence interval, 0.12-0.61) was associated with improved graft survival. Conclusion. The finding of pyelonephritis on a transplant kidney biopsy is almost always a surprise but is an important finding. Treatment with antibiotics, regardless of signs or symptoms of urinary tract infection, is associated with improved graft survival.

Evaluation of Recombinant Herpes Zoster Vaccine for Primary Immunization of Varicella-seronegative Transplant Recipients - L'Huillier, Arnaud G.; Hirzel, Cedric; Ferreira, Victor H.; Ierullo, Matthew; Ku, Terrance; Selzner, Nazia; Schiff, Jeffrey; Juvet, Stephen; Miao, Congrong; Schmid, D. Scott; Humar, Atul; Kumar, Deepali (Transplantation, 2021)
Background. Immunization of varicella-zoster virus (VZV)-seronegative solid organ transplant (SOT) patients using the live-attenuated varicella vaccine is generally contraindicated, leaving no widely applicable immunization option. The recombinant subunit herpes zoster vaccine (RZV) is indicated for VZV-seropositive persons to prevent shingles but could potentially also protect VZV-seronegative persons against varicella. We performed a safety and immunogenicity evaluation of RZV in VZV-seronegative SOT recipients as an option for protection. Methods. VZV-seronegative adult SOT patients with no history of varicella/shingles vaccine or disease were given 2 doses of RZV vaccine 2–6 mo apart. Blood was drawn prevaccination (V1), before the second dose (V2), and 4 wk after the second dose (V3). Humoral immunity (anti-glycoprotein E) and cell-mediated immunity were evaluated, with polyfunctional cells defined as cells producing ≥2 cytokines. Results. Among 31 eligible VZV-seronegative SOT patients screened, 23 were enrolled. Median age was 38 y and median time since transplant procedure was 3.8 y. The most frequent transplant types were liver (35%) and lung (30%). Median anti-glycoprotein E levels significantly increased from V1 to V3 (P = 0.001) and V2 to V3 (P < 0.001), even though only 55% had a positive seroresponse. Median polyfunctional CD4 T-cell counts increased from V1 to V2 (54/106 versus 104/106 cells; P = 0.041) and from V2 to V3 (380/106; P = 0.002). Most adverse events were mild with no rejection episodes. Conclusions. RZV was safe and elicited significant humoral and cellular responses in VZV-seronegative SOT patients and has the potential to be considered as a preventive strategy against primary varicella.

A Comprehensive Evaluation of Risk Factors for Pneumocystis jirovecii Pneumonia in Adult Solid Organ Transplant Recipients: A Systematic Review and Meta-analysis - Permpalung, Nitipong; Kittipibul, Veraprapas; Mekraksakit, Poemlarp; Rattanawong, Pattara; Nematollahi, Saman; Zhang, Sean X.; Steinke, Seema Mehta (Transplantation, 2021)
Export Background. There is no consensus guidance on when to reinitiate Pneumocystis jirovecii pneumonia (PJP) prophylaxis in solid organ transplant (SOT) recipients at increased risk. The 2019 American Society of Transplantation Infectious Diseases Community of Practice (AST IDCOP) guidelines suggested to continue or reinstitute PJP prophylaxis in those receiving intensified immunosuppression for graft rejection, cytomegalovirus (CMV) infection, higher dose of corticosteroids, or prolonged neutropenia. Methods. A literature search was conducted evaluating all literature from existence through April 22, 2020, using MEDLINE and EMBASE. (The International Prospective Register of Systematic Reviews registration number: CRD42019134204). Results. A total of 30 studies with 413 276 SOT recipients were included. The following factors were associated with PJP development: acute rejection (pooled odds ratio [pOR], 2.35; 95% confidence interval [CI], 1.69-3.26); study heterogeneity index [I2] = 23.4%), CMV-related illnesses (pOR, 3.14; 95% CI, 2.30-4.29; I2 = 48%), absolute lymphocyte count <500 cells/mm3 (pOR, 6.29; 95% CI, 3.56-11.13; I2 = 0%), BK polyomavirus-related diseases (pOR, 2.59; 95% CI, 1.22-5.49; I2 = 0%), HLA mismatch ≥3 (pOR, 1.83; 95% CI, 1.06-3.17; I2 = 0%), rituximab use (pOR, 3.03; 95% CI, 1.82-5.04; I2 = 0%), and polyclonal antibodies use for rejection (pOR, 3.92; 95% CI, 1.87-8.19; I2 = 0%). On the other hand, sex, CMV mismatch, interleukin-2 inhibitors, corticosteroids for rejection, and plasmapheresis were not associated with developing PJP. Conclusions. PJP prophylaxis should be considered in SOT recipients with lymphopenia, BK polyomavirus-related infections, and rituximab exposure in addition to the previously mentioned risk factors in the American Society of Transplantation Infectious Diseases Community of Practice guidelines.

Viral kinetics and outcomes of adenovirus viremia following allogeneic hematopoietic cell transplantation - Chandorkar, Aditya; Anderson, Anthony D.; Morris, Michele I.; Natori, Yoichiro; Jimenez, Antonio; Komanduri, Krishna V.; Camargo, Jose F. (Clinical Transplantation, 2021)
Background: Adenovirus (AdV) is a serious infection following hematopoietic cell transplantation (HCT). Little is known about AdV viral kinetics and optimal threshold for initiation of pre-emptive therapy. Methods: Single-center retrospective study of 16 consecutive adult HCT recipients with detectable AdV identified over a 5-year period. Results: Median time to AdV reactivation after HCT was 176 days (IQR 86–408). Nine patients received cidofovir, although 14/16 had no tissue-invasive disease. Among treated patients, median duration of viremia was shorter when initiating treatment at viral loads < 10,000 copies/ml (28 vs. 52 days). All-cause mortality in this cohort was 44%. All six patients (five of which were untreated) with peak viral loads < 10,000 copies/ml survived; whereas only 30% (3/10) of patients with peak viral loads greater than this threshold survived, despite most (n = 8; 80%) of them receiving cidofovir (P = .01). Three-month survival following diagnosis of AdV viremia was significantly lower with peak viremia > 10,000 copies/ml (100 vs. 17%; P = .005). Conclusion: AdV is associated with high all-cause mortality, especially for viremia > 10,000 copies/ml. Delaying therapy until viremia reaches AdV levels ≥10,000 copies/ml was associated with more protracted infection and poor outcomes. Larger studies are needed.

Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients - Hall, Victoria G.; Ferreira, Victor H.; Ku, Terrance; Ierullo, Matthew; Majchrzak-Kita, Beata; Chaparro, Cecilia; Selzner, Nazia; Schiff, Jeffrey; McDonald, Michael; Tomlinson, George; Kulasingam, Vathany; Kumar, Deepali; et al. (New England Journal of Medicine, 2021)

Phenotype and Genotype Study of Novel C480F Maribavir-Ganciclovir Cross-Resistance Mutation Detected in Hematopoietic Stem Cell and Solid Organ Transplant Recipients - Santos Bravo, Marta; Plault, Nicolas; Sánchez Palomino, Sonsoles; Mosquera Gutierrez, María Mar; Fernández Avilés, Francesc; Suarez Lledo, María; Sabé Fernández, Nuria; Rovira, Montserrat; Alain, Sophie; Marcos Maeso, M Ángeles (The Journal of Infectious Diseases, 2021)
Abstract Two transplant recipients (1 kidney and 1 hematopoietic stem cell) received maribavir (MBV) after cytomegalovirus (CMV) infection clinically resistant to standard therapy. Both patients achieved CMV DNA clearance within 30 and 18 days; however, the UL97 C480F variant emerged, causing recurrent CMV infection after a cumulative 2 months of MBV and 15 or 4 weeks of ganciclovir treatment, respectively. C480F was not detected under ganciclovir before MBV treatment. Recombinant phenotyping showed that C480F conferred the highest level of MBV resistance and ganciclovir cross-resistance, with impaired viral growth. Clinical follow-up and genotypic and phenotypic studies are essential for the assessment and optimization of patients with suspected MBV resistance.

Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults - Johnson, Stuart; Lavergne, Valéry; Skinner, Andrew M; Gonzales-Luna, Anne J; Garey, Kevin W; Kelly, Ciaran P; Wilcox, Mark H (Clinical Infectious Diseases, 2021)
Abstract This clinical practice guideline is a focused update on management of Clostridioides difficile infection (CDI) in adults specifically addressing the use of fidaxomicin and bezlotoxumab for the treatment of CDI. This guideline was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA). This guideline is intended for use by healthcare professionals who care for adults with CDI, including specialists in infectious diseases, gastroenterologists, hospitalists, pharmacists, and any clinicians and healthcare providers caring for these patients. The panel’s recommendations for the management CDI are based upon evidence derived from topic-specific systematic literature reviews. Summarized below are the recommendations for the management of CDI in adults. The panel followed a systematic process which included a standardized methodology for rating the certainty of the evidence and strength of recommendation using the GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation). A detailed description of background, methods, evidence summary and rationale that support each recommendation, and knowledge gaps can be found online in the full text.

Serology anno 2021—fungal infections: from invasive to chronic - Lass-Flörl, Cornelia; Samardzic, Eldina; Knoll, Miriam (Clinical Microbiology and Infection, 2021)
Keywords: Aspergillus; Diagnosis of invasive fungal infections; Galactomannan; Lateral flow assay; Lateral flow device; Mannan; β-d-glucan

Investigational Agents for the Treatment of Resistant Yeasts and Molds - Seiler, Garret T.; Ostrosky-Zeichner, Luis (Current Fungal Infection Reports, 2021)
This review summarizes the investigational antifungals in clinical development with the potential to address rising drug resistance patterns. The relevant pharmacodynamics, spectrum of activity, preclinical studies, and latest clinical trial data are described.
Keywords: Antifungal drugs; Antifungal resistance; Candida auris; Invasive fungal infections; Novel therapies; Review

Latent and active tuberculosis infection in allogeneic hematopoietic stem cell transplant recipients: a prospective cohort study - de Oliveira Rodrigues, Marina; de Almeida Testa, Lucia H.; dos Santos, Ana Cláudia F.; Zanetti, Lilian P.; da Silva Ruiz, Luciana; de Souza, Mair Pedro; Colturato, Vergílio R.; Machado, Clarisse M. (Bone Marrow Transplantation, 2021)
Tuberculosis (TB) is a major infectious complication in hematopoietic stem cell transplant (HSCT) recipients in countries with high TB prevalence. Identifying and treating latent tuberculosis infection (LTBI) helps to prevent TB reactivation after transplantation. Few studies have compared the tuberculin skin test (TST) with interferon Gamma release assays (IGRA) to diagnose LTBI in HSCT candidates. We compared TST and QuantiFeron TB gold in tube (QTF-GIT) and prospectively evaluated the incidence of active tuberculosis in 126 HSCT candidates and 58 HSCT recipients with chronic GVHD followed at the outpatient clinic. TB was diagnosed by culture in Mycobacteria media and by commercial real-time PCR kit. Considering the positivity of any test, the prevalence of LTBI was 8.7% in HSCT candidates (11 out of 126) and 12.5% in HSCT recipients with chronic GVHD (6 out of 48). QTF-GIT indeterminate results were detected in 2.4% of the HSCT candidates. Fair to good agreement (K > 0.50) between tests was observed in both cohorts. Cumulative incidence of TB was 3% in the GVHD cohort. TB was diagnosed in 2 chronic GVHD recipients, both cases confirmed by positive culture and PCR. None of the 11 patients with LTBI diagnosed pre-HSCT who received INH prophylaxis developed TB.

Severe acute graft-versus-host disease increases the incidence of blood stream infection and mortality after allogeneic hematopoietic cell transplantation: Japanese transplant registry study - Inoue, Yoshitaka; Okinaka, Keiji; Fuji, Shigeo; Inamoto, Yoshihiro; Uchida, Naoyuki; Toya, Takashi; Ikegame, Kazuhiro; Eto, Tetsuya; Ozawa, Yukiyasu; Iwato, Koji; Kanda, Yoshinobu; Atsuta, Yoshiko; et al. (Bone Marrow Transplantation, 2021)
This study aimed to clarify the risk factors and prognosis associated with blood stream infection (BSI) in allogeneic hematopoietic cell transplantation (allo-HCT), and the relationship between BSI and acute graft-versus-host disease (aGVHD). This retrospective analysis included 11,098 patients in the Japanese national transplant registry. A total of 2172 patients developed BSI after allo-HCT, with 2332 identified pathogens. The cumulative incidences of BSI were 15.5% at 30 days and 20.9% at 100 days after allo-HCT. In a multivariate analysis, severe (grade III–IV) aGVHD was associated with a higher risk of BSI (vs. grade 0–I aGVHD: hazard ratio [HR] 3.34 [95% confidence interval (CI), 2.85–3.92; P < 0.001]). In a multivariate analysis, severe aGVHD before BSI was associated with a higher risk of overall mortality after BSI (vs. grade 0–I aGVHD: HR 2.61 [95% CI 2.18–3.11; P < 0.001]). In addition, BSI (vs. no-BSI: HR 1.20 [95% CI, 1.12–1.29; P < 0.001]) and severe aGVHD (vs. grade 0–I aGVHD: HR 1.97 [95% CI, 1.83–2.12; P < 0.001]) were independent risk factors for overall mortality after allo-HCT. In the setting of allo-HCT, severe aGVHD was associated with increases in both BSI incidence and post-BSI overall mortality. Furthermore, BSI was an independent risk factor for overall mortality.

People With a Higher Risk of Food Poisoning | Food Safety | CDC (2021)
People at risk from food poisoning include pregnant women, children under the age of 5, people with cancer, HIV/AIDS, and the elderly. It is important for these groups to know what foods can cause food poisoning.

Third-Party BK Virus-Specific Cytotoxic T Lymphocyte Therapy for Hemorrhagic Cystitis Following Allotransplantation - Olson, Amanda; Lin, Ruitao; Marin, David; Rafei, Hind; Bdaiwi, Mustafa H.; Thall, Peter F.; Basar, Rafet; Abudayyeh, Ala; Banerjee, Pinaki; Aung, Fleur M.; Kaur, Indresh; Abueg, Glorette; et al. (Journal of Clinical Oncology, 2021)
BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of allogenic hematopoietic stem cell transplantation (AHSCT), particularly in recipients of alternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option.

Challenges with Utilizing the 1,3-Beta- d -Glucan and Galactomannan Assays To Diagnose Invasive Mold Infections in Immunocompromised Children - Hsu, Alice J.; Tamma, Pranita D.; Zhang, Sean X. (Journal of Clinical Microbiology, 2021)
Establishing the diagnosis of invasive mold infections (IMI) in immunocompromised children is challenging due to nonspeciﬁc clinical presentations and the limited sensitivity of traditional culture-based methods. Rapid non-culture-based diagnostics such as the 1,3-beta-D-glucan and galactomannan assays have emerged as promising adjuncts to conventional diagnostic tests in adults. Available data suggest that 1,3-beta-D-glucan has limited accuracy in the pediatric population and is not recommended to be used for the diagnosis of IMI in children. On the other hand, the diagnostic performance of the serum and bronchoalveolar lavage galactomannan in immunocompromised children is comparable to results observed in adults and can be used as a screening tool in children at high risk of developing invasive aspergillosis (IA) who are not receiving mold-active antifungal prophylaxis and as a diagnostic tool in symptomatic children suspected of having IA. Herein, we summarize the available evidence for the use of these rapid non-culture-based diagnostics in immunocompromised children. We also summarize potential causes of false positivity for the 1,3-beta-D-glucan and galactomannan assays.

Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients - Kamar, Nassim; Abravanel, Florence; Marion, Olivier; Couat, Chloé; Izopet, Jacques; Del Bello, Arnaud (New England Journal of Medicine, 2021)

Comparative Effectiveness of Echinocandins vs Triazoles or Amphotericin B Formulations as Initial Directed Therapy for Invasive Candidiasis in Children and Adolescents - Fisher, Brian T; Zaoutis, Theoklis E; Xiao, Rui; Wattier, Rachel L; Castagnola, Elio; Pana, Zoi Dorothea; Fullenkamp, Allison; Boge, Craig L K; Ross, Rachael K; Yildirim, Inci; Palazzi, Debra L; Danziger-Isakov, Lara; et al. (Journal of the Pediatric Infectious Diseases Society, 2021)
Abstract Background Invasive candidiasis is the most common invasive fungal disease in children and adolescents, but there are limited pediatric-specific antifungal effectiveness data. We compared the effectiveness of echinocandins to triazoles or amphotericin B formulations (triazole/amphotericin B) as initial directed therapy for invasive candidiasis. Methods This multinational observational cohort study enrolled patients aged >120 days and <18 years with proven invasive candidiasis from January 1, 2014, to November 28, 2017, at 43 International Pediatric Fungal Network sites. Primary exposure was initial directed therapy administered at the time qualifying culture became positive for yeast. Exposure groups were categorized by receipt of an echinocandin vs receipt of triazole/amphotericin B. Primary outcome was global response at 14 days following invasive candidiasis onset, adjudicated by a centralized data review committee. Stratified Mantel-Haenszel analyses estimated risk difference between exposure groups. Results Seven-hundred and fifty invasive candidiasis episodes were identified. After exclusions, 541 participants (235 in the echinocandin group and 306 in the triazole/amphotericin B group) remained. Crude failure rates at 14 days for echinocandin and triazole/amphotericin B groups were 9.8% (95% confidence intervals [CI]: 6.0% to 13.6%) and 13.1% (95% CI: 9.3% to 16.8%), respectively. The adjusted 14-day risk difference between echinocandin and triazole/amphotericin B groups was −7.1% points (95% CI: −13.1% to −2.4%), favoring echinocandins. The risk difference was −0.4% (95% CI: −7.5% to 6.7%) at 30 days. Conclusions In children with invasive candidiasis, initial directed therapy with an echinocandin was associated with reduced failure rate at 14 days but not 30 days. These results may support echinocandins as initial directed therapy for invasive candidiasis in children and adolescents. Clinical Trials Registration NCT01869829.

Immunogenicity and Safety of the 9-Valent Human Papillomavirus Vaccine in Solid Organ Transplant Recipients and Adults Infected With Human Immunodeficiency Virus (HIV) - Boey, Lise; Curinckx, Ans; Roelants, Mathieu; Derdelinckx, Inge; Van Wijngaerden, Eric; De Munter, Paul; Vos, Robin; Kuypers, Dirk; Van Cleemput, Johan; Vandermeulen, Corinne (Clinical Infectious Diseases, 2021)
The burden of human papillomavirus (HPV) in human immunodeficiency virus (HIV)-infected persons and solid organ transplant (SOT) recipients is high. Clinical trials on HPV vaccines in persons living with HIV and particularly in SOT recipients have been sparse to date, included low numbers of participants, and none of them assessed the 9-valent HPV (9vHPV) vaccine. We investigated the immunogenicity with respect to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 and the safety of the 9vHPV vaccine in persons living with HIV and recipients of a kidney, lung, or heart transplant.This is a phase III investigator-initiated study in 100 persons living with HIV (age 18–45 years) and 171 SOT recipients (age 18–55 years). The 9vHPV vaccine was administered at day 1, month 2, and month 6. Primary outcome was seroconversion rates to the 9vHPV types at month 7. Secondary outcomes were geometric mean titers (GMTs) and frequency of adverse events (AEs).All HIV-infected participants seroconverted for all HPV types, but seroconversion ranged from 46% for HPV45 to 72% for HPV58 in SOT recipients. GMTs ranged from 180 to 2985 mMU/mL in HIV-positive participants and from 17 to 170 mMU/mL in SOT recipients, depending on the HPV type. Injection-site AEs occurred in 62% of participants but were mostly mild or moderate in intensity. None of the reported serious adverse events were deemed vaccine related. No patients died during the study.Immunogenicity of the 9vHPV vaccine is high in persons living with HIV but suboptimal in SOT recipients. The vaccine is safe and well tolerated in both groups.

Emerging fungal pathogens in solid organ transplantation - Mishkin, Aaron (Current opinion in organ transplantation, 2021)
Purpose of reviewThis review examines recent cases and updated literature on emerging or newly resistant fungal infections in solid organ transplantation.Recent findingsCandida auris, a newly described candida capable of drug resistance and persistence in the environment, is a growing concern with both published cases on donor-derived transmission and a hospital outbreak involving liver transplant recipients. Infections with non-albicans candida species are also increasing in incidence in SOT recipients, leading to increasing antifungal resistance and higher mortality. Aspergillus usti has emerged in immunocompromised patients on antifungal prophylaxis. Cryptococcus species continue to be responsible for a number of infections in SOT recipients. Dimorphic fungi, endemic to geographic areas and responsible for sporadic infections in SOT recipients are noted to have an expanding geographic area. Emergomyces are newly classified groups of five species of dimorphic fungi noted to disseminated disease in immunocompromised patients including SOT recipients.SummaryEmerging fungal species and the development of resistance in well entrenched fungal pathogens impacts SOT recipients and those caring for them. Knowledge of these trends aids in the successful identification and optimal treatment of these challenging conditions.

Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases - Biggins, Scott W.; Angeli, Paulo; Garcia‐Tsao, Guadalupe; Ginès, Pere; Ling, Simon C.; Nadim, Mitra K.; Wong, Florence; Kim, W. Ray (Hepatology, 2021)
An abstract is unavailable.

Breakthrough invasive fungal infection after liver transplantation in patients on targeted antifungal prophylaxis: A prospective multicentre study - Rinaldi, Matteo; Bartoletti, Michele; Ferrarese, Alberto; Franceschini, Erica; Campoli, Caterina; Coladonato, Simona; Pascale, Renato; Tedeschi, Sara; Gatti, Milo; Cricca, Monica; Ambretti, Simone; Siniscalchi, Antonio; et al. (Transplant Infectious Disease, 2021)
Objective To investigate the rate of and the risk factors for breakthrough‐IFI (b‐IFI) after orthotopic liver transplantation (OLT) according to the new definition proposed by Mycoses‐Study‐Group‐Education‐and‐Research‐Consortium (MSG‐ERC) and the European‐Confederation‐of‐Medical‐Mycology (ECMM). Methods Multicenter prospective study of adult patients who underwent OLT at three Italian hospitals, from January 2015 to December 2018. Targeted antifungal prophylaxis (TAP) protocol was developed and shared among participating centers. Follow‐up was 1‐year after OLT. B‐IFI was defined as infection occurring during exposure to antifungal prophylaxis. Risk factors for b‐IFI were analyzed among patients exposed to prophylaxis by univariable analysis. Results We enrolled 485 OLT patients. Overall compliance to TAP protocol was 64.3%, 220 patients received antifungal prophylaxis, 172 according to TAP protocol. Twenty‐nine patients were diagnosed of IFI within 1 year after OLT. Of them, 11 presented with b‐IFI within 17 (IQR 11‐33) and 16 (IQR 4‐30) days from OLT and from antifungal onset, respectively. Then out of 11 patients with b‐IFI were classified as having high risk of IFI and were receiving anti‐mould prophylaxis, nine with echinocandins and one with polyenes. Comparison of patients with and without b‐IFI showed significant differences for prior Candida colonization, need of renal replacement therapy after OLT, re‐operation, and CMV infection (whole blood CMV‐DNA >100 000 copies/mL). Although non‐significant, a higher rate of b‐IFI in patients on echinocandins was observed (8.2% vs 1.8%, P = .06). Conclusions We observed 5% of b‐IFI among OLT patients exposed to antifungal prophylaxis. The impact of echinocandins on b‐IFI risk in this setting should be further explored.

Infectious Complications in Tocilizumab-treated Kidney Transplant Recipients - Sethi, Supreet; Peng, Alice; Najjar, Reiad; Vo, Ashley; Jordan, Stanley C.; Huang, Edmund (Transplantation, 2021)
Background. Tocilizumab is an interleukin-6 receptor antagonist recently described as a promising treatment for antibody-mediated rejection. We compared infectious complications among tocilizumab-treated kidney transplant patients with those receiving intravenous immunoglobulin (IVIG)/rituximab. Methods. Infections occurring among 148 kidney recipients treated with tocilizumab 8 mg/kg IV monthly (n = 83) or IVIG/rituximab (n = 65) for donor-specific antibodies and antibody-mediated rejection through 1 year after treatment cessation were reviewed. Incidence rates of infections were compared using Poisson regression. Results. There were 106 infections observed over 190.1 person-years, yielding an incidence rate of 558 infections/1000 patient-years. A lower incidence rate of infections was observed among tocilizumab-treated compared with IVIG/rituximab-treated patients (463 infections/1000 patient-years versus 730 infections/1000 patient-years; P = 0.02). Twenty-five of 49 infections (51%) in the IVIG/rituximab group required hospitalization compared with 31 of 57 (54%; P = 0.85) in the tocilizumab group. There were no infection-related deaths in either group. Urinary tract infections and pneumonia were the most common types of infections, whereas gastrointestinal, blood, skin/soft tissue, viral, and fungal infections were less common. On multivariable Poisson regression, there was a lower incidence rate of infections associated with tocilizumab compared with IVIG/rituximab (incidence rate ratio, 0.63; 95% confidence interval, 0.43-0.93). Conclusions. Among kidney transplant patients treated with tocilizumab, there was no excess risk of infections compared with standard therapy with IVIG/rituximab.

People with Weakened Immune Systems | Healthy Pets, Healthy People | CDC (2021)
Pets provide many benefits to humans. They comfort us and they give us companionship. However, some animals can also pass diseases to people. These diseases are called zoonoses.

People with Weakened Immune Systems | Healthy Pets, Healthy People | CDC - CDC (2021)
Pets provide many benefits to humans. They comfort us and they give us companionship. However, some animals can also pass diseases to people. These diseases are called zoonoses.

Prediction rules for ruling out endocarditis in patients with Staphylococcus aureus bacteremia - van der Vaart, Thomas W; Prins, Jan M; Soetekouw, Robin; van Twillert, Gitte; Veenstra, Jan; Herpers, Bjorn L; Rozemeijer, Wouter; Jansen, Rogier R; Bonten, Marc J M; van der Meer, Jan T M (Clinical Infectious Diseases, 2021)
Background: Staphylococcus aureus bacteremia (SAB) is in 10% to 20% of cases complicated by infective endocarditis (SA-IE). Clinical prediction scores may select SAB patients at highest risk for endocarditis, improving the diagnostic process of endocarditis. We compared the accuracy of the POSITIVE, PREDICT and VIRSTA scores for classifying the likelihood of endocarditis in SAB patients.

Pretransplant Cytomegalovirus-Specific Cellular Immunity and Risk of Viral Reactivation Following Lung Transplantation: A Prospective Cohort Study - Altaf, Mohammed; Lineburg, Katie E; Crooks, Pauline; Rehan, Sweera; Matthews, Katherine K; Neller, Michelle A; Ambalathingal, George R; Sinha, Debottam; Grant, Michelle; Hopkins, Peter M A; Chambers, Daniel; Khanna, Rajiv; et al. (The Journal of Infectious Diseases, 2021)
Cytomegalovirus (CMV) remains a significant burden in lung transplant recipients. Deficiencies in T-cell immunity posttransplant increase the risk of CMV-associated complications. However, it is not clear if underlying poor pretransplant immunity increases risk. To assess this, we recruited 39 prospective lung transplant patients and performed QuantiFERON-CMV on their peripheral blood. More than a third of prospective CMV-seropositive transplant recipients were CMV non-immune reactive (CMV-NIR) pretransplant. CMV-NIR status was associated with a significantly higher incidence of CMV reactivation posttransplant, demonstrating that dysfunctional CMV immunity in prospective lung transplant recipients is associated with an increased risk of viral reactivation posttransplant.

Incidence of CMV Infection and Disease and Adverse Events Associated with Antiviral Therapy in a Retrospective Cohort of Allogeneic Hematopoietic Cell Transplant Recipients at an Academic Children’s Hospital - Hayes, Molly; Newman, Alexander M; Boge, Craig L K; Galetaki, Despoina M; Elgarten, Caitlin W; Freedman, Jason L; Olson, Timothy S; Fisher, Brian T (Journal of the Pediatric Infectious Diseases Society, 2021)
Background.  Cytomegalovirus (CMV) is a significant source of morbidity and mortality among transplant recipients; the epidemiology is less understood in pediatric hematopoietic cell transplantation (HCT) cohorts. Furthermore, there is a paucity of data related to CMV prophylactic and preemptive strategies. Methods.  A single-center retrospective observational cohort of allogeneic HCT recipients at the Children’s Hospital of Philadelphia January 1, 2004–December 31, 2017 was constructed. Subjects were followed for 180 days after transplant to determine whether they had CMV infection or disease. Data on antiviral therapy were collected as were outcomes of CMV disease and adverse events (AEs) related to the antiviral therapy. Results.  Between January 2004 and March 2017, 345 allogeneic HCTs in 333 patients undergoing CMV surveillance testing were identified. CMV DNAemia was detected during the 180-day follow-up in 89 (25.8%) HCTs. CMV recipientpositive transplants were most likely to have CMV infection (47%). Infection rates were high for those receiving a CMVspecific prophylaxis regimen (50%). CMV DNAemia progressed to CMV disease 11.2% of the time. Of 224 subjects receiving CMV-specific prophylaxis, 19.2% experienced ≥1 AE. Of 53 receiving preemptive therapy during any CMV DNAemia episode, 32.1% experienced ≥1 AE. Conclusions.  CMV infection is common in pediatric allogeneic HCT recipients. The CMV-specific prophylaxis regimen employed in this cohort did not effectively prevent DNAemia, progression to CMV disease was uncommon, and AEs from prophylaxis and preemptive therapy were frequent. Novel approaches that reduce the impact of CMV on pediatric allogeneic HCT recipients are needed.

Letermovir and Maribavir for the Treatment and Prevention of Cytomegalovirus Infection in Solid Organ and Stem Cell Transplant Recipients - Imlay, Hannah N; Kaul, Daniel R (Clinical Infectious Diseases, 2021)
Abstract Until recently, available drugs for cytomegalovirus (CMV) prevention and treatment in transplant patients included (val)ganciclovir, foscarnet, and cidofovir. Use of these drugs is limited by toxicity and the development of resistance. The 2017 approval of letermovir for prevention of CMV after stem cell transplant marked the first approval of an anti-CMV agent since 2003. The role of letermovir in treatment of established CMV infection or disease remains largely unstudied, although early reports suggest that a low barrier to resistance will likely limit efficacy as primary therapy for patients with refractory or resistant disease. The investigational agent maribavir has shown promise as preemptive treatment; in patients with refractory or resistant disease the emergence of resistance while on treatment has been observed and ongoing studies will define efficacy in this population. Both agents have unique mechanisms of action limiting cross resistance, and neither exhibit myelotoxicity or nephrotoxicity.

Valganciclovir Dosing for Cytomegalovirus Prophylaxis in Solid-organ Transplant Recipients on Continuous Veno-venous Hemodialysis - Jarrell, Andrew S; Crow, Jessica R; Strout, Sara E; Kruer, Rachel M; Toman, Lindsey P; Dioverti-Prono, Maria V; Lees, Laura; Avery, Robin K; Marzinke, Mark A (Clinical Infectious Diseases, 2021)
Background.  Optimal valganciclovir dosing for cytomegalovirus (CMV) prophylaxis in solid-organ transplant (SOT) patients on continuous veno-venous hemodialysis (CVVHD) is not known. Ganciclovir trough concentrations ≥0.60 μg/mL have been suggested for CMV prophylaxis. This study was conducted to determine if valganciclovir 450 mg enterally every 24 hours achieves ganciclovir trough concentrations ≥0.60 μg/mL in patients on CVVHD. Methods.  This single-center, prospective, open-label, pharmacokinetic study included adult SOT patients admitted to an intensive care unit from March 2018 to June 2019 on CVVHD. All patients were receiving valganciclovir 450 mg enterally every 24 hours for CMV prophylaxis prior to enrollment. Each patient had a peak and trough sample drawn at steady state. Results.  Ten SOT patients were included in the study (6 liver, 1 simultaneous liver-kidney, 2 bilateral lung, 1 heart). The mean ± SD age was 51.8 ± 14.0 years, and average body mass index was 27 ± 6.9 kg/m2. Ganciclovir trough concentrations ranged from 0.31 to 3.16 μg/mL, and 80% of participants have trough concentrations ≥0.60 μg/mL. No patients had documented neutropenia while on valganciclovir and CVVHD; 60% of patients had significant thrombocytopenia. Conclusions.  Valganciclovir 450 mg enterally every 24 hours achieved ganciclovir trough concentrations ≥0.60 μg/mL in most patients on CVVHD, similar to those reported with intravenous ganciclovir for prophylaxis in this population. Based on these data, valganciclovir may require dosing every 24 hours to achieve concentrations equivalent to ganciclovir. Neutropenia did not occur in the study period. Thrombocytopenia was common and likely multifactorial.

Clinical Predictors Impacting Cryptococcal Dissemination and Poor Outcome in Patients With Cirrhosis - Cheng, Jia-Hui; Yip, Ching-Wan; Jiang, Ying-Kui; Zhou, Ling-Hong; Que, Chun-Xing; Luo, Yu; Wang, Xuan; Zhao, Hua-Zhen; Zhu, Li-Ping (Open Forum Infectious Diseases, 2021)
BACKGROUND: Cirrhosis is an end-stage liver disease and is reported as an independent risk factor for cryptococcosis. Information about cryptococcosis in patients with cirrhosis remains sparse. METHODS: Human immunodeficiency virus-uninfected patients with cryptococcosis and cirrhosis admitted to Huashan Hospital from July 2005 to June 2020 were reviewed. Efficacy and safety of antifungal treatments, clinical outcome, and prognostic factors of mortality were evaluated. RESULTS: A total of 49 cryptococcosis patients with cirrhosis were included. Sites of infection involved central nervous system (n = 38), lung (n = 21), bloodstream (n = 11), skin (n = 1), and bone (n = 1). Nine patients (18.4%) had pulmonary cryptococcosis alone. Viral hepatitis B infection (57.1%) was the most common cause of cirrhosis. Patients with decompensated cirrhosis (Child-Pugh class B and C) were more likely to have extrapulmonary cryptococcosis than those with compensated cirrhosis (90.7% vs 64.7%; P = .049). In patients with cryptococcal meningitis (CM), 7 were treated with amphotericin B with/without flucytosine, 5 with amphotericin B plus fluconazole with/without flucytosine, and 12 with fluconazole with/without flucytosine. Fluconazole (>400 mg/day) was well tolerated and only 1 patient had a mild adverse drug reaction. At 1-year follow-up, all patients treated with fluconazole with or without flucytosine survived, whereas the mortality rate was 14.3%-20.0% in the remaining groups. In addition, Child-Pugh class C cirrhosis (hazard ratio [HR], 7.555 [95% confidence interval CI, 1.393-40.971]) and time to diagnosis >120 days (HR, 18.619 [95% CI, 2.117-163.745]) were independent factors for 1-year mortality in patients with CM. CONCLUSIONS: Severity of cirrhosis was associated with developing extrapulmonary cryptococcosis and mortality in CM. Early diagnosis and intervention of cryptococcosis are key for outcome.
Keywords: cryptococcal meningitis; cryptococcosis; extrapulmonary cryptococcosis; liver cirrhosis; pulmonary cryptococcosis

Six-month risk of Pneumocystis pneumonia following acute cellular rejection: A case-control study in solid organ transplant recipients - Hosseini-Moghaddam, Seyed M.; Shokoohi, Mostafa; Singh, Gagandeep; Nagpal, Atul D.; Jevnikar, Anthony M. (Clinical Transplantation, 2021)
BACKGROUND: Solid organ transplant (SOT) recipients are at risk of Pneumocystis pneumonia (PCP). PCP is associated with significant morbidity and mortality. The effect of acute T cell-mediated rejection (TCMR) on post-transplant PCP has not been determined yet. METHODS: In this case-control study, we estimated the risk of PCP following acute TCMR during a lookback period of 180 days. We also determined the effects of contributing factors such as CMV infection. RESULTS: We compared 15 SOT (8 kidney, 4 heart, 2 liver, and 1 kidney-pancreas) recipients with PCP with 60 matched recipients who did not develop PCP (control group) during the study period (December 2013 to February 2016). PCP occurred after a complete course of prophylaxis (ie, late-onset PCP) in 60% of patients. Patients with PCP frequently required intensive care unit (ICU) admission (73.3%). Post-transplant PCP was associated with considerable allograft loss (53.4%) and mortality (26.7%). In the 6-month lookback period, acute TCMR (OR: 13.1, 95% CI: 3.2, 53.2), and CMV infection (OR: 15.1,95% CI: 4.0, 53.2.1) were significantly associated with post-transplant PCP. CONCLUSIONS: Post-transplant PCP is associated with substantial risk of ICU admission, allograft failure, and mortality. Anti-Pneumocystis prophylaxis for at least 6 months following acute TCMR may reduce the risk.
Keywords: Case-Control Studies; Graft Rejection; Humans; Organ Transplantation; Pneumocystis carinii; Pneumocystis jirovecii; Pneumonia, Pneumocystis; Transplant Recipients; pneumocystis pneumonia; solid organ transplantation

Kidney Transplantation in HIV-positive Patients: Current Practice and Management Strategies - Muller, Elmi; Botha, Francois C. J.; Barday, Zunaid A.; Manning, Kathryn; Chin-Hong, Peter; Stock, Peter (Transplantation, 2021)
Background. HIV-positive patients had been successfully transplanted for the last 15 y and the donor pool had successfully been expanded to also include HIV-positive donors. Methods. We aimed to evaluate the effectiveness of transplantation in HIV-positive patients and highlight some of the important issues reported in the literature. We pooled clinical data from different cohorts to show some of the common issues encountered in HIV-positive transplantation. Furthermore, we searched MEDLINE via PubMed, EMBASE, Cochrane CENTRAL to create a comprehensive table for current evidence for different issues currently encountered when transplanting HIV-positive patients. Results. We included data from 19 cohort studies and reported on outcomes of the current HIV-positive transplant programs. We made recommendations based on personal experience as well as the experience reported in the literature regarding rejection, opportunistic infection, and HIV-associated nephropathy. Opportunistic infections and malignancies are not a major problem for this population group. Conclusions. HIV-positive patients encounter very specific issues after transplantation, specifically related to drug interactions and higher rejection rates. When utilizing HIV-positive donors, the recurrence of HIV-associated nephropathy in the graft kidney is an issue which can be important. Despite some issues with high rejection rates, HIV-positive patients have similar results to HIV-negative patients posttransplantation.

Comparison of post-transplant vaccination among allogeneic and autologous hematopoietic stem cell transplant patients: a single center quality analysis - Puliafito, Benjamin; Zhao, Yan; Afshar, Solmaz; Galitzeck, Zachary; Steinberg, Amir (Bone Marrow Transplantation, 2021)

Association of antiviral prophylaxis and rituximab use with posttransplant lymphoproliferative disorders (PTLDs): A nationwide cohort study - Walti, Laura N.; Mugglin, Catrina; Sidler, Daniel; Mombelli, Matteo; Manuel, Oriol; Hirsch, Hans H.; Khanna, Nina; Mueller, Nicolas; Berger, Christoph; Boggian, Katia; Garzoni, Christian; Neofytos, Dionysios; et al. (American Journal of Transplantation, 2021)
Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation (SOT). Most PTLD cases are associated with Epstein–Barr virus (EBV) infection. The role of antiviral prophylaxis or rituximab therapy for ...

Aspergillus terreus Species Complex - Lass-Flörl, Cornelia; Dietl, Anna-Maria; Kontoyiannis, Dimitrios P.; Brock, Matthias (Clinical Microbiology Reviews, 2021)
SUMMARY Infections due to Aspergillus species are an acute threat to human health; members of the Aspergillus section Fumigati are the most frequently occurring agents, but depending on the local epidemiology, representatives of section Terrei or section Flavi are the second or third most important. Aspergillus terreus species complex is of great interest, as it is usually amphotericin B resistant and displays notable differences in immune interactions in comparison to Aspergillus fumigatus. The latest epidemiological surveys show an increased incidence of A. terreus as well as an expanding clinical spectrum (chronic infections) and new groups of at-risk patients being affected. Hallmarks of these non-Aspergillus fumigatus invasive mold infections are high potential for tissue invasion, dissemination, and possible morbidity due to mycotoxin production. We seek to review the microbiology, epidemiology, and pathogenesis of A. terreus species complex, address clinical characteristics, and highlight the underlying mechanisms of amphotericin B resistance. Selected topics will contrast key elements of A. terreus with A. fumigatus. We provide a comprehensive resource for clinicians dealing with fungal infections and researchers working on A. terreus pathogenesis, aiming to bridge the emerging translational knowledge and future therapeutic challenges on this opportunistic pathogen.

Fungal Infections in Liver Transplant Recipients - Scolarici, Michael; Jorgenson, Margaret; Saddler, Christopher; Smith, Jeannina (Journal of Fungi, 2021)
Invasive fungal infections (IFIs) are one of the most feared complications associated with liver transplantation, with high rates of morbidity and mortality. We discuss the most common invasive fungal infections in the setting of liver transplant, including Candida, Aspergillus, and Cryptococcal infections, and some less frequent but devastating mold infections. Further, we evaluate the use of prophylaxis to prevent invasive fungal infection in this population as a promising mechanism to reduce risks to patients after liver transplant.

Prospective Evaluation of Galactomannan and (1→3) β-d-Glucan Assays as Diagnostic Tools for Invasive Fungal Disease in Children, Adolescents, and Young Adults With Acute Myeloid Leukemia Receiving Fungal Prophylaxis - Fisher, Brian T; Westling, Ted; Boge, Craig L K; Zaoutis, Theoklis E; Dvorak, Christopher C; Nieder, Michael; Zerr, Danielle M; Wingard, John R; Villaluna, Doojduen; Esbenshade, Adam J; Alexander, Sarah; Gunn, Suphansa; et al. (Journal of the Pediatric Infectious Diseases Society, 2021)
Patients receiving chemotherapy for acute myeloid leukemia (AML) are at high risk for invasive fungal disease (IFD). Diagnosis of IFD is challenging, leading to interest in fungal biomarkers. The objective was to define the utility of surveillance testing with Platelia Aspergillus galactomannan (GM) enzyme immunoassay (EIA) and Fungitell β-d-glucan (BDG) assay in children with AML receiving antifungal prophylaxis.Twice-weekly surveillance blood testing with GM EIA and BDG assay was performed during periods of neutropenia in the context of a randomized trial of children, adolescents, and young adults with AML allocated to fluconazole or caspofungin prophylaxis. Proven or probable IFD was adjudicated using blinded central reviewers. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for Platelia and Fungitell assays alone and in combination for the outcomes of proven and probable invasive aspergillosis (IA) or invasive candidiasis (IC).Among 471 patients enrolled, 425 participants (209 fluconazole and 216 caspofungin) contributed ≥1 blood specimen. In total, 6103 specimens were evaluated, with a median of 15 specimens per patient (range 1–43). The NPV was >99% for GM EIA and BDG assay alone and in combination. However, there were no true positive results, resulting in sensitivity and PPV for each assay of 0%.The GM EIA and the BDG assay alone or in combination were not successful at detecting IA or IC during periods of neutropenia in children, adolescents, and young adults with AML receiving antifungal prophylaxis. Utilization of these assays for surveillance in this clinical setting should be discouraged.

Ganciclovir therapeutic drug monitoring in transplant recipients - Märtson, Anne-Grete; Edwina, Angela E; Burgerhof, Johannes G M; Berger, Stefan P; de Joode, Anoek; Damman, Kevin; Verschuuren, Erik A M; Blokzijl, Hans; Bakker, Martijn; Span, Lambert F; van der Werf, Tjip S; Touw, Daan J; et al. (Journal of Antimicrobial Chemotherapy, 2021)
The use of (val)ganciclovir is complicated by toxicity, slow response to treatment and acquired resistance.To evaluate a routine therapeutic drug monitoring (TDM) programme for ganciclovir in a transplant patient population.An observational study was performed in transplant recipients from June 2018 to February 2020. Dose adjustments were advised by the TDM pharmacist as part of clinical care. For prophylaxis, a trough concentration (Cmin) of 1–2 mg/L and an AUC24h of >50 mg·h/L were aimed for. For treatment, a Cmin of 2–4 mg/L and an AUC24h of 80–120 mg·h/L were aimed for.Ninety-five solid organ and stem cell transplant patients were enrolled. Overall, 450 serum concentrations were measured; with a median of 3 (IQR = 2–6) per patient. The median Cmin and AUC24h in the treatment and prophylaxis groups were 2.0 mg/L and 90 mg·h/L and 0.9 mg/L and 67 mg·h/L, respectively. Significant intra- and inter-patient patient variability was observed. The majority of patients with an estimated glomerular filtration rate of more than 120 mL/min/1.73 m2 and patients on continuous veno-venous haemofiltration showed underexposure. The highest Cmin and AUC24h values were associated with the increase in liver function markers and decline in WBC count as compared with baseline.This study revealed that a standard weight and kidney function-based dosing regimen resulted in highly variable ganciclovir Cmin and under- and over-exposure were observed in patients on dialysis and in patients with increased renal function. Clearly there is a need to explore the impact of concentration-guided dose adjustments in a prospective study.

Fatal Brucellosis Infection in a Liver Transplant Patient: A Case Report and Review of the Literature - Piedrahita, Daniela; Martinez-Valencia, Alvaro Jose; Agudelo Rojas, Olga Lucia; Tafur, Eric; Rosso, Fernanto (Case Reports in Infectious Diseases, 2021)
Brucellosis is the most common zoonosis, particularly in developing countries. The true incidence of human brucellosis is unknown. The WHO points out that 500,000 cases of brucellosis are reported each year from around the world. In Colombia, there is currently no regular surveillance of the event in humans and its prevalence is low due a low clinical suspicion. We report a case of a 66-year-old man, an urban merchant, who had received a liver transplant 11 years ago. The patient presented to the emergency department for two months of fatigue, severe myalgia, paresis of the extremities, loss of muscle strength, and progressive deterioration of functional class. In the emergency room, he became disoriented and was transferred to the intensive-care unit. He had a white blood cell count of 18990/uL and creatine phosphokinase 10302 U/L. Routine blood cultures were positive for Brucella melitensis. The patient reported consumption of unpasteurized bovine milk. He was treated with doxycycline and ciprofloxacin. Despite antibiotic management, after one month of hospitalization and in the context of septic shock with multiorgan failure, the patient died. Brucellosis is an unsuspected and underdiagnosed disease. It can occur in people with or without risk factors. Although the mortality is low, immunocompromised patients can develop fatal infections. A presumptive diagnosis can be established through the correlation of patient history and classic laboratory findings, which include transaminitis, anemia, and leukopenia with relative lymphocytosis; however, other findings can help us to guide the diagnosis, such as rhabdomyolysis, which appears as a complication in different infections; however, it had not been described before in brucellosis. A partnership between clinical suspicion laboratory diagnostic tests and improved disease surveillance systems is necessary to fight the disease.

The Evolving Challenge of Infections in Cirrhosis - Bajaj, Jasmohan S.; Kamath, Patrick S.; Reddy, K. Rajender (New England Journal of Medicine, 2021)

The safety and efficacy of Bacillus Calmette‐Guerin intravesical therapy in kidney transplant recipients with superficial bladder cancer - Alkassis, Marwan; Abi Tayeh, Georges; Khalil, Nour; Mansour, Raymond; Lilly, Eddy; Sarkis, Julien; Moukarzel, Maroun (Clinical Transplantation, 2021)

Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis - Goldsmith, Scott R.; Abid, Muhammad Bilal; Auletta, Jeffery J.; Bashey, Asad; Beitinjaneh, Amer; Castillo, Paul; Chemaly, Roy F.; Chen, Min; Ciurea, Stefan; Dandoy, Christopher E.; Díaz, Miguel Ángel; Fuchs, Ephraim; et al. (Blood, 2021)
Prior studies suggest increased cytomegalovirus (CMV) infection after haploidentical donor transplantation with posttransplant cyclophosphamide (HaploCy). The role of allograft source and posttransplant cyclophosphamide (PTCy) in CMV infection is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection, and effects of serostatus and CMV infection on transplant outcomes. We examined patients reported to the Center for International Blood and Marrow Transplantation Research between 2012 and 2017 who had received HaploCy (n = 757), matched related (Sib) with PTCy (SibCy, n = 403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n = 1605). Cumulative incidences of CMV infection by day 180 were 42%, 37%, and 23%, respectively (P < .001). CMV disease was statistically comparable. CMV infection risk was highest for CMV-seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor (HaploCy [n = 545]: hazard ratio [HR], 50.3; SibCy [n = 279]: HR, 47.7; SibCNI [n = 1065]: HR, 24.4; P < .001). D+/R− patients also had increased risk for CMV infection. Among R+ or those developing CMV infection, HaploCy had worse overall survival and nonrelapse mortality. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic graft-versus-host disease (GVHD) overall, but CMV infection in PTCy recipients was associated with higher chronic GVHD (P = .006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally, CMV infection may negate the chronic GVHD protection of PTCy. This study supports aggressive prevention strategies in all receiving PTCy.

Risk factors for post‐transplant Epstein‐Barr virus events in pediatric recipients of hematopoietic stem cell transplants - Enok Bonong, Pascal R.; Buteau, Chantal; Duval, Michel; Lacroix, Jacques; Laporte, Louise; Tucci, Marisa; Robitaille, Nancy; Spinella, Philip C.; Cuvelier, Geoffrey D. E.; Lewis, Victor; Vercauteren, Suzanne; Alfieri, Caroline; et al. (Pediatric Transplantation, 2021)
Background: Epstein-Barr virus (EBV) can cause severe disease following hematopoietic stem cell transplant (HSCT), including post-transplant lymphoproliferative disorder (PTLD). The objective was to analyze risk factors associated with post-transplant EBV outcomes among pediatric allogeneic HSCT recipients.

Valganciclovir Prophylaxis Extension from 3 to 6 Months in High Risk Pancreas Transplant Recipients Does Not Impact Incidence of Cytomegalovirus Infection at 12 months - Jorgenson, Margaret R; Marka, Nicholas; Leverson, Glen E; Smith, Jeannina A; Odorico, Jon S (Clinical Transplantation, 2021)
Problem: Incidence and impact of CMV infection in pancreas-transplant recipients (PTRs) in the valganciclovir prophylaxis era has not be completely elucidated.

Association between Mycoplasma and Ureaplasma airway positivity, ammonia levels, and outcomes post–lung transplantation: A prospective surveillance study - Buzo, Bruno F.; Preiksaitis, Jutta K.; Halloran, Kieran; Nagendran, Jayan; Townsend, Derek R.; Zelyas, Nathan; Sligl, Wendy I. (American Journal of Transplantation, 2021)
Keywords: CSA-IRD; Canadian Standards Association increased-risk donor; HS; IQR; NAAT; NML; National Microbiology Laboratory; OPO; PCR; SDs; SOFA; Sequential Organ Failure Assessment; clinical research/practice; donors and donation: donor-derived infections; hyperammonemia syndrome; infection and infectious agents; infection and infectious agents – bacterial; infectious disease; lung disease: infectious; lung transplantation/pulmonology; medians and interquartile ranges; nucleic acid amplification testing; organ procurement and allocation; organ procurement organization; polymerase chain reaction; standard deviations

Predictors of CMV Infection in CMV-Seropositive Kidney Transplant Recipients: Impact of Pretransplant CMV-Specific Humoral Immunity - Kirisri, Similan; Vongsakulyanon, Apirom; Kantachuvesiri, Surasak; Razonable, Raymund R; Bruminhent, Jackrapong (Open Forum Infectious Diseases, 2021)
Background.  Although cytomegalovirus (CMV)-seropositive solid organ transplant recipients have a relatively lower risk of CMV infection than CMV-seronegative recipients who receive allograft from CMV-seropositive donors, some patients remain at risk of CMV infection after transplant. We investigated the pretransplant CMV-specific humoral immunity (CHI) and other CMV infection predictors in CMV-seropositive kidney transplant (KT) recipients. Methods.  This retrospective study was conducted on adult CMV-seropositive KT recipients during 2017 and 2018. The cumulative incidence of CMV infection was estimated using the Kaplan-Meier method. CHI, measured with an enzyme-linked fluorescent immunoassay and other predictors for CMV infection, was analyzed using Cox proportional hazards models. Results.  Of the 340 CMV-seropositive KT recipients (37% female; mean ± SD age, 43 ± 11 years), 69% received deceased-donor allograft and 64% received induction therapy. During a mean follow-up of 14 months, the cumulative incidence of CMV infection was 14.8%. In multivariate analysis, low pretransplant CHI (defined as anti-CMV immunoglobulin [IgG] titer <20 AU/mL) was significantly associated with CMV infection (hazard ratio [HR], 2.98; 95% CI, 1.31–6.77; P = .009). Other significant predictors of CMV infection included older donor age (HR, 1.03; 95% CI, 1.01–1.06; P = .005), antithymocyte induction therapy (HR, 2.90; 95% CI, 1.09–7.74; P = .033), and prolonged cold ischemic time (HR, 1.06; 95% CI, 1.02–1.10; P = .002). Conclusions.  A low pretransplant CHI is independently associated with post-transplant CMV infection in CMV-seropositive KT recipients. A quantitative anti-CMV IgG assay could potentially stratify CMV-seropositive patients at risk of CMV infection after KT.

Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance - Koehler, Philipp; Bassetti, Matteo; Chakrabarti, Arunaloke; Chen, Sharon C. A.; Colombo, Arnaldo Lopes; Hoenigl, Martin; Klimko, Nikolay; Lass-Flörl, Cornelia; Oladele, Rita O.; Vinh, Donald C.; Zhu, Li-Ping; Böll, Boris; et al. (The Lancet Infectious Diseases, 2021)

Norovirus in Cancer Patients: A Review - Kondapi, Divya Samantha; Ramani, Sasirekha; Estes, Mary K; Atmar, Robert L; Okhuysen, Pablo C (Open Forum Infectious Diseases, 2021)
Abstract Norovirus (NoV) is the leading cause of viral-related diarrhea in cancer patients, in whom it can be chronic, contributing to decreased quality of life, interruption of cancer care, malnutrition, and altered mucosal barrier function. Immunosuppressed cancer patients shed NoV for longer periods of time than immunocompetent hosts, favoring quasispecies development and emergence of novel NoV variants. While nucleic acid amplification tests (NAATs) for NoV diagnosis have revolutionized our understanding of NoV burden of disease, not all NAATs provide information on viral load or infecting genotype. There is currently no effective antiviral or vaccine for chronic NoV infections. Screening for inhibitors of NoV replication in intestinal organoid culture models and creation of NoV-specific adoptive T cells are promising new strategies to develop treatments for chronic NoV in immunosuppressed patients. Herein we summarize data on the epidemiology, clinical manifestations, diagnostic challenges, and treatment of NoV infection in patients with cancer.

Impact of Susceptibility to Injectable Antibiotics on the Treatment Outcomes of Mycobacterium abscessus Pulmonary Disease - Park, Youngmok; Park, Yea Eun; Jhun, Byung Woo; Park, Jimyung; Kwak, Nakwon; Jo, Kyung-Wook; Yim, Jae-Joon; Shim, Tae Sun; Kang, Young Ae (Open Forum Infectious Diseases, 2021)
Background.  Current guidelines recommend a susceptibility-based regimen for Mycobacterium abscessus subspecies abscessus pulmonary disease (MAB-PD), but the evidence is weak. We aimed to investigate the association between treatment outcomes and in vitro drug susceptibility to injectable antibiotics in MAB-PD patients. Methods.  We enrolled MAB-PD patients treated with intravenous amikacin and beta-lactams for ≥4 weeks at 4 referral hospitals in Seoul, South Korea. Culture conversion and microbiological cure at 1 year were evaluated based on susceptibility to injectable antibiotics among patients treated with those antibiotics for ≥2 weeks. Results.  A total of 82 patients were analyzed. The mean age was 58.7 years, and 65.9% were women. Sputum culture conversion and microbiological cure were achieved in 52.4% and 41.5% of patients, respectively. Amikacin was the most common agent to which the M. abscessus subspecies abscessus isolates were susceptible (81.7%); 9.8% and 24.0% of the isolates were resistant to cefoxitin and imipenem, respectively. The clarithromycin-inducible resistance (IR) group (n = 65) had a lower microbiological cure rate than the clarithromycin-susceptible group (35.4% vs 64.7%). The treatment outcomes appeared to be similar regardless of in vitro susceptibility results with regard to intravenous amikacin, cefoxitin, imipenem, and moxifloxacin. In the subgroup analysis of the clarithromycin-IR group, the treatment outcomes did not differ according to antibiotic susceptibility. Conclusions.  We did not find evidence supporting the use of susceptibility-based treatment with intravenous amikacin and beta-lactams in patients with MAB-PD. Further research is required.

Emerging Fungal Infections - Spallone, Amy; Schwartz, Ilan S. (Infectious Disease Clinics of North America, 2021)
The quest for new antifungal and antitubercular drugs is a need of the hour because of morbid co-pathogenesis and an increase in immunocompromised patients. One of the ways forward is to explore and repurpose the established pharmacophores for the desired application. Oxazolidinones are well-known antibacterial agents, with few investigations reported to exploit their antifungal properties. Herein, we report the design and synthesis of a series of linezolid-based oxazolidinones as potent anticandidiasis and antitubercular agents. Studies revealed that two of the novel oxazolidinones 2 and 3a exhibited excellent anticandidiasis activity against different Candida fungus strains, superior to standard drugs. Mechanistic and docking studies revealed that oxazolidinones were better inhibitors of the ergosterol biosynthesis pathway than the controls used. In addition, the oxazolidinones 2 and 3a also exhibited prominent inhibitory activity against M. tuberculosis H37Rv with MIC values of 1 and 2 μg/ml, respectively. Computational studies demonstrated the binding of the compounds to the transcriptional regulatory repressor protein, which was reinforced by the molecular dynamics simulations. The pharmacophore modeling experiments validated the molecular docking results in both the target proteins. Histoplasma, a genus of dimorphic fungi, is the etiological agent of histoplasmosis, a pulmonary disease widespread across the globe. Whole genome sequencing has revealed that the genus harbors a previously unrecognized diversity of cryptic species. To date, studies have focused on Histoplasma isolates collected in the Americas with little knowledge of the genomic variation from other localities. In this report, we report the existence of a well-differentiated lineage of Histoplasma occurring in the Indian subcontinent. The group is differentiated enough to satisfy the requirements of a phylogenetic species, as it shows extensive genetic differentiation along the whole genome and has little evidence of gene exchange with other Histoplasma species. Next, we leverage this genetic differentiation to identify genetic changes that are unique to this group and that have putatively evolved through rapid positive selection. We found that none of the previously known virulence factors have evolved rapidly in the Indian lineage but find evidence of strong signatures of selection on other alleles potentially involved in clinically-important phenotypes. Our work serves as an example of the importance of correctly identifying species boundaries to understand the extent of selection in the evolution of pathogenic lineages. Whole genome sequencing has revolutionized our understanding of microbial diversity, including human pathogens. In the case of fungal pathogens, a limiting factor in understanding the extent of their genetic diversity has been the lack of systematic sampling. In this piece, we show the results of a collection in the Indian subcontinent of the pathogenic fungus Histoplasma, the causal agent of a systemic mycosis. We find that Indian samples of Histoplasma form a distinct clade which is highly differentiated from other Histoplasma species. We also show that the genome of this lineage shows unique signals of natural selection. This work exemplifies how the combination of a robust sampling along with population genetics, and phylogenetics can reveal the precise genetic changes that differentiate lineages of fungal pathogens.
Keywords: Emerging fungal pathogens; Emerging fungi; Emerging infectious diseases; Endemic fungi; Opportunistic infections

Fungal Infection in Lung Transplantation - Kennedy, Cassie C.; Pennington, Kelly M.; Beam, Elena; Razonable, Raymund R. (Seminars in Respiratory and Critical Care Medicine, 2021)
Invasive fungal infections threaten lung transplant outcomes with high associated morbidity and mortality. Pharmacologic prophylaxis may be key to prevent posttransplant invasive fungal infections, but cost, adverse effects, and absorption issues are barriers to effective prophylaxis. Trends in fungal infection diagnostic strategies utilize molecular diagnostic methodologies to complement traditional histopathology and culture techniques. While lung transplant recipients are susceptible to a variety of fungal pathogens, Candida spp. and Aspergillus spp. infections remain the most common. With emerging resistant organisms and multiple novel antifungal agents in the research pipeline, it is likely that treatment strategies will continue to evolve.

Cytomegalovirus retinitis after allogeneic hematopoietic stem cell transplantation under cytomegalovirus antigenemia-guided active screening - Mori, Takehiko; Kikuchi, Taku; Koh, Miki; Koda, Yuya; Yamazaki, Rie; Sakurai, Masatoshi; Tomita, Yohei; Ozawa, Yoko; Kohashi, Sumiko; Abe, Ryohei; Saburi, Masuho; Kato, Jun (Bone Marrow Transplantation, 2021)
Although cytomegalovirus (CMV) remains a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), the incidence of CMV retinitis is considered to be lower than the incidence of CMV infection in other organs following allogeneic HSCT. In this study, the incidence and characteristics of CMV retinitis were retrospectively evaluated in recipients of allogeneic HSCT. Ophthalmological screening was performed at the development of ocular symptoms or positive CMV infection using peripheral blood evaluated by pp65 antigenemia or polymerase chain reaction. Of the 514 patients, 13 patients developed CMV retinitis. The median onset of CMV retinitis was day 34 (range, 21–118) post transplant, and the cumulative incidence was 2.5% (95% CI, 1.6–4.2) at 6 months after transplantation. Five patients presented ocular symptoms at the onset. In the remaining eight asymptomatic patients, the diagnosis of CMV retinitis was made by the screening guided by positive CMV infection. All evaluable patients responded to antiviral treatment but three showed incomplete improvement with ocular sequela. Our results suggest that the incidence of CMV retinitis after allogeneic HSCT is not negligible and active ophthalmological screening based not only on symptoms but also positive CMV infection monitoring contributes to the early diagnosis of CMV retinitis.

Increasing Multiorgan Heart Transplantation With Hepatitis C Virus Donors In The Current-era - Madan, Shivank; Patel, Snehal R.; Vlismas, Peter; Hemmige, Vagish; Saeed, Omar; Goldstein, Daniel J.; Jorde, Ulrich P. (The Journal of Heart and Lung Transplantation, 2021)
Abstarct The trends and outcomes of multiorgan heart-transplantation(HT) using hepatitis C virus(HCV) donors in the contemporary era are sparsely known. Using UNOS registry, 1322 adult multiorgan-HTs(n=986 heart-kidney, n=155 heart-lung, n=181 heart-liver) between August-2015 and August-2020 were identified, of which 109 were performed using HCV-donors[n=77 HCV nucleic-acid-amplification testing(NAT) positive irrespective of antibody(Ab) status(HCV-viremic); and n=32 HCV Ab+/NAT-(HCV Ab+ nonviremic)]. The percentage of HCV-donors used for multiorgan-HT increased from 0% in 2015 to 14% in 2020(p<0.001), but there was wide variation across UNOS regions and center volumes. Recipients of multiorgan heart-kidney transplants from HCV-donors(n=90) and HCV-naïve(HCV Ab-/NAT-) donors(n=896) had similar 1-year survival using unadjusted and adjusted Cox-proportional hazards-regression models including in propensity-score matched cohorts. Post-HT rates of cardiac-allograft-vasculopathy(5.4%vs.5.8%) and chronic-dialysis(7.3%vs.4.9%) at 1-year were also similar. Use of HCV-donors(HCV-viremic, HCV Ab+ nonviremic) for multiorgan-HT has increased significantly. Encouraging 1-year outcomes in heart-kidney recipients from HCV-donors should support further expansion of heart-kidney transplantation using HCV-donors.

Post-allogeneic hematopoietic stem cell transplantation viral reactivations and viremias: a focused review on human herpesvirus-6, BK virus and adenovirus - Wang, Xin; Patel, Shyam A.; Haddadin, Michael; Cerny, Jan (Therapeutic Advances in Infectious Disease, 2021)
Human cytomegalovirus and Epstein–Barr virus have been recognized as potential drivers of morbidity and mortality of patients undergoing allogeneic stem cell transplantation for years. Specific protocols for monitoring, prophylaxis and pre-emptive therapy are in place in many transplant settings. In this review, we focus on the next three most frequent viruses, human herpesvirus-6, BK virus and adenovirus, causing reactivation and/or viremia after allogeneic transplant, which are increasingly detected in patients in the post-transplant period owing to emerging techniques of molecular biology, recipients’ characteristics, treatment modalities used for conditioning and factors related donors or stem cell source. Given the less frequent detection of an illness related to these viruses, there are often no specific protocols in place for the management of affected patients. While some patients develop significant morbidity (generally older), others may not need therapy at all (generally younger or children). Furthermore, some of the antiviral therapies used are potentially toxic. With the addition of increased risk of secondary infections, risk of graft failure or increased risk of graft-versus-host disease as well as the relationship with other post-transplant complications, the outcomes of patients with these viremias remain unsatisfactory and even long-term survivors experience increased morbidity.

Genetic and Epidemiologic Analyses of an Outbreak of Pneumocystis jirovecii Pneumonia Among Kidney Transplant Recipients in the United States - Azar, Marwan M; Cohen, Elizabeth; Ma, Liang; Cissé, Ousmane H; Gan, Geliang; Deng, Yanhong; Belfield, Kristen; Asch, William; Grant, Matthew; Gleeson, Shana; Koff, Alan; Gaston, David C; et al. (Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 2021)
In a Pneumocystis jiroveci pneumonia (PCP) outbreak among 19 kidney-transplant recipients in the United States, strain genotyping suggested coinfection and interhuman transmission of multiple P. jiroveci strains. Belatacept was a risk factor for PCP, potentially via increased clinic exposure.

Antibiotic Utilization in Deceased Organ Donors - Anesi, Judith A; Lautenbach, Ebbing; Han, Jennifer; Lee, Dong Heun; Clauss, Heather; Climaco, Antonette; Hasz, Richard; Bilker, Warren B; Molnar, Esther; Alimenti, Darcy; West, Sharon; Tolomeo, Pam; et al. (Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 2021)
Antibiotic use in deceased organ donors has not been previously described. In a retrospective cohort of 440 donors, we found 427 (97%) received at least one antibiotic course, 312 (71%) received broad-spectrum antibiotics, and 61 (14%) received potentially redundant antibiotics during their terminal hospitalization, suggesting a need for stewardship.

Seasonal Human Coronavirus Respiratory Tract Infection in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation - Piñana, Jose Luis; Xhaard, Aliénor; Tridello, Gloria; Passweg, Jakob; Kozijn, Anne; Polverelli, Nicola; Heras, Inmaculada; Perez, Ariadna; Sanz, Jaime; Berghuis, Dagmar; Vázquez, Lourdes; Suárez-Lledó, María; et al. (The Journal of Infectious Diseases, 2021)
Background.  Little is known about characteristics of seasonal human coronaviruses (HCoVs) (NL63, 229E, OC43, and HKU1) after allogeneic stem cell transplantation (allo-HSCT). Methods.  This was a collaborative Spanish and European bone marrow transplantation retrospective multicenter study, which included allo-HSCT recipients (adults and children) with upper respiratory tract disease (URTD) and/or lower respiratory tract disease (LRTD) caused by seasonal HCoV diagnosed through multiplex polymerase chain reaction assays from January 2012 to January 2019. Results.  We included 402 allo-HSCT recipients who developed 449 HCoV URTD/LRTD episodes. Median age of recipients was 46 years (range, 0.3–73.8 years). HCoV episodes were diagnosed at a median of 222 days after transplantation. The most common HCoV subtype was OC43 (n = 170 [38%]). LRTD involvement occurred in 121 episodes (27%). HCoV infection frequently required hospitalization (18%), oxygen administration (13%), and intensive care unit (ICU) admission (3%). Three-month overall mortality after HCoV detection was 7% in the whole cohort and 16% in those with LRTD. We identified 3 conditions associated with higher mortality in recipients with LRTD: absolute lymphocyte count <0.1 × 109/mL, corticosteroid use, and ICU admission (hazard ratios: 10.8, 4.68, and 8.22, respectively; P < .01). Conclusions.  Seasonal HCoV after allo-HSCT may involve LRTD in many instances, leading to a significant morbidity.

Hyperammonemia syndrome associated with Ureaplasma spp. Infections in immunocompromised patients and transplant recipients: A systematic review and meta‐analysis - Tantengco, Ourlad Alzeus G.; De Jesus, Federico Cristobal C.; Gampoy, Eloina Faye S.; Ornos, Eric David B.; Vidal, Manuel S.; Abad, Cybele Lara R. (Clinical Transplantation, 2021)
Background: Hyperammonemia syndrome (HS) is reported to occur in patients with Ureaplasma spp. infections. We performed a systematic review and meta-analysis of studies reporting HS in patients with Ureaplasma spp. infection. Methods: We searched several databases (CINAHL, OVID, ProQuest, and Scopus) from inception to January 2021. We described case reports and series, and performed a meta-analysis for all cohort studies. The pooled risk ratio (RR) for the association between HS and Ureaplasma spp. infections was derived using a random-effects model. Results: The systematic review yielded 18 studies. HS was reported in 53 patients with Ureaplasma spp. infections. The most common clinical manifestations were neurologic. Meta-analysis showed a higher incidence of HS (41.67%) and peak ammonia concentration among Ureaplasma spp.–infected lung transplant recipients compared with Ureaplasma spp.–negative recipients (2.84%). The risk of HS was significantly increased in Ureaplasma spp.–infected recipients compared with Ureaplasma spp.– negative recipients (RR: 14.64; CI: 2.85–75.24). Mortality from Ureaplasma-associated HS was 27.27% compared with 5.24% in those with HS from other causes. Conclusions: The risk of developing HS is higher among Ureaplasma-infected patients compared with uninfected patients. Lung transplant recipients appear to be disproportionally affected, and HS should be suspected in those who present with neurologic symptoms.

Impact of the inclusion of an aminoglycoside to the initial empirical antibiotic therapy for Gram-negative bloodstream infections in hematological neutropenic patients: a propensity-matched cohort study (AMINOLACTAM study) - Albasanz-Puig, A.; Gudiol, C.; Puerta-Alcalde, P.; Ayaz, C. M.; Machado, M.; Herrera, F.; Martín-Dávila, P.; Laporte-Amargós, J.; Cardozo, C.; Akova, M.; Álvarez-Uría, A.; Torres, D.; et al. (Antimicrobial Agents and Chemotherapy, 2021)
Objective: To test the hypothesis that the addition of an aminoglycoside to a ß-lactam antibiotic could provide better outcomes than ß-lactam monotherapy for the initial empirical treatment of hematological neutropenic patients with subsequently documented Gram-negative bacilli (GNB) bloodstream infection (BSI). Methods: Multinational, retrospective, cohort study of GNB BSI episodes in hematological neutropenic patients in six centers (2010–2017). Combination therapy (ß-lactam plus aminoglycoside) was compared to ß-lactam monotherapy. The primary endpoint was the case-fatality rate assessed at 7 and 30-days from BSI onset. Secondary endpoints were nephrotoxicity and persistent BSI. Propensity score (PS) matching was performed. Results: Among 542 GNB BSI episodes, 304 (56%) were initially treated with combination therapy, with cefepime plus amikacin being most common (158/304, 52%). Overall, Escherichia coli (273/304, 50.4%) was the main etiological agent, followed by Pseudomonas aeruginosa, which predominated in the combination group [76/304 (25%) vs. 28/238 (11.8%); p<0.001]. Multidrug resistance rates were similar between groups [83/294 (28.2%) vs. 63/233 (27%); p=0.95]. In the multivariate analysis combination therapy was associated with lower 7-day case-fatality rate (OR 0.37, 95%CI 0.14-0.91;p=0.035) with a tendency towards lower mortality at 30 days (OR 0.56, 95%CI 0.29–1.08;p=0.084). After PS-matching, these differences remained for the 7-day case-fatality rate (OR 0.33, 95%CI 0.13–0.82;p=0.017). In addition, aminoglycoside use was not significantly associated with renal function impairment (OR 1.12, 95%CI 0.26–4.87;p=0.9). Conclusions: The addition of an aminoglycoside to the initial empirical therapy regimen for febrile neutropenic hematological patients should be considered.

Molecular Epidemiology, Natural History, and Long-Term Outcomes of Multidrug-Resistant Enterobacterales Colonization and Infections Among Solid Organ Transplant Recipients - Hong Nguyen, M; Shields, Ryan K; Chen, Liang; William Pasculle, A; Hao, Binghua; Cheng, Shaoji; Sun, Jonathan; Kline, Ellen G; Kreiswirth, Barry N; Clancy, Cornelius J (Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 2021)
Twenty-five percent of transplant recipients were gastrointestinally colonized by multidrug-resistant Enterobacterales, which predisposed to invasive infections. Infections were associated with low short-term and long-term mortality, but recurrences were common for years. Whole-genome phylogenetic analyses linked infections to colonizing strains.

Deceased-Donor Acute Kidney Injury and BK Polyomavirus in Kidney Transplant Recipients - Hall, Isaac E.; Reese, Peter Philip; Mansour, Sherry G.; Mohan, Sumit; Jia, Yaqi; Thiessen-Philbrook, Heather R.; Brennan, Daniel C.; Doshi, Mona D.; Muthukumar, Thangamani; Akalin, Enver; Harhay, Meera Nair; Schröppel, Bernd; et al. (Clinical Journal of the American Society of Nephrology, 2021)
Visual Abstract Download figureOpen in new tabDownload powerpoint Background and objectives BK polyomavirus (BKV) infection commonly complicates kidney transplantation, contributing to morbidity and allograft failure. The virus is often donor-derived and influenced by ischemia-reperfusion processes and disruption of structural allograft integrity. We hypothesized that deceased-donor AKI associates with BKV infection in recipients. Design, setting, participants, & measurements We studied 1025 kidney recipients from 801 deceased donors transplanted between 2010 and 2013, at 13 academic centers. We fitted Cox proportional-hazards models for BKV DNAemia (detectable in recipient blood by clinical PCR testing) within 1 year post-transplantation, adjusting for donor AKI and other donor- and recipient-related factors. We validated findings from this prospective cohort with analyses for graft failure attributed to BKV within the Organ Procurement and Transplantation Network (OPTN) database. Results The multicenter cohort mean kidney donor profile index was 49±27%, and 26% of donors had AKI. Mean recipient age was 54±13 years, and 25% developed BKV DNAemia. Donor AKI was associated with lower risk for BKV DNAemia (adjusted hazard ratio, 0.53; 95% confidence interval, 0.36 to 0.79). In the OPTN database, 22,537 (25%) patients received donor AKI kidneys, and 272 (0.3%) developed graft failure from BKV. The adjusted hazard ratio for the outcome with donor AKI was 0.7 (95% confidence interval, 0.52 to 0.95). Conclusions In a well-characterized, multicenter cohort, contrary to our hypothesis, deceased-donor AKI independently associated with lower risk for BKV DNAemia. Within the OPTN database, donor AKI was also associated with lower risk for graft failure attributed to BKV. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_03_10_CJN18101120_final.mp3
Keywords: acute kidney injury; kidney transplantation; transplant outcomes

Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis - Dorman, Susan E.; Nahid, Payam; Kurbatova, Ekaterina V.; Phillips, Patrick P.J.; Bryant, Kia; Dooley, Kelly E.; Engle, Melissa; Goldberg, Stefan V.; Phan, Ha T.T.; Hakim, James; Johnson, John L.; Lourens, Madeleine; et al. (New England Journal of Medicine, 2021)

Epidemiology of laboratory-confirmed influenza among kidney transplant recipients compared to the general population—A nationwide cohort study - Helanterä, Ilkka; Gissler, Mika; Rimhanen-Finne, Ruska; Ikonen, Niina; Kanerva, Mari; Lempinen, Marko; Finne, Patrik (American Journal of Transplantation, 2021)
Keywords: ICU; SIR; clinical research/practice; epidemiology; infectious disease; intensive care unit; kidney disease: infectious; kidney transplantation/nephrology; standardized incidence ratio

Prospective Evaluation of the Turbidimetric β-D-Glucan Assay and 2 Lateral Flow Assays on Serum in Invasive Aspergillosis - Mercier, Toine; Guldentops, Ellen; Lagrou, Katrien; Maertens, Johan (Clinical Infectious Diseases, 2021)
Invasive aspergillosis (IA) remains a potentially lethal disease and requires timely diagnosis and initiation of antifungal therapy. Recently, the IMMY lateral flow assay (LFA), the OLM Diagnostics lateral flow device (LFD), and the Wako turbidimetric β-d-glucan assay have been approved for use as a diagnostic aid. However, their performance in diagnosing IA on serum samples from at-risk patients and the added value to the existing detection of serum galactomannan remain to be investigated.We prospectively collected serum samples from 239 hematology patients and evaluated the diagnostic performance of these 3 assays while using the 2019 EORTC/MSG definitions (study number S59863/S61797, NCT03004092).We identified 5 cases of proven IA, 36 cases of probable IA, and 188 controls. The LFA had the highest negative predictive value (NPV) and sensitivity (0.90 and 0.49, respectively) while galactomannan detection had the highest positive predictive value and specificity (0.93 and 0.99, respectively). Sensitivity was not significantly different between both tests. When used in combination, the highest NPV was seen in patients with a negative LFA and a negative β-d-glucan test. The sensitivity of the LFD was significantly lower than the LFA. After omitting serum galactomannan from the definitions to control for incorporation bias, the sensitivity of the LFA outperformed galactomannan detection (0.41 vs 0.31, P = .046).The LFA is a fast and effective alternative to serum galactomannan detection for the diagnosis of IA and is especially useful for centers with low sample throughputs. The addition of the Wako β-D-glucan assay further improves the diagnostic performance.

Burden, epidemiology, and outcomes of microbiologically confirmed respiratory viral infections in solid organ transplant recipients: a nationwide, multi-season prospective cohort study - Mombelli, Matteo; Lang, Brian M.; Neofytos, Dionysios; Aubert, John-David; Benden, Christian; Berger, Christoph; Boggian, Katia; Egli, Adrian; Soccal, Paola M.; Kaiser, Laurent; Hirzel, Cédric; Pascual, Manuel; et al. (American Journal of Transplantation, 2021)
Solid organ transplant (SOT) recipients are exposed to respiratory viral infection (RVI) during seasonal epidemics; however, the associated burden of disease has not been fully characterized. We describe the epidemiology and outcomes of RVI in a cohort enrolling 3294 consecutive patients undergoing SOT from May 2008 to December 2015 in Switzerland. Patient and allograft outcomes, and RVI diagnosed during routine clinical practice were prospectively collected. Median follow-up was 3.4 years (interquartile range 1.61–5.56). Six hundred ninety-six RVIs were diagnosed in 151/334 (45%) lung and 265/2960 (9%) non-lung transplant recipients. Cumulative incidence was 60% (95% confidence interval [CI] 53%-69%) in lung and 12% (95% CI 11%-14%) in non-lung transplant recipients. RVI led to 17.9 (95% CI 15.7–20.5) hospital admissions per 1000 patient-years. Intensive care unit admission was required in 4% (27/691) of cases. Thirty-day all-cause case fatality rate was 0.9% (6/696). Using proportional hazard models we found that RVI (adjusted hazard ratio [aHR] 2.45; 95% CI 1.62–3.73), lower respiratory tract RVI (aHR 3.45; 95% CI 2.15–5.52), and influenza (aHR 3.57; 95% CI 1.75–7.26) were associated with graft failure or death. In this cohort of SOT recipients, RVI caused important morbidity and may affect long-term outcomes, underlying the need for improved preventive strategies.
Keywords: CI; CLAD; CMV; D; HAdV; HBoV; HCoV; HMPV; HPIV; HR; ICU; IQR; LRTI; OR; R; RSV; RVI; Respiratory syncytial virus; Respiratory viral infection; SOT; STCS; Swiss Transplant Cohort Study; URTI; chronic lung allograft dysfunction; clinical research / practice; complication: infectious; confidence interval; cytomegalovirus; donor; epidemiology; hazard ratio; human adenovirus; human bocavirus; human coronavirus; human metapneumovirus; human parainfluenza virus; infection and infectious agents - viral; infection and infectious agents - viral: influenza; infectious disease; intensive care unit; interquartile range; lower respiratory tract infection; mTOR; mammalian target of rapamycin; odds ratio; recipient; solid organ transplant; upper respiratory tract infection

Cellular Therapy During COVID-19: Lessons Learned and Preparing for Subsequent Waves - Nawas, Mariam T.; Shah, Gunjan L.; Feldman, Darren R.; Ruiz, Josel D.; Robilotti, Elizabeth V.; Aslam, Anoshe A.; Dundas, Mary; Kamboj, Mini; Barker, Juliet N.; Cho, Christina; Chung, David J.; Dahi, Parastoo B.; et al. (Transplantation and Cellular Therapy, 2021)
An evidence-based triage plan for cellular therapy distribution is critical in the face of emerging constraints on healthcare resources. We evaluated the impact of treatment delays related to COVID-19 on patients scheduled to undergo hematopoietic cell transplantation (HCT) or chimeric antigen receptor T-cell (CAR-T) therapy at our center. Data were collected in real time between March 19 and May 11, 2020, for patients who were delayed to cellular therapy. We evaluated the proportion of delayed patients who ultimately received cellular therapy, reasons for not proceeding to cellular therapy, and changes in disease and health status during delay. A total of 85 patients were delayed, including 42 patients planned for autologous HCT, 36 patients planned for allogeneic HCT, and 7 patients planned for CAR-T therapy. Fifty-six of these patients (66%) since received planned therapy. Five patients died during the delay. The most common reason for not proceeding to autologous HCT was good disease control in patients with plasma cell dyscrasias (75%). The most common reason for not proceeding to allogeneic HCT was progression of disease (42%). All patients with acute leukemia who progressed had measurable residual disease (MRD) at the time of delay, whereas no patient without MRD at the time of delay progressed. Six patients (86%) ultimately received CAR-T therapy, including 3 patients who progressed during the delay. For patients with high-risk disease such as acute leukemia, and particularly those with MRD at the time of planned HCT, treatment delay can result in devastating outcomes and should be avoided if at all possible.
Keywords: COVID-19; Cellular therapy; Chimeric antigen receptor T cell therapy; Hematopoietic cell transplantation

Influenza Virus Infection and Transplantation - Marinelli, Tina M.; Kumar, Deepali (Transplantation, 2021)
Influenza infection poses significant risk for solid organ transplant recipients who often experience more severe infection with increased rates of complications, including those relating to the allograft. Although symptoms of influenza experienced by transplant recipients are similar to that of the general population, fever is not a ubiquitous symptom and lymphopenia is common. Annual inactivated influenza vaccine is recommended for all transplant recipients. Newer strategies such as using a higher dose vaccine or multiple doses in the same season appear to provide greater immunogenicity. Neuraminidase inhibitors are the mainstay of treatment and chemoprophylaxis although resistance may occur in the transplant setting. Influenza therapeutics are advancing, including the recent licensure of baloxavir; however, many remain to be evaluated in transplant recipients and are not yet in routine clinical use. Further population-based studies spanning multiple influenza seasons are needed to enhance our understanding of influenza epidemiology in solid organ transplant recipients. Specific assessment of newer influenza therapeutics in transplant recipients and refinement of prevention strategies are vital to reducing morbidity and mortality.

Cryptococcus transmission through solid organ transplantation in the United States: A Report from the Ad Hoc Disease Transmission Advisory Committee - Penumarthi, Lasya R.; La Hoz, Ricardo M.; Wolfe, Cameron R.; Jackson, Brendan R.; Mehta, Aneesh K.; Malinis, Maricar; Danziger-Isakov, Lara; Strasfeld, Lynne; Florescu, Diana F.; Vece, Gabriel; Basavaraju, Sridhar V.; Michaels, Marian G. (American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2021)
Cryptococcus species can cause serious life-threatening infection in solid organ transplant recipients by reactivation of prior infection, post-transplant de novo infection, or donor transmission from the transplanted organ. Although previously reported in the literature, the extent of donor-derived cryptococcosis in the United States has not been documented. We analyzed potential donor-derived Cryptococcus transmission events reported to the Organ Procurement and Transplantation Network (OPTN) for investigation by the ad hoc Disease Transmission Advisory Committee (DTAC). All reports between 2009–2019 in which transmission to recipients was designated proven or probable, or determined to be averted due to implementation of prophylaxis (intervention without disease transmission – “IWDT”) were included. During 2009–2019, 58 reports of potential donor-derived cryptococcosis were submitted to DTAC. Among these reports, 12 donors were determined to have resulted in proven or probable transmission to 23/34 (67.6%) recipients. Most of these donors (10/12 (83%)) exhibited central nervous system-related symptoms prior to death and 5/23 (22%) infected recipients died. For 11 different donors, prophylaxis, most often with fluconazole, was administered to 23/35 (65.7%) recipients. Clinicians should maintain awareness of donor-derived cryptococcosis and consider prompt prophylaxis or treatment followed by reporting to OPTN for further investigation.

Use of letermovir in off-label indications: Infectious Diseases Working Party of European Society of Blood and Marrow Transplantation retrospective study - Styczyński, Jan; Tridello, Gloria; Xhaard, Alienor; Medinger, Michael; Mielke, Stephan; Taskinen, Mervi; Blijlevens, Nicole; Rodriguez, M. Aranzazu Bermudez; Solano, Carlos; Nikolousis, Emmanouil; Biffi, Alessandra; Groll, Andreas H.; et al. (Bone Marrow Transplantation, 2021)
Letermovir (LMV) is licensed for prophylaxis of CMV infection in allogeneic hematopoietic cell transplant adult CMV-seropositive patients. Due to its favorable safety profile, LMV brings potential for use in other clinical situations, outside the approved indication. The objective of the study was to analyze the efficacy and safety of the use of LMV in off-label indications in EBMT centers. A total of 49 patients were reported including 44 adults and 5 children. LMV was administered for: secondary prophylaxis (37 adults, 3 children), primary prophylaxis (2 children), pre-emptive treatment (5 adults), and therapy of CMV disease (2 adults; pneumonia, colitis). Cyclosporine was concomitantly used in 26 patients. Overall, LMV was used for a median 112 days (range: 10–473). Cumulative incidence of breakthrough infections during secondary prophylaxis was 10.1% (95% CI = 3.1–21.9). Prophylactic treatment with LMV resulted in 94.9% (95% CI = 81.0–98.7), and 81.9% (95% CI = 65.7–90.9) probability of, respectively, 60 and 120-day survival without CMV infection in patients receiving secondary prophylaxis. During therapy of CMV infection/disease, probability of 60 and 120-day overall survival was 100% and 71.4% (95% CI = 25.8–92.0), respectively. No breakthrough infection occurred in children on LMV prophylaxis. Adverse events were reported in 15/49 (30.4%) patients: the most common being nausea/vomiting (22.4%). In conclusion, the efficacy of the use of LMV as secondary prophylaxis was high, and the preliminary experience with the use of LMV for the treatment of patients with refractory CMV infection/disease was positive. Our data showed that higher dose or prolonged therapy did not result in increased rate of adverse events.

Clinicopathologic Characteristics of JC Virus Nephropathy in Kidney Transplant Recipients - Wiegley, Nasim; Walavalkar, Vighnesh; Aujla, Harleen; Chen, Ling-Xin; Huang, Yihung; Lee, Brian K.; Jen, Kuang-Yu (Transplantation, 2021)
Background. The vast majority of polyomavirus nephropathy (PVN) is due to BK virus, but rare cases result from JC virus reactivation. To date, only a handful of biopsy-proven JC-PVN cases have been reported. Here, we describe the clinical and pathologic findings in 7 patients with biopsy-proven JC-PVN. Methods. Search of the pathology archives at 2 institutions found 7 cases of JC-PVN. Clinical data were extracted from the electronic medical records, and the biopsies were reviewed. Results. Four cases were diagnosed at 6 y posttransplant or later. The remaining 3 cases presented within approximately 2 y posttransplant, of which 2 showed subclinical JC-PVN on surveillance biopsy. Two early presenting patients were treated for acute rejection just before acquiring JC-PVN. Late presenting patients had higher chronicity, which correlated to worse outcome. All but 1 biopsy showed nonspecific inflammation within areas of interstitial fibrosis without significant inflammation in unscarred cortex. The earliest presenting patient was the exception and showed active inflammation with tubulitis. Viral cytopathic changes were detected in all cases with moderate or high-histologic viral load (pvl), showing preference for the distal tubules and medulla. The 2 cases with low pvl did not demonstrate cytopathic changes but were SV40 positive. Conclusions. JC-PVN can be insidious in presentation, which may cause delayed or missed diagnosis. Unlike BK-PVN, which typically occurs early in the posttransplant period, JC-PVN can occur both early and late following transplant. Overreliance on negative plasma and urine BK viral loads to exclude PVN can be a pitfall.

A Randomized Trial of Caspofungin vs Triazoles Prophylaxis for Invasive Fungal Disease in Pediatric Allogeneic Hematopoietic Cell Transplant - Dvorak, Christopher C; Fisher, Brian T; Esbenshade, Adam J; Nieder, Michael L; Alexander, Sarah; Steinbach, William J; Dang, Ha; Villaluna, Doojduen; Chen, Lu; Skeens, Micah; Zaoutis, Theoklis E; Sung, Lillian (Journal of the Pediatric Infectious Diseases Society, 2021)
Background.  Children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) are at high risk for invasive fungal disease (IFD). Methods.  This multicenter, randomized, open-label trial planned to enroll 560 children and adolescents (3 months to <21 years) undergoing allogeneic HCT between April 2013 and September 2016. Eligible patients were randomly assigned to antifungal prophylaxis with caspofungin or a center-specific comparator triazole (fluconazole or voriconazole). Prophylaxis was administered from day 0 of HCT to day 42 or discharge. The primary outcome was proven or probable IFD at day 42 as adjudicated by blinded central review. Exploratory analysis stratified this evaluation by comparator triazole. Results.  A planned futility analysis demonstrated a low rate of IFD in the comparator triazole arm, so the trial was closed early. A total of 290 eligible patients, with a median age of 9.5 years (range 0.3–20.7), were randomized to caspofungin (n = 144) or a triazole (n = 146; fluconazole, n = 100; voriconazole, n = 46). The day 42 cumulative incidence of proven or probable IFD was 1.4% (95% confidence interval [CI], 0.3%–5.4%) in the caspofungin group vs 1.4% (95% CI, 0.4%–5.5%) in the triazole group (P = .99, log-rank test). When stratified by specific triazole, there was no significant difference in proven or probable IFD at day 42 between caspofungin vs fluconazole (1.0%, 95% CI, 0.1%–6.9%, P = .78) or caspofungin vs voriconazole (2.3%, 95% CI, 0.3%–15.1%, P = .69). Conclusions.  In pediatric HCT patients, prophylaxis with caspofungin did not significantly reduce the cumulative incidence of early proven or probable IFD compared with triazoles. Future efforts to decrease IFD-related morbidity and mortality should focus on later periods of risk.

Disease Prevention Not Decolonization: A Model for Fecal Microbiota Transplantation in Patients Colonized With Multidrug-resistant Organisms - Ghani, Rohma; Mullish, Benjamin H.; McDonald, Julie A. K.; Ghazy, Anan; Williams, Horace R. T.; Brannigan, Eimear T.; Mookerjee, Siddharth; Satta, Giovanni; Gilchrist, Mark; Duncan, Neill; Corbett, Richard; Innes, Andrew J.; et al. (Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 2021)
Fecal microbiota transplantation (FMT) yields variable intestinal decolonization results for multidrug-resistant organisms (MDROs). This study showed significant reductions in antibiotic duration, bacteremia, and length of stay in 20 patients colonized/infected with MDRO receiving FMT (compared with pre-FMT history, and a matched group not receiving FMT), despite modest decolonization rates.
Keywords: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Humans; Intestines; allogeneic hematopoietic cell transplantation; antimicrobial resistance; fecal microbiota transplant; gut microbiome; multidrug-resistant bacteria

Invasive Aspergillosis Due to Aspergillus Section Usti: A Multicenter Retrospective Study - Glampedakis, Emmanouil; Cassaing, Sophie; Fekkar, Arnaud; Dannaoui, Eric; Bougnoux, Marie-Elisabeth; Bretagne, Stéphane; Neofytos, Dionysios; Schreiber, Peter W.; Hennequin, Christophe; Morio, Florent; Shadrivova, Olga; Bongomin, Felix; et al. (Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 2021)
BACKGROUND: Aspergillus spp. of section Usti (A. ustus) represent a rare cause of invasive aspergillosis (IA). This multicenter study describes the epidemiology and outcome of A. ustus infections. METHODS: Patients with A. ustus isolated from any clinical specimen were retrospectively identified in 22 hospitals from 8 countries. When available, isolates were sent for species identification (BenA/CaM sequencing) and antifungal susceptibility testing. Additional cases were identified by review of the literature. Cases were classified as proven/probable IA or no infection, according to standard international criteria. RESULTS: Clinical report forms were obtained for 90 patients, of whom 27 had proven/probable IA. An additional 45 cases were identified from literature review for a total of 72 cases of proven/probable IA. Hematopoietic cell and solid-organ transplant recipients accounted for 47% and 33% cases, respectively. Only 8% patients were neutropenic at time of diagnosis. Ongoing antimold prophylaxis was present in 47% of cases. Pulmonary IA represented 67% of cases. Primary or secondary extrapulmonary sites of infection were observed in 46% of cases, with skin being affected in 28% of cases. Multiple antifungal drugs were used (consecutively or in combination) in 67% of cases. The 24-week mortality rate was 58%. A. calidoustus was the most frequent causal agent. Minimal inhibitory concentrations encompassing 90% isolates (MIC90) were 1, 8, >16, and 4 µg/mL for amphotericin B, voriconazole, posaconazole, and isavuconazole, respectively. CONCLUSIONS: Aspergillus ustus IA mainly occurred in nonneutropenic transplant patients and was frequently associated with extrapulmonary sites of infection. Mortality rate was high and optimal antifungal therapy remains to be defined.
Keywords: Aspergillus calidoustus; Aspergillus insuetus; Aspergillus pseudodeflectus; Aspergillus puniceus; Aspergillus ustus

High Incidence of Herpes Zoster After Cord Blood Hematopoietic Cell Transplant Despite Longer Duration of Antiviral Prophylaxis - Xue, Elisabetta; Xie, Hu; Leisenring, Wendy M; Kimball, Louise E; Goyal, Sonia; Chung, Lisa; Blazevic, Rachel; Maltez, Byron; Edwards, Anna; Dahlberg, Ann E; Salit, Rachel B; Delaney, Colleen; et al. (Clinical Infectious Diseases, 2021)
Cord blood transplant (CBT) recipients have a high incidence of herpes zoster (HZ) in the context of short-term peritransplant antiviral prophylaxis. In 2009, international guidelines recommended HZ prophylaxis for at least 1 year after hematopoietic cell transplant. The impact of longer-term antiviral prophylaxis on HZ incidence after CBT is unknown.We retrospectively analyzed varicella zoster virus (VZV)–seropositive CBT recipients who were transplanted between 2006 and 2016. We abstracted HZ events and other variables for up to 5 years post-CBT. We calculated the cumulative incidence of HZ and used Cox proportional hazards regression to identify variables associated with HZ.The study cohort consisted of 227 patients. Among 1-year survivors, 91% were still receiving prophylaxis, for a median duration of 20.6 months. HZ occurred in 44 patients (19%) at a median of 23.6 months. The cumulative incidence of HZ by 1 year after CBT was 1.8% (95% confidence interval [CI], .1%–4%), but increased to 26% (95% CI, 19%–33%) by 5 years. In a multivariable analysis, acute graft-vs-host disease was associated with increased risk, whereas antiviral prophylaxis was associated with reduced risk for HZ (adjusted hazard ratio, 0.19 [95% CI, .09–.4]). There was no association between CD4+ T-cell counts at 1 year post-CBT and subsequent risk for HZ.We found a high incidence of HZ after CBT despite antiviral prophylaxis for > 1 year. Based on these findings, we suggest longer duration of prophylaxis for HZ after CBT. Compliance with antiviral prophylaxis, VZV-specific immune monitoring, and vaccination to mitigate HZ after CBT also require further study.

The growing dilemma of legalized cannabis and heart transplantation - Olt, Caroline; Faulkenberg, Kathleen D.; Hsich, Eileen M. (The Journal of Heart and Lung Transplantation, 2021)
This in-depth review discusses cannabis as it relates to heart transplantation and the growing dilemma of legalization around the world creating disparities in transplant candidacy. One will learn about two of the most common cannabinoids: Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These cannabinoids are metabolized by cytochrome P-450 and P glycoprotein, which are essential for the metabolism of drugs for transplantation, such as calcineurin inhibitors. Addiction, withdrawal, and cannabis use disorder will be reviewed as well as hyperemesis syndrome. Maintaining adequate immunosuppression will depend on a variety of factors, including drug-drug interactions, pharmacokinetics of cannabinoids and chronicity of cannabis usage. These drug interactions are further confounded by varying concentrations of cannabis products available at medical dispensaries. One will also learn about the outcomes of transplant recipients using cannabis such as graft failure and the risk of infections. Although more research is needed to establish transplant guidelines, the available data is concerning and fairness in organ distribution should not vary by transplant program or institution.

Clinical Presentation, Management, and Outcomes of Patients With Brain Abscess due to Nocardia Species - Corsini Campioli, Cristina; Castillo Almeida, Natalia E; O’Horo, John C; Challener, Douglas; Go, John Raymond; DeSimone, Daniel C; Sohail, M Rizwan (Open Forum Infectious Diseases, 2021)
Background.    Nocardial brain abscesses are rare, and published literature describing brain abscesses due to Nocardia species is limited to individual case reports or small series. We report one of the largest contemporary retrospective studies describing risk factors, diagnostic evaluation, management, and outcomes of nocardial brain abscess. Methods.    Retrospective review of all adults with brain abscess due to culture-confirmed Nocardia species at our institution between January 1, 2009, and June 30, 2020. Results.    Overall, 24 patients had nocardial brain abscesses during the study period. The median age at presentation was 64 years, and 62.5% were immunocompromised. Pulmonary and cutaneous infections were the most common primary sites of nocardial infection. All 24 patients had magnetic resonance imaging performed, and the frontal lobe was the most commonly involved. The most common organism isolated was Nocardia farcinica, followed by Nocardia wallacei and Nocardia cyriacigeorgica. Thirteen patients were managed with antimicrobial therapy alone, while 11 had both medical and surgical management. In all patients, dual therapy was recommended for the initial 6 weeks of treatment, and 22 patients received at least 1 oral agent as part of their final antibiotic regimen, predominantly trimethoprim-sulfamethoxazole and linezolid. Fourteen patients achieved complete clinical and radiographic resolution of infection. Conclusions.    Nocardia is an important cause of brain abscess in the immunocompromised host. Early diagnostic and therapeutic aspiration may help health care providers confirm the diagnosis, choose an appropriate antimicrobial regimen, and achieve source control.

Tedizolid vs Linezolid for the Treatment of Nontuberculous Mycobacteria Infections in Solid Organ Transplant Recipients - Poon, Yi Kee; La Hoz, Ricardo M; Hynan, Linda S; Sanders, James; Monogue, Marguerite L (Open Forum Infectious Diseases, 2021)
Background.    Treatment options for nontuberculous mycobacteria (NTM) infections are limited by the pathogen’s intrinsic resistance profile and toxicities. Tedizolid and linezolid display in vitro activity against NTM species. However, safety data and treatment outcomes are limited in the solid organ transplant (SOT) population. Methods.    This was a single-center retrospective cohort study of adult SOT recipients receiving linezolid or tedizolid for an NTM infection from January 1, 2010, to August 31, 2019. The primary outcome compared the hematologic safety profiles of tedizolid vs linezolid. We also described nonhematological adverse drug events (ADEs) and therapy discontinuation rates. In an exploratory analysis, we assessed symptomatic microbiologic and clinical outcomes in those receiving tedizolid or linezolid for at least 4 weeks. Results.   Twenty-four patients were included (15 tedizolid, 9 linezolid). No differences were identified comparing the effects of tedizolid vs linezolid on platelet counts, absolute neutrophil counts (ANCs), and hemoglobin over 7 weeks using mixed-effects analysis of variance models. ANC was significantly decreased in both groups after 7 weeks of therapy (P = .04). Approximately 20% of patients in each arm discontinued therapy due to an ADE. Seven of 12 (58%) and 2 of 3 (67%) patients were cured or clinically cured with tedizolidand linezolid-containing regimens, respectively. Conclusions.    This study suggests no significant safety benefit of tedizolid over linezolid for the treatment of NTM infections in SOT recipients. Tedizolid or linezolid-containing regimens demonstrated a potential benefit in symptomatic and

Effect of Hepatitis C Virus Infection on Heart Transplants in the Current Era - Fujisaki, Tomohiro; Mikami, Takahisa; Kuno, Toshiki; Moss, Noah; Itagaki, Shinobu (Transplantation, 2021)
Background: The effect of hepatitis C virus (HCV) infection in recipients or donors on heart transplants is less known in the current era after the introduction of direct-acting antiviral agents (DAAs) in 2011. Methods: Using the United Network for Organ Sharing registry, 24 871 adult heart transplant recipients between 2005 and 2019 were identified. The trend in prevalence of HCV infected recipients and in utilization of HCV infected donors and their effect on the transplant outcomes were investigated in the past era versus the current era separated by 2011, using Cox proportional hazard regression. Results: HCV antibody positive recipients (n=520, 2.1%) had stable prevalence (P=0.18). They had a lower survival estimate when compared to HCV antibody negative recipients in the past era (55.3% versus 70.9% at 7 years; hazard ratio (HR), 1.56; 95% confidence interval (CI), 1.27-1.91; P<0.001), however not in the current era (73.1% versus 71.5% at 7 years; HR, 1.00; 95% CI, 0.75-1.32; P=0.98) (Pinteraction<0.001). Organ use from HCV antibody positive donors (n=371, 1.5%) was concentrated in the recent years (P<0.001) and provided the similar survival estimate up to 2 years (84.2% versus 87.6%; HR, 0.97; 95% CI, 0.65-1.44; P=0.87). The similar findings were confirmed with a subgroup cohort with positive nucleic acid amplification test (NAT). Conclusions: Positive HCV antibody in recipients did not adversely affect the long-term transplant outcomes in the current era. Graft utilization from positive HCV antibody or NAT positive donors are rapidly more prevalent and appeared to be promising up to 2 years posttransplant.

Human Metapneumovirus and Parainfluenza Virus Infections in Lung Transplant Recipients: the Effects on Lung Allograft and Clinical Outcomes - Permpalung, Nitipong; Sait, Afrah S.; Bazemore, Katrina; Avery, Robin K.; Mathew, Joby; Shah, Pali D. (Transplantation, 2021)
Background: Human metapneumovirus (HMPVi) and parainfluenza virus (PIV) infections are common community acquired infection in lung transplant recipients (LTRs), but data is extremely limited. Methods: A retrospective study including all LTRs at the Johns Hopkins Hospital during July 2010-June 2019 with positive HMPV and PIV polymerase chain reaction (PCR) respiratory specimens was performed. Results: Thirty-one HMPV- and 53 PIV-infected LTRs were identified. LTRs with HMPVi and PIVi had similar baseline characteristics, infection parameters, treatment allocation, and allograft function outcomes. Among entire cohort, 31.6% had CLAD stage progression within 1-year post infections (29.2% vs 35.5% for PIV vs HMPV, respectively, p= 0.56). In forced expiratory volume in 1 second percent (FEV1%) trajectory analysis showed steadily decline of FEV1 across time among CLAD stage progressor from both viruses. FEV1% decline ≥ 10% at 90 days had adjusted hazard ratio for CLAD stage progression of 18.4 [4.98, 67.76] and 4.6 [1.36, 15.34] for PIVi and HMPVi, respectively. PIVi caused higher DSA development (11.8% vs 3.2%, p=0.18) and 1-year mortality (9.4% vs 0%, p=0.11), compared to HMPVi, even though the results were not statistically significant. Ribavirin did not show protective effect and mycophenolate discontinuation during infection did not increase risk of CLAD stage progression. Conclusion: One-third of HMPV- and PIV- infected LTRs developed CLAD stage progression within 1 year. The lack of early lung function recovery may predict long term CLAD progression.

Guidance on Imaging for Invasive Pulmonary Aspergillosis and Mucormycosis: From the Imaging Working Group for the Revision and Update of the Consensus Definitions of Fungal Disease from the EORTC/MSGERC - Alexander, Barbara D; Lamoth, Frédéric; Heussel, Claus Peter; Prokop, Cornelia Schaefer; Desai, Sujal R; Morrissey, C Orla; Baddley, John W (Clinical Infectious Diseases, 2021)
Clinical imaging in suspected invasive fungal disease (IFD) has a significant role in early detection of disease and helps direct further testing and treatment. Revised definitions of IFD from the EORTC/MSGERC were recently published and provide clarity on the role of imaging for the definition of IFD. Here, we provide evidence to support these revised diagnostic guidelines.We reviewed data on imaging modalities and techniques used to characterize IFDs.Volumetric high-resolution computed tomography (CT) is the method of choice for lung imaging. Although no CT radiologic pattern is pathognomonic of IFD, the halo sign, in the appropriate clinical setting, is highly suggestive of invasive pulmonary aspergillosis (IPA) and associated with specific stages of the disease. The ACS is not specific for IFD and occurs in the later stages of infection. By contrast, the reversed halo sign and the hypodense sign are typical of pulmonary mucormycosis but occur less frequently. In noncancer populations, both invasive pulmonary aspergillosis and mucormycosis are associated with “atypical” nonnodular presentations, including consolidation and ground-glass opacities.A uniform definition of IFD could improve the quality of clinical studies and aid in differentiating IFD from other pathology in clinical practice. Radiologic assessment of the lung is an important component of the diagnostic work-up and management of IFD. Periodic review of imaging studies that characterize findings in patients with IFD will inform future diagnostic guidelines.

Risk Factors for Extended-Spectrum β-lactamase–Producing Enterobacterales Bloodstream Infection Among Solid-Organ Transplant Recipients - Anesi, Judith A; Lautenbach, Ebbing; Tamma, Pranita D; Thom, Kerri A; Blumberg, Emily A; Alby, Kevin; Bilker, Warren B; Werzen, Alissa; Tolomeo, Pam; Omorogbe, Jacqueline; Pineles, Lisa; Han, Jennifer H (Clinical Infectious Diseases, 2021)
Approximately 40% of all Enterobacterales (EB) bloodstream infections (BSIs) among solid organ transplant recipients (SOTRs) are due to extended-spectrum β-lactamase (ESBL)–producing organisms, but risk factors for such infections remain ill defined in this population. We sought to determine the risk factors for ESBL-EB BSIs among SOTRs.A multicenter case-control study was performed. All SOTRs with an EB BSI at the Hospital of the University of Pennsylvania and University of Maryland Medical Center between 1 January 2007 and 30 June 2018 and at The Johns Hopkins Hospital between 1 January 2005 and 31 December 2015 were included. Cases were those with an ESBL-EB BSI. Controls were those with a non–ESBL-EB BSI. Multivariable logistic regression was performed to determine risk factors for ESBL-EB BSI.There were 988 episodes of EB BSI, of which 395 (40%) were due to an ESBL-EB. On multivariable analysis, the independent risk factors for ESBL-EB BSI included: ESBL-EB on prior culture (aOR, 12.75; 95% CI, 3.23–50.33; P < .001), a corticosteroid-containing immunosuppression regimen (aOR 1.30; 95% CI 1.03–1.65; P = .030), acute rejection treated with corticosteroids (aOR 1.18; 95% CI 1.16–1.19; P < .001), and exposure to third-generation cephalosporins (aOR 1.95; 95% CI 1.48–2.57; P < .001), echinocandins (aOR 1.61; 95% CI 1.08–2.40; P = .020), and trimethoprim-sulfamethoxazole (aOR 1.35; 95% CI 1.10–1.64; P = .003).We identified several novel risk factors that are uniquely important to the SOTR population, including exposure to trimethoprim-sulfamethoxazole and corticosteroid-containing immunosuppressive regimens. Further studies exploring these associations and testing interventions aimed at these modifiable risk factors among SOTRs are needed.

EORTC/MSGERC Definitions of Invasive Fungal Diseases: Summary of Activities of the Intensive Care Unit Working Group - Bassetti, Matteo; Azoulay, Elie; Kullberg, Bart-Jan; Ruhnke, Markus; Shoham, Shmuel; Vazquez, Jose; Giacobbe, Daniele Roberto; Calandra, Thierry (Clinical Infectious Diseases, 2021)
The EORTC/MSGERC recently revised and updated the consensus definitions of invasive fungal disease (IFD). These definitions primarily focus on patients with cancer and stem cell or solid-organ transplant patients. They may therefore not be suitable for intensive care unit (ICU) patients. More in detail, while the definition of proven IFD applies to a broad range of hosts, the categories of probable and possible IFD were primarily designed for classical immunocompromised hosts and may therefore not be ideal for other populations. Moreover, the scope of the possible category of IFD has been diminished in the recently revised definitions for classically immunocompromised hosts. Diagnosis of IFD in the ICU presents many challenges, which are different for invasive candidiasis and for invasive aspergillosis. The aim of this article is to review progresses made in recent years and difficulties remaining in the development of definitions applicable in the ICU setting.

Donor to recipient transmission of SARS‐CoV‐2 by lung transplantation despite negative donor upper respiratory tract testing - Kaul, Daniel R.; Valesano, Andrew L.; Petrie, Joshua G.; Sagana, Rommel; Lyu, Dennis; Lin, Jules; Stoneman, Emily; Smith, Lane M.; Lephart, Paul; Lauring, Adam S. (American Journal of Transplantation, 2021)
We describe a case of proven transmission of SARS‐CoV‐2 from lung donor to recipient. The donor had no clinical history or findings suggestive of infection with SARS‐CoV‐2 and tested negative by reverse transcriptase polymerase chain reaction (RT‐PCR) on a nasopharyngeal (NP) swab obtained within 48 h of procurement. Lower respiratory tract testing was not performed. The recipient developed fever, hypotension, and pulmonary infiltrates on posttransplant day (PTD) 3, and RT‐PCR testing for SARS‐CoV‐2 on an NP swab specimen was non‐reactive, but positive on bronchoalveolar lavage (BAL) fluid. One thoracic surgeon present during the transplantation procedure developed COVID‐19. Sequence analysis of isolates from donor BAL fluid (obtained at procurement), the recipient, and the infected thoracic surgeon proved donor origin of recipient and health‐care worker (HCW) infection. No other organs were procured from this donor. Transplant centers and organ procurement organizations should perform SARS‐CoV‐2 testing of lower respiratory tract specimens from potential lung donors, and consider enhanced personal protective equipment for HCWs involved in lung procurement and transplantation.

Pneumocystis jirovecii Disease: Basis for the Revised EORTC/MSGERC Invasive Fungal Disease Definitions in Individuals Without Human Immunodeficiency Virus - Lagrou, Katrien; Chen, Sharon; Masur, Henry; Viscoli, Claudio; Decker, Catherine F; Pagano, Livio; Groll, Andreas H (Clinical Infectious Diseases, 2021)
Pneumocystis jirovecii pneumonia (PCP) causes substantive morbidity in immunocompromised patients. The EORTC/MSGERC convened an expert group to elaborate consensus definitions for Pneumocystis disease for the purpose of interventional clinical trials and epidemiological studies and evaluation of diagnostic tests.Definitions were based on the triad of host factors, clinical-radiologic features, and mycologic tests with categorization into probable and proven Pneumocystis disease, and to be applicable to immunocompromised adults and children without human immunodeficiency virus (HIV). Definitions were formulated and their criteria debated and adjusted after public consultation. The definitions were published within the 2019 update of the EORTC/MSGERC Consensus Definitions of Invasive Fungal Disease. Here we detail the scientific rationale behind the disease definitions.The diagnosis of proven PCP is based on clinical and radiologic criteria plus demonstration of P. jirovecii by microscopy using conventional or immunofluorescence staining in tissue or respiratory tract specimens. Probable PCP is defined by the presence of appropriate host factors and clinical-radiologic criteria, plus amplification of P. jirovecii DNA by quantitative real-time polymerase chain reaction (PCR) in respiratory specimens and/or detection of β-d-glucan in serum provided that another invasive fungal disease and a false-positive result can be ruled out. Extrapulmonary Pneumocystis disease requires demonstration of the organism in affected tissue by microscopy and, preferably, PCR.These updated definitions of Pneumocystis diseases should prove applicable in clinical, diagnostic, and epidemiologic research in a broad range of immunocompromised patients without HIV.

Assessment of the Role of 1,3-β-d-Glucan Testing for the Diagnosis of Invasive Fungal Infections in Adults - Lamoth, F; Akan, H; Andes, D; Cruciani, M; Marchetti, O; Ostrosky-Zeichner, L; Racil, Z; Clancy, C J (Clinical Infectious Diseases, 2021)
Detection of 1,3-β-d-glucan (BDG) in serum has been evaluated for its inclusion as a mycological criterion of invasive fungal infections (IFI) according to EORTC and Mycoses Study Group (MSG) definitions. BDG testing may be useful for the diagnosis of both invasive aspergillosis and invasive candidiasis, when interpreted in conjunction with other clinical/radiological signs and microbiological markers of IFI. However, its performance and utility vary according to patient population (hematologic cancer patients, solid-organ transplant recipients, intensive care unit patients) and pretest likelihood of IFI. The objectives of this article are to provide a systematic review of the performance of BDG testing and to assess recommendations for its use and interpretation in different clinical settings.

Defining Galactomannan Positivity in the Updated EORTC/MSGERC Consensus Definitions of Invasive Fungal Diseases - Mercier, Toine; Castagnola, Elio; Marr, Kieren A; Wheat, L Joseph; Verweij, Paul E; Maertens, Johan A (Clinical Infectious Diseases, 2021)
The consensus definitions of invasive fungal diseases from the EORTC/MSGERC were recently revised and updated. They now include consensus cutoff values for the galactomannan test that support the diagnosis of probable invasive aspergillosis. In this supplement article, we provide a rationale for these proposed thresholds based on the test’s characteristics and performance in different patient populations and in different specimen types.

The Evidence Supporting the Revised EORTC/MSGERC Definitions for Invasive Fungal Infections - Pappas, Peter G; Chen, Sharon C-A; Donnelly, J Peter (Clinical Infectious Diseases, 2021)
Invasive fungal infections (IFIs) in much of the developed world are associated with medical progress. In addition to the millions of individuals worldwide living with human immunodeficiency virus who constitute a significant host group, these infections are also common among other immunocompromised individuals as a reflection of technologic and therapeutic advances that have led to an enlarging susceptible host population. Examples include novel chemotherapy and other antineoplastic treatments, the aggressive use of glucocorticosteroids for a variety of underlying conditions, the rapidly expanding use of monoclonal antibodies and other biologic agents for the treatment of autoimmune disorders, and the extensive use of intravascular catheters and other medical devices that can provide a nidus for IFIs in otherwise immunocompetent individuals [1, 2]. With the exception of the endemic mycoses, cryptococcosis, and isolated mold infections, collectively, IFIs were relatively uncommon before 1950. Since that time, IFIs have been increasingly encountered in hospitalized and immunocompromised individuals, burgeoning to a point that these are dominant causes of undifferentiated fever, pulmonary infiltrates, skin lesions, and central nervous system disorders in a significant proportion of these patients.

Risk Factors for Cytomegalovirus Viremia following Liver Transplantation With a Seropositive Donor and Seronegative Recipient Receiving Antiviral Therapy - Singh, Nina; Winston, Drew J; Razonable, Raymund R; Lyon, G Marshall; Silveira, Fernanda P; Wagener, Marilyn M; Limaye, Ajit P (The Journal of Infectious Diseases, 2021)
The risk factors for development of viremia in high-risk donor cytomegalovirus (CMV)-seropositive and recipient CMV-seronegative (D+R−) transplant recipients are incompletely defined.The study population comprised patients in the preemptive therapy (PET) arm of a randomized, controlled trial of PET versus prophylaxis using valganciclovir in D+R− liver transplant recipients. Weekly surveillance monitoring for viremia for 100 days was performed using a sensitive CMV-DNA polymerase chain reaction assays. Risk factors for viremia and time to onset (≤4 vs >4 weeks) of viremia were examined using logistic regression models.Viremia developed in 84% (79/94) of recipients and older donor age was the only independent factor associated with viremia (odds ratio, 2.20 for each quartile increase in donor age; 95% confidence interval [CI], 1.07–4.52; P = .031). Recipients who developed early-onset viremia (within 4 weeks) also had significantly older donors than those with later-onset viremia (difference in age 10.1 years; 95% CI, 2–19; P = .03).Older donor age was an independent predictor of viremia and earlier-onset of viremia in D+R− liver transplant recipients. Future studies should assess the mechanistic links underlying this novel association.NCT01552369.

Kidney Transplantation From Hepatitis B Surface Antigen (HBsAg)–Positive Living Donors to HBsAg-Negative Recipients: Clinical Outcomes at a High-Volume Center in China - Wang, Xian-ding; Liu, Jin-peng; Song, Tu-run; Huang, Zhong-li; Fan, Yu; Shi, Yun-ying; Chen, Li-yu; Lv, Yuan-hang; Xu, Zi-lin; Li, Xiao-hong; Wang, Li; Lin, Tao (Clinical Infectious Diseases, 2021)
Data on kidney transplantation (KTx) from hepatitis B surface antigen (HBsAg)–positive (HBsAg+) donors to HBsAg-negative (HBsAg−) recipients [D(HBsAg+)/R(HBsAg-)] are limited. We aimed to report the outcomes of D(HBsAg+)/R(HBsAg−) KTx in recipients with or without hepatitis B surface antibody (HBsAb).Eighty-three D(HBsAg+)/R(HBsAg−) living KTx cases were retrospectively identified. The 384 cases of KTx from hepatitis B core antibody–positive (HBcAb+) living donors to HBcAb-negative (HBcAb−) recipients [D(HBcAb+)/R(HBcAb−)] were used as the control group. The primary endpoint was posttransplant HBsAg status change from negative to postive (-− →+).Before KTx, 24 donors (28.9%) in the D(HBsAg+)/R(HBsAg−) group were hepatitis B virus (HBV) DNA positive, and 20 recipients were HBsAb−. All 83 D(HBsAg+)/R(HBsAg−) recipients received HBV prophylaxis, while no D(HBcAb+)/R(HBcAb−) recipients received prophylaxis. After a median follow-up of 36 months (range, 6–106) and 36 months (range, 4–107) for the D(HBsAg+)/R(HBsAg−) and D(HBcAb+)/R(HBcAb−) groups, respectively, 2 of 83 (2.41%) D(HBsAg+)/R(HBsAg−) recipients and 1 of 384 (0.26%) D(HBcAb+)/R(HBcAb−) became HBsAg+, accompanied by HBV DNA-positive (P = .083). The 3 recipients with HBsAg−→+ were exclusively HBsAb−/HBcAb− before KTx. Recipient deaths were more frequent in the D(HBsAg+)/R(HBsAg−) group (6.02% vs 1.04%, P = .011), while liver and graft function, rejection, infection, and graft loss were not significantly different. In univariate analyses, pretransplant HBsAb−/HBcAb− combination in the D(HBsAg+)/R(HBsAg−) recipients carried a significantly higher risk of HBsAg−→+, HBV DNA−→+, and death.Living D(HBsAg+)/R(HBsAg−) KTx in HBsAb+ recipients provides excellent graft and patient survivals without HBV transmission. HBV transmission risks should be more balanced with respect to benefits of D(HBsAg+)/R(HBsAg−) KTx in HBsAb-/HBcAb− candidates.

Aspergillus Polymerase Chain Reaction—An Update on Technical Recommendations, Clinical Applications, and Justification for Inclusion in the Second Revision of the EORTC/MSGERC Definitions of Invasive Fungal Disease - White, P Lewis; Bretagne, Stephane; Caliendo, Angela M; Loeffler, Juergen; Patterson, Thomas F; Slavin, Monica; Wingard, John R (Clinical Infectious Diseases, 2021)
Aspergillus polymerase chain reaction testing of blood and respiratory samples has recently been included in the second revision of the EORTC/MSGERC definitions for classifying invasive fungal disease. This is a result of considerable efforts to standardize methodology, the availability of commercial assays and external quality control programs, and additional clinical validation. This supporting article provides both clinical and technical justifications for its inclusion while also summarizing recent advances and likely future developments in the molecular diagnosis of invasive aspergillosis.

Donor Graft Cytomegalovirus Serostatus and the Risk of Arterial and Venous Thrombotic Events in Seronegative Recipients After Non-Thoracic Solid Organ Transplantation - Belga, Sara; MacDonald, Clayton; Chiang, Diana; Kabbani, Dima; Shojai, Soroush; Abraldes, Juan G; Cervera, Carlos (Clinical Infectious Diseases, 2021)
Cytomegalovirus (CMV) is the most common opportunistic pathogen, following solid organ transplantation (SOT), that leads to direct and indirect effects. The aim of this study was to assess the impact of CMV exposure at transplantation on the rate of posttransplant thrombotic events (TEs).We conducted a retrospective cohort study of patients transplanted at the University of Alberta Hospital between July 2005 and January 2018. We included adult SOT CMV-seronegative recipients at transplantation who received an allograft from either a seropositive donor (D+/R-) or a seronegative donor (D-/R-).A total of 392 SOT recipients were included: 151 (39%) liver, 188 (48%) kidney, 45 (11%) pancreas, and 8 (2%) other transplants. The mean age was 47 years, 297 (76%) were males, and 181 (46%) had a CMV D+/R- donor. Patients in the CMV D+/R- cohort were slightly older (51 years versus 48 years in the D-/R- cohort; P = .036), while other variables, including cardiovascular risk factors and pretransplant TEs, were not different between groups. Overall, TEs occurred in 35 (19%) patients in the CMV D+/R- group, versus 21 (10%) in the CMV D-/R- group, at 5 years of follow-up (P = .008); the incidence rates per 100 transplant months were 5.12 and 1.02 in the CMV D+/R- and CMV D-/R- groups, respectively (P = .003). After adjusting for potential confounders with a Cox regression model, a CMV D+/R- transplantation was independently associated with an increased risk of a TE over 5 years (adjusted hazard ratio, 3.027; 95% confidence interval, 1.669–5.488).A CMV D+/R- transplantation is associated with an increased risk of a TE posttransplantation.

Human herpesvirus 6 and central nervous system disease in oncology patients: A retrospective case series and literature review - Handley, Guy; Hasbun, Rodrigo; Okhuysen, Pablo (Journal of Clinical Virology, 2021)
Background Human herpesvirus 6 (HHV-6) can reactivate with immunosuppression and cause central nervous system (CNS) dysfunction. Much of the literature describes cases after hematopoietic stem cell transplantation (HSCT), ranging from encephalitis to a post-transplant acute limbic encephalitis syndrome (PALE). Outside of HSCT, studies of HHV-6 encephalitis are limited to case reports. Objectives This study was designed to review HHV-6 CNS infection, and evaluate all patients admitted to MD Anderson Cancer Center between March 2016 and December 2018 with detectable HHV-6 DNA in the cerebrospinal fluid (CSF). Study Design Patients with HHV-6 DNA detected in the CSF using the Viracor or Biofire® Meningitis Encephalitis Panel platforms and no other identified etiology were identified and demographic features, known risk factors, imaging findings, CSF analysis, treatments and patient outcomes were extracted from medical records. Results 725 patients underwent HHV-6 testing during the study timeframe, with 19 cases (2.6 %) of HHV-6 mediated CNS disease identified. Most patients, 13/19 (68 %), had undergone HSCT with median time to presentation of 31 days after transplant. Survival at 240 days after transplant was 62 %. CSF had lymphocyte predominance and nearly all patients had peripheral lymphopenia. Other at risk populations identified included patients who received chimeric antigen receptor (CAR) T-cell therapy and biologic immunotherapy. Notable discordance among testing platforms was found in 5/9 (55 %) instances. Conclusions In addition to HSCT patients, HHV-6 reactivation leading to CNS disease also occurs in settings such as following adoptive T cell therapy or biologic immunotherapy. Significant diagnostic discordance exists between testing platforms.
Keywords: Chimeric antigen receptor T-cell therapy; Encephalitis; Hematopoietic stem cell transplantation; Human herpesvirus 6; Post-Transplant acute limbic encephalitis

Donor Cytomegalovirus Transmission Patterns in Solid Organ Transplant Recipients With Primary Infection - Hasing, Maria E; Pang, Xiaoli L; Mabilangan, Curtis; Preiksaitis, Jutta K (The Journal of Infectious Diseases, 2021)
The epidemiology of single versus multiple cytomegalovirus (CMV) strain transmission from donor (D+) to seronegative solid organ transplant (SOT) recipients (R−) is uncertain, as is whether “relapsing” recipient infection represents changing strain predominance when multiple strains are transmitted. Here we characterized CMV strain transmission patterns in D+/R− SOT recipients.We studied pairs or groups of D+/R− SOT recipients who received organs from a common donor (group A) and recipients who experienced ≥2 waves of CMV DNAemia (group B). CMV in plasma was characterized by genotype-specific real-time PCR for genes gB and gH.Single concordant genotypes were identified in 12 of 18 recipient pairs/group sharing a common donor (group A); at least 6 of 18 (33%) donors transmitted > 1 strain. A single CMV strain was detected in 14 of 15 recipients in group B; only 1 recipient had coinfection. A shift in CMV strain predominance occurred after the first posttransplant year in at least 4 recipients with coinfection.Using a common donor approach, we confirmed that multiple CMV strain transmission from donors to R− SOT recipients is not uncommon. D+/R− SOT recipients with CMV coinfection can undergo changes in strain predominance in late waves of CMV DNAemia.

HHV-6 associated diseases are one of the major factors on higher early CNS complications in CB recipients than in those of BM/PBSC - Kageyama, Kosei; Uchida, Naoyuki; Yamamoto, Hisashi; Takagi, Shinsuke; Ebihara, Michiho; Yuasa, Mitsuhiro; Kaji, Daisuke; Nishida, Aya; Ishiwata, Kazuya; Yamamoto, Go; Asano-Mori, Yuki; Izutsu, Koji; et al. (Bone Marrow Transplantation, 2021)

Prophylactic Ureaplasma-directed Antimicrobials in Lung Donors Can Prevent Fatal Hyperammonemia - Kurihara, Chitaru; Manerikar, Adwaiy; Kandula, Viswajit; Cerier, Emily; Bharat, Ankit (Transplantation, 2021)
An abstract is unavailable.

The Impact of Antifungal Prophylaxis in Lung Transplant Recipients - Pennington, Kelly M.; Dykhoff, Hayley J.; Yao, Xiaoxi; Sangaralingham, Lindsey R.; Shah, Nilay D.; Peters, Steve G.; Barreto, Jason N.; Razonable, Raymund R.; Kennedy, Cassie C. (Annals of the American Thoracic Society, 2021)
Rationale: Many lung transplant centers prescribe antifungal medications after transplantation to prevent invasive fungal infections (IFIs); however, the effectiveness of antifungal prophylaxis at reducing the risk of all-cause mortality or IFI has not been established., Objectives: We aimed to evaluate the effect of antifungal prophylaxis on all-cause mortality and IFI in lung transplant patients., Methods: Using administrative claims data, we identified adult patients who underwent lung transplantation between January 1, 2005, and December 31, 2018. Propensity score analysis using inverse probability treatment–weighting approach was used to balance the differences in baseline characteristics between those receiving antifungal prophylaxis and those not receiving antifungal prophylaxis. Cox proportional hazards regression was used to compare rates of all-cause mortality and IFI in both groups., Results: We identified 662 lung transplant recipients (LTRs) (387 received prophylaxis and 275 did not). All-cause mortality was significantly lower in those receiving antifungal prophylaxis compared with those not receiving antifungal prophylaxis (event rate per 100 person-years, 8.36 vs. 19.49; hazard ratio, 0.43; 95% confidence interval, 0.26–0.71; P = 0.003). Patients receiving antifungal prophylaxis had a lower rate of IFI compared with those not receiving prophylaxis (event rate per 100 person-years, 14.94 vs. 22.37; hazard ratio, 0.68; 95% confidence interval, 0.44–1.05; P = 0.079), but did not reach statistical significance., Conclusions: In this real-world analysis, antifungal prophylaxis in LTRs was associated with reduced all-cause mortality compared with those not receiving antifungal prophylaxis. Rates of IFI were also lower in those receiving prophylaxis, but this was not statistically significant in our primary analysis.

Association of HHV-6 With Outcomes in CMV-Seronegative Liver Transplant Recipients With CMV-Seropositive Donors Receiving Preemptive Antiviral Therapy - Singh, Nina; Winston, Drew J.; Razonable, Raymund R.; Lyon, G. Marshall; Huang, Meei-Li; Jerome, Keith R.; Silveira, Fernanda P.; Wagener, Marilyn M.; Limaye, Ajit P. (Transplantation, 2021)
Background: Risk factors, virologic parameters and outcomes associated with HHV-6 viremia in high-risk donor CMV-seropositive and recipient CMV-seronegative (D+R-) liver transplant recipients in the current era are incompletely defined. Methods: The study population consisted of patients in the preemptive therapy (PET) arm of a randomized, controlled trial of PET versus valganciclovir prophylaxis for CMV prevention in D+R- liver transplant recipients. Weekly blood samples through 100 days in the PET group were tested for HHV-6 viremia using a real-time quantitative PCR. Assessments included virologic characteristics and relationship with CMV, risk factors and impact of HHV-6 viremia with outcomes through 12 months post-transplant. Results: HHV-6 viremia at any level developed in 42% (40/96). Older patient age (p=0.03), longer hospitalization (p=0.015), and ICU stay at transplantation (p=0.029) were significantly associated with high-grade viremia. Concurrent HHV-6 and CMV viremia was associated with earlier onset of HHV-6 viremia (p=0.004), higher HHV-6 AUC (p=0.043), and higher peak HHV-6 viral load (p=0.006) vs HHV-6 viremia alone. High-grade viremia was independently associated with biopsy-proven rejection within 12 months (p=0.045) post-transplant. Conclusions: Among D+R- liver transplant recipients receiving valganciclovir as PET, high-grade HHV-6 viremia was associated with increased age and critical-illness in ICU at time of transplant and was independently associated with allograft rejection.

DAS181 Treatment of Severe Lower Respiratory Tract Parainfluenza Virus Infection in Immunocompromised Patients: A Phase 2 Randomized, Placebo-Controlled Study - Chemaly, Roy F; Marty, Francisco M; Wolfe, Cameron R; Lawrence, Steven J; Dadwal, Sanjeet; Soave, Rosemary; Farthing, Jason; Hawley, Stephen; Montanez, Paul; Hwang, Jimmy; Ho, Jennifer Hui-Chun; Lewis, Stanley; et al. (Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 2021)
Immunocompromised adults with severe parainfluenza received nebulized DAS181 or placebo for up to 10 days. The primary endpoint was not met, but a subgroup of severely immunocompromised patients experienced a faster return to room air by day 28 (P = .012).

Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: a phase 3, randomised, controlled, non-inferiority trial - Maertens, Johan A.; Rahav, Galia; Lee, Dong-Gun; Ponce-de-León, Alfredo; Sánchez, Isabel Cristina Ramírez; Klimko, Nikolay; Sonet, Anne; Haider, Shariq; Vélez, Juan Diego; Raad, Issam; Koh, Liang-Piu; Karthaus, Meinolf; et al. (The Lancet, 2021)

Management of BK virus-associated haemorrhagic cystitis in allogeneic stem cell transplant recipients - Jandial, Aditya; Mishra, Kundan; Sandal, Rajeev; Kant Sahu, Kamal (Therapeutic Advances in Infectious Disease, 2021)
BK virus (BKV)-related haemorrhagic cystitis (HC) is an important cause of morbidity following allogeneic haematopoietic stem cell transplantation (HSCT). The various risk factors include high-level BKV viruria and/or viremia, myeloablative conditioning, acute graft versus host disease (GVHD), cytomegalovirus viremia, and unrelated or HLA-mismatched donor. The presence of high plasma BK viral load and cytopenias have been implicated as important predictors for protracted disease course. These patients frequently require hospitalisation which may extend for several weeks. Supportive measures in the form of analgesics, intravenous hydration, bladder irrigation, and transfusion support remain the mainstay of management. Various drugs have been used with limited success in this setting. These include antiviral drugs, fluoroquinolones, leflunomide, growth factors, clotting factors, estrogens, and prostaglandins. The role of adoptive cellular immunotherapy has also been explored but lacks clinical validation. The strategies aimed at expediting urothelial repair like hyperbaric oxygen therapy (HBOT), intravesical fibrin glue and platelet-rich plasma (PRP) are emerging. Some patients with severe disease do require surgical intervention to relieve urinary obstruction. The frequent co-occurrence of acute GVHD and CMV disease further complicates the management in such patients. There is an unmet need for effective and evidence-based options for the prevention and management of this disease. Due to lack of robust data supported by randomised trials, the acceptability of the available guidelines to simplify the treatment is expected to be low. Despite the availability of various treatment options, the management of BKV-related HC in day-to-day practice continues to be a challenge. The aim of this article is to put forward an up-to-date review of the preventive and therapeutic strategies for BKV-related HC.

Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial - Bassetti, Matteo; Echols, Roger; Matsunaga, Yuko; Ariyasu, Mari; Doi, Yohei; Ferrer, Ricard; Lodise, Thomas P; Naas, Thierry; Niki, Yoshihito; Paterson, David L; Portsmouth, Simon; Torre-Cisneros, Julian; et al. (The Lancet Infectious Diseases, 2021)
Background New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections. Methods We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7–14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23). Findings Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8–66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9–75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2–65·5) of 23 patients in the cefiderocol group and six (43%, 17·7–71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8–77·0) of 17 patients in the cefiderocol group and one (20%, 0·5–71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug. Interpretation Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options. Funding Shionogi.

American Society for Transplantation and Cellular Therapy Infectious Disease Guidelines: Preface to the Series - Carpenter, Paul A.; Papanicolaou, Genovefa; Chemaly, Roy F.; Boeckh, Michael; Savani, Bipin N. (Transplantation and Cellular Therapy, 2021)